piperidines and Neoplasms

Granuloma annulare (GA) is an inflammatory granulomatous skin disease that can be localized (localized GA) or disseminated (generalized GA), with patch, perforating, and subcutaneous subtypes being less common variants of this benign condition. Recently, new research has emerged that further elucidates GA epidemiology and etiopathogenesis; importantly, new therapeutic options for GA have also been described, although there remains a paucity of randomized controlled studies. In this review, we summarize recent updates on GA epidemiology and etiopathogenesis and offer an updated review of the therapeutic options for GA currently reported in the literature. We hope that the current review galvanizes randomized controlled studies that will in turn help lead to the recommendation of evidence-based treatments for GA.

Topics: Anti-Infective Agents; Antimalarials; Biological Therapy; Comorbidity; Dermatologic Agents; Diabetes Complications; Diagnosis, Differential; Glucocorticoids; Granuloma Annulare; Humans; Iatrogenic Disease; Infections; Methotrexate; Neoplasms; Pentoxifylline; Phosphodiesterase 4 Inhibitors; Phototherapy; Piperidines; Pyrimidines; Thalidomide

Bruton's tyrosine kinase (BTK) regulates multiple important signaling pathways and plays a key role in the proliferation, survival, and differentiation of B-lineage cells and myeloid cells. BTK is a promising target for the treatment of hematologic malignancies. Ibrutinib, the first-generation BTK inhibitor, was approved to treat several B-cell malignancies. Despite the remarkable potency and efficacy of ibrutinib against various lymphomas and leukemias in the clinics, there are also some clinical limitations, such as off-target toxicities and primary/acquired drug resistance. As strategies to overcome these challenges, second- and third-generation BTK inhibitors, BTK-PROTACs, as well as combination therapies have been explored. In this review, we summarize clinical developments of the first-, second- and third-generation BTK inhibitors, as well as recent advances in BTK-PROTACs and ibrutinib-based combination therapies.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; B-Lymphocytes; Cyclin-Dependent Kinase 4; Drug Resistance, Neoplasm; Drug Therapy, Combination; Humans; Immunotherapy; Neoplasms; Piperidines; Protein Kinase Inhibitors

The recent development of high throughput compound screening has allowed drug repurposing to emerge as an effective avenue for discovering novel treatments for cancer. FDA-approved antipsychotic drugs fluspirilene, penfluridol, and pimozide are clinically used for the treatment of psychotic disorders, primarily schizophrenia. These compounds, belong to diphenylbutylpiperidine class of antipsychotic drugs, are the potent inhibitors of dopamine D2 receptor and calcium channel. A correlation has been found that patients treated for schizophrenia have lower incidences of certain types of cancer, such as respiratory, prostate, and bladder cancers. These compounds have also been shown to inhibit cancer proliferation in a variety of cancer cells, including melanoma, lung carcinoma, breast cancer, pancreatic cancer, glioma, and prostate cancer, among others. Antipsychotic drugs induce apoptosis and suppress metastasis in in vitro and in vivo models through mechanisms involving p53, STAT3, STAT5, protein phosphatase 2A, cholesterol homeostasis, integrins, autophagy, USP1, wnt/β-catenin signaling, and DNA repair. Additionally, pre-clinical evidence suggests that penfluridol and pimozide act synergistically with existing chemotherapeutic agents, such as dasatinib, temozolomide, and cisplatin. Some studies have also reported that the cytotoxic activity of the antipsychotics is selective for dividing cells. Based on this growing body of evidence and the availability and previous FDA-approval of the drugs, the compounds appear to be promising anti-cancer agents.

Topics: Animals; Antineoplastic Agents; Antipsychotic Agents; Butyrophenones; Drug Discovery; Drug Repositioning; Humans; Neoplasms; Piperidines

The use of Janus kinase (JAK) inhibitors is a new approach in the therapy of inflammatory diseases with immune base. Tofacitinib is one of these inhibitors targeting JAK1 and JAK3, and its efficacy has been demonstrated in the treatment of moderate to severe ulcerative colitis (UC). It is a small synthetic molecule administered orally, with a fast bioavailability and elimination rate, predictable pharmacokinetics and lack of immunogenicity, which are convenient characteristics for both efficacy and safety. This article reviews the pharmacological characteristics of tofacitinib and its safety profile.

Topics: Arthritis, Rheumatoid; Colitis, Ulcerative; Drug Interactions; Herpes Zoster; Herpes Zoster Vaccine; Humans; Janus Kinase 1; Janus Kinase 3; Janus Kinase Inhibitors; Neoplasms; Piperidines; Pyrimidines; Venous Thromboembolism

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

The outbreak of the novel coronavirus disease 2019 (COVID-19) has emerged as one of the biggest global health threats worldwide. As of October 2020, more than 44 million confirmed cases and more than 1,160,000 deaths have been reported globally, and the toll is likely to be much higher before the pandemic is over. There are currently little therapeutic options available and new potential targets are intensively investigated. Recently, Bruton tyrosine kinase (BTK) has emerged as an interesting candidate. Elevated levels of BTK activity have been reported in blood monocytes from patients with severe COVID-19, compared with those from healthy volunteers. Importantly, various studies confirmed empirically that administration of BTK inhibitors (acalabrutinib and ibrutinib) decreased the duration of mechanical ventilation and mortality rate for hospitalized patients with severe COVID-19. Herein, we review the current information regarding the role of BTK in severe acute respiratory syndrome coronavirus 2 infections and the suitability of its inhibitors as drugs to treat COVID-19. The use of BTK inhibitors in the management of COVID-19 shows promise in reducing the severity of the immune response to the infection and thus mortality. However, BTK inhibition may be contributing in other ways to inhibit the effects of the virus and this will need to be carefully studied.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antiviral Agents; Benzamides; COVID-19; COVID-19 Drug Treatment; Humans; Lung; Molecular Targeted Therapy; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazines; Thrombosis

We aimed to evaluate the risk of PARP inhibitors (PARPis) causing pneumonitis in randomized controlled trials (RCTs) and in the real-world practice.. First, a systematic review based on meta-analysis was conducted. RCTs with available data reporting pneumonitis events for PARPis were eligible for analysis. Second, we conducted a disproportionality analysis based on data from the FDA Adverse Event Reporting System (FAERS) database to characterize the main features of PARPi-related pneumonitis.. PARPis increased the risk of pneumonitis that can result in serious outcomes and tend to occur early. Early recognition and management of PARPi-pneumonitis is of vital importance in clinical practice. The mechanisms and risk factors should be studied further to improve clinical understanding and innovative treatment strategies for these diseases.

Topics: Adverse Drug Reaction Reporting Systems; Humans; Incidence; Indazoles; Neoplasms; Phthalazines; Piperazines; Piperidines; Pneumonia; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic; Time Factors

Drug repurposing aims to find new uses for already existing and approved drugs. We now provide a brief overview of recent developments in drug repurposing using machine learning alongside other computational approaches for comparison. We also highlight several applications for cancer using kinase inhibitors, Alzheimer's disease as well as COVID-19.

Topics: Alzheimer Disease; Antineoplastic Agents; Antiviral Agents; Clemastine; Computational Biology; COVID-19 Drug Treatment; Dipyridamole; Drug Repositioning; Humans; Hydroxychloroquine; Lenalidomide; Machine Learning; Neoplasms; Neuroprotective Agents; Piperazines; Piperidines; Protein Kinase Inhibitors

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Chemistry, Pharmaceutical; COVID-19 Drug Treatment; Drug Delivery Systems; Hematologic Neoplasms; Humans; Inflammation; Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; SARS-CoV-2

We aimed to evaluate comparative safety and tolerability of the approved PARP inhibitors in people with cancer.. Eligible studies included randomized controlled trials comparing an approved PARP inhibitor (fluzoparib, olaparib, rucaparib, niraparib, or talazoparib) with placebo or chemotherapy in cancer patients. Outcomes of interest included: serious adverse event (SAE), discontinuation due to adverse event (AE), interruption of treatment due to AE, dose reduction due to AE, and specific grade 1-5 AEs.. Ten trials including 3763 participants and six treatments (olaparib, rucaparib, niraparib, talazoparib, placebo, and protocol-specified single agent chemotherapy) were identified. SAE and discontinuation of treatment did not differ significantly among the four approved PARP inhibitors. Regarding interruption of treatment and dose reduction due to AE, statistically significant differences and statistically non-significant trend were observed. Talazoparib is associated with a higher risk of interruption of treatment and dose reduction (excluding rucaparib) due to AE as compared with the other drugs. Niraparib showed a trend of lower risk of AE related dose reduction as compared with the other drugs. Furthermore, there were significant differences in specific grade 1-5 AE among the four drugs.. The safety profile of the four approved PARP inhibitors is comparable in terms of SAE and AE-related discontinuation of treatment. Statistically significant differences in the AEs spectrum and AEs related dose interruption and dose reduction demonstrated the prompt identification of AE and dose personalization seem mandatory to obtain maximal benefit from PARP inhibitors.

Topics: Humans; Indazoles; Indoles; Neoplasms; Network Meta-Analysis; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic

Flavonoids have been proposed as potential chemotherapeutic agents because they are toxic against cancer cells but not harmful to healthy cells. This systematic review analyzed flavonoid effectiveness in human cancer chemotherapy. Overall, 22 phase II and 1 phase III clinical trials (PubMed, Scopus, and Web of Science) that used flavonoids as a single agent or combined with other therapeutics against hematopoietic/lymphoid or solid cancer published by January 2019 were selected for analysis. Flavopiridol was the most commonly used flavonoid (at a dose of 50-mg/m

Topics: Antineoplastic Agents; Clinical Trials as Topic; Flavonoids; Humans; Neoplasms; Piperidines; Polyphenols

Observational studies and meta-analyses of randomized trials on dipeptidyl peptidase-4 inhibitors (DPP4i) reported discordant results on the risk of malignancies with this class of drugs. Aim of the present meta-analysis is the assessment of the effect of DPP4i treatment on the incidence of different types of cancer, collecting all available evidence from randomized controlled trials.. An extensive MEDLINE, EMBASE, and Cochrane database search for sitagliptin or vildagliptin or omarigliptin or saxagliptin or alogliptin or trelagliptin or anagliptin or linagliptin or gemigliptin or evogliptin or teneligliptin was performed up to September 30th, 2019. All trials performed on type 2 diabetes, with duration ≥ 24 weeks, and comparing of DPP4i with placebo or active drugs were collected. The study has been registered on PROSPERO (#153344). Mantel-Haenszel odds ratio (MH-OR) with 95% confidence interval (95% CI) was calculated for all outcomes.. A total of 157 eligible trials were identified. DPP-4i were not associated with an increased risk of overall cancer (MH-OR 0.93 [0.86, 1.00]; p = 0.07), with no significant differences across individual molecules of the class. When compared with placebo/none, a lower risk of cancer with DPP-4i was observed in placebo-controlled trials (MH-OR 0.90 [0.82, 0.99], p = 0.030), whereas no significant differences have been detected with any other comparators. DPP-4i was associated with a significant reduction in colorectal cancer (MH-OR 0.70 [0.53, 0.94], p = 0.020).. Available data do not support the hypothesis of an association of DPP4i treatment with malignancies, with a possible beneficial effect for colon-rectal cancer.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incidence; Neoplasms; Piperidines; Randomized Controlled Trials as Topic; Risk Factors; Sitagliptin Phosphate; Uracil; Vildagliptin

The human ether-à-go-go related gene (HERG) encodes the alpha subunit of Kv11.1, which is a voltage-gated K

Topics: Antineoplastic Agents; Apoptosis; Benzimidazoles; Carcinogenesis; Cell Movement; Cell Proliferation; Epigenesis, Genetic; ERG1 Potassium Channel; Fluoxetine; Gene Expression Regulation, Neoplastic; Humans; Integrin beta1; Long QT Syndrome; Membrane Potentials; Molecular Docking Simulation; Mutation; Myocytes, Cardiac; Neoplasms; Piperidines; Protein Conformation, alpha-Helical; Protein Interaction Mapping; Protein Structure, Quaternary; Pyridines; Signal Transduction; STAT1 Transcription Factor; Sulfanilamides

The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Autoimmune Diseases; Drug Approval; Drug Design; Humans; Inflammation; Janus Kinase Inhibitors; Janus Kinases; Neoplasms; Nitriles; Piperidines; Protein Binding; Protein Conformation; Pyrazoles; Pyrimidines; United States; United States Food and Drug Administration

To assess the risk of developing cancer in patients with rheumatoid arthritis (RA) exposed to non-TNF inhibitors (TNFi) biologics or tofacitinib therapy.. Systematical search of PubMed, EMBASE and Cochrane Library plus a hand search of conference proceedings were performed. Observational studies that reported cancer incidence in patients with RA treated with biologics or tofacitinib with active comparator of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or TNFi were eligible for inclusion. The pooled relative risk (RR) and 95% confidence interval (CI) were calculated with fix-effects or random-effects model.. Of 2,819 identified articles, a total of 10 studies involving over 40,587 patients with more than 87,622 patient-years of exposure to non-TNF inhibitors (TNFi) biologics and 2,221 patients with more than 4,506 patient-years of exposure to tofacitinib were included. Pooled analysis showed there was no increased risk of developing cancer in general or specific cancer types in RA patients receiving treatment with rituximab (pooled RR 0.87, 95% CI 0.74-1.03), tocilizumab (pooled RR 0.92, 95% CI 0.79-1.06), or tofacitinib, compared with those receiving csDMARDs or TNFi. But abatacept was associated with a slightly increased overall cancer risk (pooled RR 1.13, 95% CI 1.02-1.24) and non-melanoma skin cancer (pooled RR 1.26, 95% CI 1.09-1.45), relative to csDMARDs or TNFi in RA patients.. Among RA patients, a small statistically significant increase in developing cancer was observed for abatacept exposure, while no increased cancer risk for rituximab, tocilizumab or tofacitinib, in comparison with csDMARDs or TNFi.

Topics: Arthritis, Rheumatoid; Biological Products; Humans; Neoplasms; Observational Studies as Topic; Piperidines; Pyrimidines; Tumor Necrosis Factor Inhibitors

Alopecia areata is a common autoimmune condition that disproportionately affects children and can significantly hinder quality of life. Few safe and effective therapies are available for the treatment of severely affected pediatric patients. JAK inhibitors have been recently established as an effective and well-tolerated therapy in adults, but there are limited data regarding the use of JAK inhibitors to treat alopecia areata in children. Here, we review the available literature regarding the use of JAK inhibitors in children in dermatology and across other medical disciplines.

Topics: Administration, Cutaneous; Administration, Oral; Adolescent; Alopecia Areata; Arthritis, Juvenile; Child; Child, Preschool; Humans; Janus Kinase Inhibitors; Neoplasms; Nitriles; Piperidines; Pyrazoles; Pyrimidines

With a rapidly evolving complement of advanced targeted therapies in inflammatory bowel disease, additional safety and side effect concerns emerge. It is the purpose of this review to consider various risks with biologic therapies in inflammatory bowel disease and discuss mitigating strategies.. Two recently approved monoclonal antibodies (vedolizumab and ustekinumab) and a Janus kinase inhibitor small molecule (tofacitnib) have introduced a number of novel safety and risk considerations. We review the clinical trial and real-world safety data to date on these agents as well as review new data and considerations with anti-tumor necrosis factor agents. New vaccines for varicella zoster virus, hepatitis B virus, and high-dose influenza have been studied, and we discuss the clinical importance of these findings. Lastly, we make management recommendations in the event of particular side effects or complications. Understanding the risks of new agents in inflammatory bowel disease, potential mitigating strategies, and management considerations is important to achieving and maintaining clinical outcomes in IBD patients.

Topics: Antibodies, Monoclonal, Humanized; Biological Products; Demyelinating Diseases; Deprescriptions; Drug Substitution; Gastrointestinal Agents; Humans; Infections; Inflammatory Bowel Diseases; Lymphoma; Melanoma; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Risk; Risk Assessment; Skin Neoplasms; Tumor Necrosis Factor-alpha; Ustekinumab

Topics: Antineoplastic Agents; Antineoplastic Agents, Immunological; Clinical Trials as Topic; Humans; Incidence; Molecular Targeted Therapy; Neoplasms; Nivolumab; Photosensitivity Disorders; Piperidines; Quinazolines; Risk Assessment; Vemurafenib

Cancer is among the leading causes of death worldwide. Several pharmacological protocols have been developed in order to block tumor progression often showing partial efficacy and severe counterproductive effects. It is now conceived that a healthy lifestyle coupled with the consumption of certain phytochemicals can play a protective role against tumor development and progression. According to this vision, it has been introduced the concept of "chemoprevention". This term refers to natural agents with the capability to interfere with the tumorigenesis and metastasis, or at least, attenuate the cancer-related symptoms. Piperine (1-Piperoylpiperidine), a main extract of Piper longum and Piper nigrum, is an alkaloid with a long history of medicinal use. In fact, it exhibits a variety of biochemical and pharmaceutical properties, including chemopreventive activities without significant cytotoxic effects on normal cells, at least at doses < of 250 µg/ml. The aim of this review is to discuss the relevant molecular and cellular mechanisms underlying the chemopreventive action of this natural alkaloid.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Cell Proliferation; Chemoprevention; Disease Progression; Humans; Neoplasm Metastasis; Neoplasms; Piperidines; Plant Extracts; Polyunsaturated Alkamides

Recently many studies showed anticancer activities of piperine, a pungent alkaloid found in black pepper and some other Piper species. We attempted to summarize acquired data that support anticancer potential of this natural agent. Piperine has been reported to possess effective chemopreventive activity. It has been studied to affect via several mechanisms of action, in brief enhancing antioxidant system, increasing level and activity of detoxifying enzymes and suppressing stem cell self-renewal. Moreover, piperine has been found to inhibit proliferation and survival of various cancerous cell lines via modulating cell cycle progression and exhibiting anti-apoptotic activity, respectively. This compound has been shown to modify activity of various enzymes and transcription factors to inhibit invasion, metastasis and angiogenesis. Interestingly, piperine has exhibited antimutagenic activity and also inhibited activity and expression of multidrug resistance transporters such as P-gp and MRP-1. Besides, about all reviewed studies have reported selective cytotoxic activity of piperine on cancerous cells in compared with normal cells. Altogether, the studies completely underline promising candidacy of piperine for further development. The collected preclinical data we provided in this article can be useful in the design of future researches especially clinical trials with piperine.

Topics: Alkaloids; Animals; Anticarcinogenic Agents; Antimutagenic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Benzodioxoles; Biological Availability; Cell Proliferation; Cell Survival; Drug Evaluation, Preclinical; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Inactivation, Metabolic; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Piper; Piperidines; Polyunsaturated Alkamides; Stem Cells

Anaplastic lymphoma kinase (ALK) gene activation is involved in the carcinogenesis process of several human cancers such as anaplastic large cell lymphoma, lung cancer, inflammatory myofibroblastic tumors and neuroblastoma, as a consequence of fusion with other oncogenes (NPM, EML4, TIM, etc) or gene amplification, mutation or protein overexpression. ALK is a transmembrane tyrosine kinase receptor that, upon ligand binding to its extracellular domain, undergoes dimerization and subsequent autophosphorylation of the intracellular kinase domain. When activated in cancer it represents a target for specific inhibitors, such as crizotinib, ceritinib, alectinib etc. which use has demonstrated significant effectiveness in ALK-positive patients, in particular ALK-positive non- small cell lung cancer. Several mechanisms of resistance to these inhibitors have been described and new strategies are underway to overcome the limitations of current ALK inhibitors.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life.This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care.. To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care.. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data.. We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced.. Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE.. We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm.In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea.The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events.In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (. In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children.

Topics: Constipation; Defecation; Female; Gastrointestinal Agents; Humans; Intestinal Diseases; Male; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Neoplasms; Opioid-Related Disorders; Oxycodone; Palliative Care; Piperidines; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic; Receptors, Opioid, mu

Mutations within the activation loop of members of the class III receptor tyrosine kinase (RTK) subfamily, which includes KIT, PDGFRA, and FLT3, have been observed in multiple human tumor types. These mutations confer constitutive activation as well as resistance to the type II tyrosine kinase inhibitors (TKI) that are currently clinically available, such as imatinib and sunitinib. It is now understood that activation loop mutations in class III RTKs shift the activation state equilibrium away from inactive states, to which type II TKIs bind, to the active state by destabilizing the inactive conformation. Recently, type I TKIs, which can bind to active kinase conformations, have been developed with specificity for class III RTK members. Some type I TKIs, such as crenolanib and avapritinib (BLU-285), have entered clinical studies for patients with activation loop mutations in KIT, PDGFRA, or FLT3. Preliminary results suggest that these type I TKIs show activity in these patient populations that previously lacked effective treatments. This article reviews the inactive and active structures of KIT, PDGFRA, and FLT3, how the mutations seen in human cancers affect kinase structure, and the clinical implications of these mutations in terms of type I vs. type II TKI binding.

Topics: Antineoplastic Agents; Benzimidazoles; Drug Development; fms-Like Tyrosine Kinase 3; Humans; Mutation; Neoplasms; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Receptor Protein-Tyrosine Kinases; Receptor, Platelet-Derived Growth Factor alpha

Piperidine is an important pharmacophore, a privileged scaffold and an excellent heterocyclic system in the field of drug discovery which provides numerous opportunities in studying/exploring this moiety as an anticancer agent by acting on various receptors of utmost importance. Cancer is an uncontrolled division of cells that results in the formation of tumour which have the potential to migrate to other parts of the body (metastasis) finally becoming a major threat to human population. Since piperidine displayed great potential in this area it is being further probed to get novel entities for the treatment of cancer. This review throws light on recent biological expansions of piperidine along with structure activity relationships to deliver association between various synthesized newer/novel derivatives and receptor sites.

Topics: Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Structure; Neoplasms; Piperidines; Structure-Activity Relationship

Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase that belongs to the TEC-family tyrosine kinases together with bone marrow-expressed kinase (BMX), redundant-resting lymphocyte kinase (RLK), and IL-2 inducible T-Cell kinase (ITK). All these proteins play a key role in the intracellular signaling of both B and T lymphocytes. Recently, some preclinical data have demonstrated that BTK is present in certain tumor subtypes and in other relevant cells that are contributing to the tumor microenvironment such as dendritic cells, macrophages, myeloid derived suppressor cells and endothelial cells. Ibrutinib (PCI-32765) is an orally available small molecule that acts as an inhibitor of the BTK and is approved for the treatment of patients with some hematological malignancies. It has been suggested that ibrutinib may also have a potential antitumor activity in solid neoplasms. In this sense, ibrutinib has the ability to revert polarization of TCD4+ to Th1 lymphocytes to increase the cytotoxic ability of T CD8+ and to regulate tumor-induced immune tolerance by acting over tumor infiltrating cells activity and immunosuppressive cytokines release. Furthermore, based on its molecular activity and safety, ibrutinib has been considered as a partner for treatment combination with PI3K/AKT/mTOR inhibitors or with immune-checkpoint inhibitors, inhibiting immunosuppressive signals from the tumor microenvironment, and overcoming the immune resistance to current anti-PD1/PDL1 immunotherapeutic drugs by the CXCR4/CXCL2 pathway regulation. Currently, a broad range of different studies are evaluating the activity of ibrutinib either as single agent or in combination in patients with solid tumors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Humans; Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction

Vandetanib, a tyrosine kinase inhibitor used as an anticancer therapeutic agent, has adverse events associated with treatment resulting in noncompliance and withdrawal from the therapy. Here, we performed meta-analysis of published clinical trials to determine relative risk (RR) and incidence of gastrointestinal events during vandetanib therapy in patients with cancer. A comprehensive literature search was performed and summary incidence, RR, and 95% confidence intervals (CIs) were calculated employing fixed- or random-effects models, depending on the heterogeneity of trials. Twenty-two trials with 6382 patients were included summary incidences of all-grade gastrointestinal events in patients with cancer were anorexia 24% (95% CI, 20%-28%), constipation 17% (95% CI, 13%-20%), diarrhea 46% (95% CI, 40%-53%), nausea 29% (95% CI, 25%-33%), and vomiting 17% (95% CI, 14%-21%). Incidences of vandetanib-associated gastrointestinal events stratified by tumor histology were statistically insignificant. Vandetanib was associated with a significant risk of all-grade diarrhea (RR 1.75, 95% CI, 1.42-2.16) and high-grade diarrhea (RR 1.94, 95% CI, 1.43-2.64) and significantly decreased risk of all-grade constipation (RR 0.80, 95% CI, 0.71-0.91). Summary RR showed a significant risk of vandetanib-associated constipation (RR 0.82, 95% CI, 0.72-0.93) and diarrhea (all-grade: RR 1.68, 95% CI, 1.31-2.14 and high-grade: RR 1.57, 95% CI, 1.14-2.17) in patients with non-small-cell lung cancer. This study revealed a significantly increased risk of diarrhea and a reduced risk of constipation in patients with cancer receiving vandetanib, suggesting that appropriate and frequent clinical monitoring should be emphasized.

Topics: Antineoplastic Agents; Drug Monitoring; Gastrointestinal Diseases; Humans; Incidence; Neoplasms; Piperidines; Protein Kinase Inhibitors; Quinazolines

During the last decade, guanine G-rich sequences folding into G-quadruplex (G4) structures have received a lot of attention and their biological role is now a matter of large debate. Rising amounts of experimental evidence have validated several G-rich motifs as molecular targets in cancer treatment. Despite that an increasing number of small molecules has been reported to possess excellent G4 stabilizing properties, none of them has progressed through the drug-development pipeline due to their poor drug-like properties. In this context, the identification of G4 ligands with more favorable pharmacological properties and with a well-defined target activity could be fruitful for anticancer therapy application.. This manuscript outlines the current state of knowledge regarding EMICORON, a G4-interactive molecule structurally and biologically similar, on the one side, to coronene and, on the other side, to a bay-monosubstituted perylene.. Overall this work evidences that EMICORON, a new promising G4 ligand, possesses a marked antitumoral activity both standing alone and in combination with chemotherapeutics. Moreover, EMICORON represents a good example of multimodal class of antitumoral drug, able to simultaneously affect multiple targets participating in several distinct signaling pathways, thus simplifying the treatment modalities and improving the selectivity against cancer cells.. Due to the importance of G4 forming sequences in crucial biological processes participating in tumor progression, their successful targeting with small molecules could represent a very important innovation in the development of effective therapeutic strategies against cancer. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Binding Sites; Cell Proliferation; DNA, Neoplasm; Drug Design; G-Quadruplexes; Guanosine; Humans; Imides; Ligands; Models, Molecular; Neoplasms; Piperidines; Signal Transduction; Structure-Activity Relationship; Telomere; Tumor Burden

The use of biologics such as anti-tumor necrosis factor and oral Janus kinase inhibitors have revolutionized the treatment of rheumatoid arthritis (RA). The risk of malignancies such as lymphomas, lung cancer, and nonmelanoma skin cancers (NMSCs) is greater in patients with RA compared with the general population. The incidence of all malignancy (excluding NMSC) was similar in tofacitinib users compared with the general population. The rates of overall and site-specific malignancies in patients with RA treated with tofacitinib are similar to what is expected in the RA population and not different from disease-modifying antirheumatic drugs and biologics.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Incidence; Janus Kinases; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Neoplasms

The old-fashioned anticancer approaches, aiming at arresting cancer cell proliferation interfering with non-specific targets (e.g. DNA), have been replaced, in the last decades, by more specific target oriented ones. Nonetheless, single-target approaches have not always led to optimal outcomes because, for its complexity, cancer needs to be tackled at various levels by modulation of several targets. Although at present, combinations of individual singletarget drugs represent the most clinically practiced therapeutic approaches, the modulation of multiple proteins by a single drug, in accordance with the polypharmacological strategy, has become more and more appealing. In the perspective of a multi-target approach, the closely related evolutionary members of the tyrosine kinase family are ideal candidates. Indeed, tyrosine kinase activities are not only critical in tumor phenotype maintenance, but also modulate several functions in the tumor microenvironment. Consequently, several multikinase inhibitors were approved in the last decade, and many new molecules are currently in preclinical or clinical development. In the present review we report on the most widely FDA-approved multitargeted drugs, discussing about their mechanism of action and outlining the clinical trials that have brought them to approval.

Topics: Anilides; Crizotinib; Humans; Imatinib Mesylate; Imidazoles; Indoles; Neoplasms; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Pyridines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Sorafenib; Sunitinib

Tofacitinib is the first Janus kinase (JAK) inhibitor commercially approved for the treatment of rheumatoid arthritis. This compound and a number of other JAK inhibitors are currently being tested in phase II and III trials for the treatment of a variety of autoimmune inflammatory diseases. Whereas a characteristic safety profile is emerging for some JAK inhibitors, differences between individual agents might emerge on the basis of distinct potency against their molecular targets. Similarly to biological therapy, JAK inhibition can lead to serious and opportunistic infections, and viral infections seem to be particularly frequent. Although no malignancy signals have been identified to date, long-term follow-up and further research are needed to understand the risk of malignancy associated with these compounds. As is the case for biologic agents, vaccination is important to mitigate the risks of these emerging therapies.

Topics: Azetidines; Humans; Infections; Janus Kinases; Neoplasms; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Pyrroles; Rheumatic Diseases; Signal Transduction; Sulfonamides

Biologic disease-modifying anti-rheumatic drugs (DMARDs: referred to as biologics) are effective in treating rheumatoid arthritis (RA), however there are few head-to-head comparison studies. Our systematic review, standard meta-analysis and network meta-analysis (NMA) updates the 2009 Cochrane overview, 'Biologics for rheumatoid arthritis (RA)' and adds new data. This review is focused on biologic or tofacitinib therapy in people with RA who had previously been treated unsuccessfully with biologics.. To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (placebo or methotrexate (MTX)/other DMARDs) in people with RA, previously unsuccessfully treated with biologics.. On 22 June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE, and Embase; and trials registries (WHO trials register, Clinicaltrials.gov). We carried out article selection, data extraction, and risk of bias and GRADE assessments in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparison (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We have also presented results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). Outcomes measured included four benefits (ACR50, function measured by Health Assessment Questionnaire (HAQ) score, remission defined as DAS < 1.6 or DAS28 < 2.6, slowing of radiographic progression) and three harms (withdrawals due to adverse events, serious adverse events, and cancer).. This update includes nine new RCTs for a total of 12 RCTs that included 3364 participants. The comparator was placebo only in three RCTs (548 participants), MTX or other traditional DMARD in six RCTs (2468 participants), and another biologic in three RCTs (348 participants). Data were available for four tumor necrosis factor (TNF)-biologics: (certolizumab pegol (1 study; 37 participants), etanercept (3 studies; 348 participants), golimumab (1 study; 461 participants), infliximab (1 study; 27 participants)), three non-TNF biologics (abatacept (3 studies; 632 participants), rituximab (2 studies; 1019 participants), and tocilizumab (2 studies; 589 participants)); there was only one study for tofacitinib (399 participants). The majority of the trials (10/12) lasted less than 12 months.We judged 33% of the studies at low risk of bias for allocation sequence generation, allocation concealment and blinding, 25% had low risk of bias for attrition, 92% were at unclear risk for selective reporting; and 92% had low risk of bias for major baseline imbalance. We downgraded the quality of the evidence for most outcomes to moderate or low due to study limitations, heterogeneity, or rarity of direct comparator trials. Biologic monotherapy versus placeboCompared to placebo, biologics were associated with clinically meaningful and statistically significant improvement in RA as demonstrated by higher ACR50 and RA remission rates. RR was 4.10 for ACR50 (95% CI 1.97 to 8.55; moderate-quality evidence); absolute benefit RD 14% (95% CI 6% to 21%); and NNTB = 8 (95% CI 4 to 23). RR for RA remission was 13.51 (95% CI 1.85 to 98.45, one study available; moderate-quality evidence); absolute benefit RD 9% (95% CI 5% to 13%); and NNTB = 11 (95% CI 3 to 136). Results for withdrawals due to adverse events and serious adverse events did not show any statistically significant or clinically meaningful differences. There were no studies available for analysis for function measured by HAQ, radiographic progression, or cancer outcomes. There were not enough data for any of the outcomes to look at subgroups. Biologic + MTX versus active comparator (MTX/other traditional DMARDs)Compared to MTX/other traditional DMARDs, biologic + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50, function measured by HAQ, and RA remission rates in direct comparisons. RR for ACR50 was 4.07 (95% CI 2.76 to 5.99; high-quality evidence); absolute benefit RD 16% (10%. Biologic (with or without MTX) or tofacitinib (with MTX) use was associated with clinically meaningful and statistically significant benefits (ACR50, HAQ, remission) compared to placebo or an active comparator (MTX/other traditional DMARDs) among people with RA previously unsuccessfully treated with biologics.No studies examined radiographic progression. Results were not clinically meaningful or statistically significant for withdrawals due to adverse events and serious adverse events, and were inconclusive for cancer.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bayes Theorem; Biological Products; Disease Progression; Humans; Methotrexate; Neoplasms; Network Meta-Analysis; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Treatment Failure

To summarize and compare the risks of malignancies accompanying biologic DMARDs (b-DMARDs) and tofacitinib in rheumatoid arthritis (RA) in randomized clinical trials (RCTs) and long-term extension studies (LTEs).. Articles in Medline, Embase, Cochrane Library, and the Web of Science dated from 2000 to February 2015. Selection criteria were as follows: (1) focus on RCTs or LTEs in RA; (2) treatment with b-DMARDs or tofacitinib; (3) data on malignancies; and (4) a minimum follow-up of 12 weeks. Data included publication details, study design, risk of bias, number and types of malignancies, and patient characteristics and treatments.. Of 113 articles and one updated report that were meta-analyzed, overall malignancies in RCTs showed odds ratio (95% confidence intervals) of 1.01 (0.72, 1.42) for all TNF antagonists, 1.12 (0.33, 3.81) for abatacept, 0.54 (0.20, 1.50) for rituximab, 0.70 (0.20, 2.41) for tocilizumab, and 2.39 (0.50, 11.5) for tofacitinib. Network meta-analysis of overall malignancies showed odds ratio (95% predictive intervals) of 1.68 (0.48-5.92) for infliximab, 0.79 (0.44-1.40) for etanercept, 0.93 (0.43-2.03) for adalimumab, 0.87 (0.28-2.75) for certolizumab, 0.87 (0.39-1.95) for golimumab, 1.04 (0.32-3.32) for abatacept, 0.58 (0.21-1.56) for rituximab, 0.60 (0.16-2.28) for tocilizumab, and 1.15 (0.24-5.47) for tofacitinib. Marginal numerical differences in the incidence rate of solid and hematological malignancies and non-melanoma skin cancers appeared in LTEs.. In RCTs, treatment of RA with b-DMARDs or tofacitinib does not increase the risk for malignancies. Generalizability of the differences in the rate of specific malignancies encountered in LTEs requires continuous pharmacovigilance of real-world patients.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Humans; Neoplasms; Network Meta-Analysis; Piperidines; Pyrimidines; Pyrroles; Risk

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To further assess the potential role of Janus kinase inhibition in the development of malignancies, we performed an integrated analysis of data from the tofacitinib RA clinical development programme.. Malignancy data (up to 10 April 2013) were pooled from six phase II, six Phase III and two long-term extension (LTE) studies involving tofacitinib. In the phase II and III studies, patients with moderate-to-severe RA were randomised to various tofacitinib doses as monotherapy or with background non-biological disease-modifying antirheumatic drugs (DMARDs), mainly methotrexate. The LTE studies (tofacitinib 5 or 10 mg twice daily) enrolled patients from qualifying prior phase I, II and III index studies.. Of 5671 tofacitinib-treated patients, 107 developed malignancies (excluding non-melanoma skin cancer (NMSC)). The most common malignancy was lung cancer (n=24) followed by breast cancer (n=19), lymphoma (n=10) and gastric cancer (n=6). The rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time. Standardised incidence ratios (comparison with Surveillance, Epidemiology and End Results) for all malignancies (excluding NMSC) and selected malignancies (lung, breast, lymphoma, NMSC) were within the expected range of patients with moderate-to-severe RA.. The overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Female; Humans; Incidence; Janus Kinase 3; Male; Middle Aged; Multicenter Studies as Topic; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Young Adult

Targeted therapies have appeared as new treatment options for several disease types, including cancer and autoimmune disorders. Of several targets, tyrosine kinases (TKs) are among the most promising. Overexpression of TKs provides a target for novel therapeutic agents, including small molecule inhibitors of tyrosine kinases (TKI). Ibrutinib (PCI-32765) is a TKI of Bruton's tyrosine kinase (Btk), a key kinase of the B-cell receptor signaling pathway that plays a significant role in the proliferation, differentiation and survival of B cells. In addition to inhibitory effects, recent studies have shown that ibrutinib has multiple immunomodulatory effects. It binds covalently to IL-2 inducible tyrosine kinase (Itk) in T lymphocytes and suppresses the survival of T-helper (Th) 2 cells. This changes the balance of Th1/Th2 cells toward Th1 subset, which are the main immune cells targeting tumor cells. The dual activity of ibrutinib has paid a great attention and several studies are evaluating the anti-tumor and immunomodulatory effects in cancer, autoimmune disorders and infectious diseases. In this article we review the inhibitory and immunomodulatory effects of ibrutinib in B-cell malignancies, autoimmune diseases and infections, as well as the communication between the Ror1 receptor tyrosine kinase and BCR and effects of ibrutinib on this crosstalk.

Topics: Adenine; Animals; Autoimmune Diseases; Humans; Immunologic Factors; Neoplasms; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

CDK9 is a protein in constant development in cancer therapy. Herein we present an overview of the enzyme as a target for cancer therapy. We provide data on its characteristics and mechanism of action. In recent years, CDK9 inhibitors that have been designed with molecular modeling have demonstrated good antitumoral activity in vitro. Clinical studies of the drugs flavopiridol, dinaciclib, seliciclib, SNS-032 and RGB-286638 used as CDK9 inhibitors are also reviewed, with their additional targets and their relative IC50 values. Unfortunately, treatment with these drugs remains unsuccessful and involves many adverse effects. We could conclude that there are many small molecules that bind to CDK9, but their lack of selectivity against other CDKs do not allow them to get to the clinical use. However, drug designers currently have the tools needed to improve the selectivity of CDK9 inhibitors and to make successful treatment available to patients.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle; Cyclic N-Oxides; Cyclin-Dependent Kinase 9; Flavonoids; Humans; Indolizines; Molecular Targeted Therapy; Neoplasms; Oxazoles; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridinium Compounds; Roscovitine; Thiazoles; Urea

Spices have been widely used as food flavorings and folk medicines for thousands of years. Numerous studies have documented the antioxidant, anti-inflammatory and immunomodulatory effects of spices, which might be related to prevention and treatment of several cancers, including lung, liver, breast, stomach, colorectum, cervix, and prostate cancers. Several spices are potential sources for prevention and treatment of cancers, such as Curcuma longa (tumeric), Nigella sativa (black cumin), Zingiber officinale (ginger), Allium sativum (garlic), Crocus sativus (saffron), Piper nigrum (black pepper) and Capsicum annum (chili pepper), which contained several important bioactive compounds, such as curcumin, thymoquinone, piperine and capsaicin. The main mechanisms of action include inducing apoptosis, inhibiting proliferation, migration and invasion of tumors, and sensitizing tumors to radiotherapy and chemotherapy. This review summarized recent studies on some spices for prevention and treatment of cancers, and special attention was paid to bioactive components and mechanisms of action.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Apoptosis; Benzodioxoles; Benzoquinones; Capsaicin; Capsicum; Cell Proliferation; Crocus; Curcuma; Curcumin; Garlic; Humans; Neoplasms; Nigella sativa; Phytotherapy; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Spices; Zingiber officinale

Poly(ADP-ribose) polymerases(PARP) synthesize the ADP-ribose polymers onto proteins and play a role in DNA repair. PARP inhibitors block the repair of single-strand breaks, which in turn gives rise to double-strand breaks during DNA replication. Thus, PARP inhibitors elicit synthetic lethality in cancer with BRCA1/2 loss-of-function mutations that hamper homologous recombination repair of double-strand breaks. Olaparib, the first-in-class PARP inhibitor, was approved for treatment of BRCA-mutated ovarian cancer in Europe and the United States in 2014. Other PARP inhibitors under clinical trials include rucaparib, niraparib, veliparib, and the "PARP-trapping" BMN-673. BRCA1/2 sequencing is an FDA-approved companion diagnostics, which predicts the cancer vulnerability to PARP inhibition. Together, synthetic lethal PARP inhibition is a novel promising strategy for cancer intervention even in cases without prominent driver oncogenes.

Topics: Antineoplastic Agents; Benzimidazoles; BRCA1 Protein; BRCA2 Protein; DNA Breaks, Double-Stranded; DNA Replication; DNA, Single-Stranded; Enzyme Inhibitors; Humans; Indazoles; Indoles; Molecular Targeted Therapy; Mutation; Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Recombinational DNA Repair

Tumor angiogenesis contributes to the development of tumor progression. Several vascular endothelial growth factor(VEGF)-targeted agents, administered either as single agents or in combination with chemotherapy, have been shown to benefit patients with advanced-stage malignancies. In particular, bevacizumab is a humanized monoclonal antibody that specifically targets VEGF, inhibiting angiogenesis, thereby impeding tumor growth and survival. It is also possible that combined VEGF and the epidermal growth factor (EGFR) pathway blockade could further enhance antitumor efficacy and help prevent resistance to therapy. Preclinical and clinical studies have shown new various molecular targets and the functional characteristics of tumor angiogenesis, which may provide strategies for improving the therapeutic benefit.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Humans; Indoles; Molecular Targeted Therapy; Neoplasms; Niacinamide; Oligonucleotides; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyrroles; Quinazolines; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

Multidrug resistance is a principal mechanism by which tumors become resistant to structurally and functionally unrelated anticancer drugs. Resistance to chemotherapy has been correlated with overexpression of p-glycoprotein (p-gp), a member of the ATP-binding cassette (ABC) superfamily of membrane transporters. P-gp mediates resistance to a broad-spectrum of anticancer drugs including doxorubicin, taxol, and vinca alkaloids by actively expelling the drugs from cells. Use of specific inhibitors/blocker of p-gp in combination with clinically important anticancer drugs has emerged as a new paradigm for overcoming multidrug resistance. The aim of this paper is to review p-gp regulation by dietary nutraceuticals and to correlate this dietary nutraceutical induced-modulation of p-gp with activity of anticancer drugs.

Topics: Abietanes; Alkaloids; Allyl Compounds; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Benzodioxoles; beta Carotene; Biflavonoids; Capsaicin; Catechin; Catechols; Curcumin; Dietary Supplements; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Fatty Alcohols; Furocoumarins; Humans; Indoles; Limonins; Neoplasms; Phytotherapy; Piperidines; Polyunsaturated Alkamides; Proanthocyanidins; Quercetin; Resveratrol; Stilbenes; Sulfides; Tea; Triterpenes; Xanthophylls

Targeting of oncogenic driver mutations with small-molecule inhibitors resulted in powerful treatment options for cancer patients in recent years. The RAS (rat sarcoma) pathway is among the most frequently mutated pathways in human cancer. Whereas targeting mutant Kirsten RAS (KRAS) remains difficult, mutant B rapidly accelerated fibrosarcoma (BRAF) kinase is an established drug target in cancer. Now data show that neuroblastoma RAS (NRAS) and even Harvey RAS (HRAS) mutations could be predictive markers for treatment with mitogen-activated protein kinase (MEK) inhibitors. This review discusses recent preclinical and clinical studies of MEK inhibitors in BRAF and RAS mutant cancer.

Topics: Animals; Azetidines; Benzamides; Benzimidazoles; Diphenylamine; Genes, ras; GTP Phosphohydrolases; Humans; Membrane Proteins; Mice; Mitogen-Activated Protein Kinases; Mutation; Neoplasms; Niacinamide; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Signal Transduction; Sulfonamides

Excessive free radical generation overbalancing the rate of their removal leads to oxidative stress. Oxidative stress has been implicated in the etiology of cardiovascular disease, inflammatory diseases, cancer, and other chronic diseases. Antioxidants are compounds that hinder the oxidative processes and thereby delay or suppress oxidative stress. There is a growing interest in natural antioxidants found in plants. Herbs and spices are most important targets to search for natural antioxidants from the point of view of safety. A wide variety of phenolic compounds present in spices that are extensively used as food adjuncts possess potent antioxidant, anti-inflammatory, antimutagenic, and cancer preventive activities. This paper reviews a host of spice compounds as exogenous antioxidants that are experimentally evidenced to control cellular oxidative stress, both in vitro and in vivo, and their beneficial role in preventing or ameliorating oxidative-stress-mediated diseases, from atherosclerosis to diabetes to cataract to cancer. The antioxidative effects of turmeric/curcumin, clove/eugenol, red pepper/capsaicin, black pepper/piperine, ginger/gingerol, garlic, onion, and fenugreek, which have been extensively studied and evidenced as potential antioxidants, are specifically reviewed in this treatise.

Topics: Alkaloids; Anti-Inflammatory Agents; Antimutagenic Agents; Antioxidants; Benzodioxoles; Capsaicin; Cardiotonic Agents; Catechols; Curcumin; Eugenol; Fatty Alcohols; Garlic; Humans; Neoplasms; Onions; Oxidative Stress; Phenols; Piperidines; Polyunsaturated Alkamides; Spices; Trigonella

Emerging evidence demonstrates that the high mobility group A1 (HMGA1) chromatin remodeling protein is a key molecular switch required by cancer cells for tumor progression and a poorly differentiated, stem-like state. Because the HMGA1 gene and proteins are expressed at high levels in all aggressive tumors studied to date, research is needed to determine how to 'turn off' this master regulatory switch in cancer.. In this review, we describe prior studies that underscore the central role of HMGA1 in refractory cancers and we discuss approaches to target HMGA1 in cancer therapy.. Given the widespread overexpression of HMGA1 in diverse, aggressive tumors, further research to develop technology to target HMGA1 holds immense promise as potent anticancer therapy. Previous work in preclinical models indicates that delivery of short hairpin RNA or interfering RNA molecules to 'switch off' HMGA1 expression dramatically impairs cancer cell growth and tumor progression. The advent of nanoparticle technology to systemically deliver DNA or RNA molecules to tumors brings this approach even closer to clinical applications, although further efforts are needed to translate these advances into therapies for cancer patients.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Cell Differentiation; Chromatin; Clinical Trials as Topic; Cyclooxygenase 2 Inhibitors; Disease Progression; Drug Screening Assays, Antitumor; Flavonoids; Gene Expression Regulation, Neoplastic; Genetic Therapy; HMGA1a Protein; HMGA1b Protein; Humans; Mice; Molecular Targeted Therapy; Nanoparticles; Neoplasm Invasiveness; Neoplasm Proteins; Neoplasms; Oxazines; Piperidines; RNA, Small Interfering; Stem Cells

Bruton's TK (BTK) is a promising biological target for therapeutic intervention of several diseases including inflammatory diseases and cancer/B cell malignancies. Numerous research groups are actively engaged in investigating the functions of BTK, and discovering potent and selective BTK inhibitors as drug candidates. Revealed by x-ray crystal structures with ligands of diverse chemical structures, the ability of BTK kinase domain to adopt various inactive conformations offers unique opportunities to identify highly potent and exquisitely selective inhibitors. Both reversible and covalent inhibitor approaches have yielded candidates demonstrating safety profiles and efficacies in multiple preclinical models of autoimmunity and oncology. Two BTK inhibitors have entered human clinical trials for oncology indications. Ibrutinib won the US FDA approval in November 2013 to become the first-in-class BTK inhibitor for treating mantle cell lymphoma. This encouraging outcome and the other on-going human studies could ultimately expand the utility of BTK inhibitors to broader autoimmune disease areas.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Autoimmune Diseases; Clinical Trials as Topic; Crystallography, X-Ray; Drug Discovery; Humans; Models, Molecular; Neoplasms; Piperidines; Protein Conformation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Small Molecule Libraries

Ibrutinib (formerly PCI-32765) is a potent, covalent inhibitor of Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor that is critical for B-cell survival and proliferation. In preclinical studies, ibrutinib bound to Bruton's tyrosine kinase with high affinity, leading to inhibition of B-cell receptor signaling, decreased B-cell activation and induction of apoptosis. In clinical studies, ibrutinib has been well-tolerated and has demonstrated profound anti-tumor activity in a variety of hematologic malignancies, most notably chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), leading to US FDA approval for relapsed CLL and MCL. Ongoing studies are evaluating ibrutinib in other types of non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma and Waldenström's macrogobulinemia, in larger Phase III studies in CLL and MCL, and in combination studies with monoclonal antibodies and chemotherapy. Future studies will combine ibrutinib with other promising novel agents currently in development in hematologic malignancies.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Combined Modality Therapy; Drug Evaluation, Preclinical; Humans; Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Treatment Outcome

Various studies highlight cognitive impairments in cancer patients. This paper proposes a review of longitudinal controlled studies evaluating the efficacy of interventions aiming to reduce these cognitive impairments. Longitudinal controlled studies evaluating the efficacy of interventions aiming to reduce cognitive impairments in adult cancer patients and published between 1993 and 2013 were identified, with the exception of studies that implied patients suffering from CNS tumor or metastasis. Pharmacological interventions (n = 11) suggested the positive impact of modafinil on memory and executive functions. Non-pharmacological interventions (n = 10) suggested the positive impact of cognitive revalidation and stimulation programs, psycho-education and meditation on several memory, attentional and executive objective as well as subjective functions. Non-pharmacological interventions show more significant cognitive benefits than pharmacological interventions. Some longitudinal controlled studies support the usefulness of interventions aiming to reduce cognitive impairments in cancer patients. Further studies should evaluate the effectiveness of programs combining technics aiming to reduce cognitive impairments and psychotherapeutic technics aiming to support patients' coping with illness.

Topics: Adult; Benzhydryl Compounds; Case-Control Studies; Central Nervous System Stimulants; Cognition; Cognition Disorders; Darbepoetin alfa; Donepezil; Erythropoietin; Estradiol; Executive Function; Female; Humans; Indans; Longitudinal Studies; Male; Meditation; Methylphenidate; Modafinil; Neoplasms; Piperidines

Survivors of childhood cancer frequently experience cancer-related cognitive dysfunction, commonly months to years after treatment for pediatric brain tumors, acute lymphoblastic leukemia (ALL), or tumors involving the head and neck. Risk factors for cancer-related cognitive dysfunction include young age at diagnosis, treatment with cranial irradiation, use of parenteral or intrathecal methotrexate, female sex, and pre-existing comorbidities. Limiting use and reducing doses and volume of cranial irradiation while intensifying chemotherapy have improved survival and reduced the severity of cognitive dysfunction, especially in leukemia. Nonetheless, problems in core functional domains of attention, processing speed, working memory and visual-motor integration continue to compromise quality of life and performance. We review the epidemiology, pathophysiology and assessment of cancer-related cognitive dysfunction, the impact of treatment changes for prevention, and the broad strategies for educational and pharmacological interventions to remediate established cognitive dysfunction following childhood cancer. The increased years of life saved after childhood cancer warrants continued study toward the prevention and remediation of cancer-related cognitive dysfunction, using uniform assessments anchored in functional outcomes.

Topics: Adolescent; Adult; Age Factors; Antimetabolites, Antineoplastic; Attention; Benzhydryl Compounds; Brain Neoplasms; Central Nervous System Stimulants; Child; Child, Preschool; Cognitive Dysfunction; Comorbidity; Cranial Irradiation; Donepezil; Early Intervention, Educational; Education, Special; Head and Neck Neoplasms; Human Growth Hormone; Humans; Indans; Infant; Injections, Spinal; Memory, Short-Term; Methotrexate; Methylphenidate; Modafinil; Neoplasms; Neurosurgical Procedures; Nootropic Agents; Patient Education as Topic; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Psychomotor Performance; Quality of Life; Radiotherapy Dosage; Risk Factors; Severity of Illness Index; Sex Factors; Survivors; Thinking; Wakefulness-Promoting Agents; Young Adult

Recent advances in molecular biology have permitted the identification and characterization of specific abnormalities regarding cell signaling and function in cancer cells. Proteins that are found to be dysregulated in cancer cells can serve as relevant targets for therapeutic intervention. Although there are several approaches to block proteins that contribute to cellular dysfunction, the one most commonly used involves a class of therapeutics called small molecule inhibitors. Such inhibitors work by disrupting critical pathways/processes in cancer cells, thereby preventing their ability to grow and survive.

Topics: Animals; Benzamides; Cat Diseases; Cats; Dog Diseases; Dogs; Indoles; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrroles; Thiazoles

Farnesyltransferase inhibitors (FTIs) have mainly been used in cancer therapy. However, more recently, investigations on these inhibitors revealed that FTIs can be used for the treatment of other diseases such as Progeria, P. falciparum resistant malaria, Trypnosomatid, etc. Hence the development of novel FTIs is an important task for the drug discovery program. Initially, numerous peptidomimetic FTIs were developed from the template of CAAX (CVIM was the first pharmacophore model used as a peptidomimetic). Later, many non-peptidomimetic FTIs have been discovered with the structural modification of the peptidomimetics. The structural analysis of those developed FTIs by various researchers suggested that the presence of a heterocycle or a polar group in place of the thiol group is required for interaction with the Zn(2+) ion. The bulky naphthyl, quinolinyl, phenyl, phenothazine, etc in this position provide better hydrophobicity to the molecules which interact with the aromatic amino acid moieties in the hydrophobic pocket. A hydrophilic region with polar groups is necessary for the polar or hydrogen bonding interactions with the amino acids or water molecules in the active site. Many FTIs have been isolated from natural products, which possessed inhibitory activity against farnesyltransferase (FTase). Among them, pepticinnamin E (9R), fusidienol (9T), gliotoxin (9V), cylindrol A (9X), etc possessed potential FTase inhibitory activities and their structural features are comparable to those of the synthetic molecules. The clinical studies progressing on FTIs showed that tipifarnib in combination with bortezomib is used for the treatment of patients with advanced acute leukemias. Successful phase I and II studies are undergoing for tipifarnib alone or in combination with other drugs/radiation for the treatment of multiple myeloma, AML, breast cancer, mantle cell lymphoma, solid tumors, non-small cell lung cancer (NSCLC), pancreatic cancer, glioblastoma, etc. Phase I pharmacokinetic (maximum tolerated dose, toxicity) and pharmacodynamic studies of AZD3409 (an orally active double prodrug) is progressing on patients with solid malignancies taking 500 mg once a day. A phase II study is undergoing on lonafarnib alone and in combination with zoledronic acid and pravastatin for the treatment of Hutchinson-Gilford Progeria syndrome (HGPS) and progeroid laminopathies. Lonafarnib therapy improved cardiovascular status of children with HGPS, by improved peripheral art

Topics: Antineoplastic Agents; Biological Products; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Neoplasms; Piperidines; Pyridines; Quantitative Structure-Activity Relationship; Quinolones

In humans, hibernoma is a very rare, benign neoplasm of brown adipose tissue (BAT) that typically occurs at subcutaneous locations and is successfully treated by surgical excision. No single cause has been accepted to explain these very rare human tumors. In contrast, spontaneous hibernoma in rats is rare, often malignant, usually occurs in the thoracic or abdominal cavity, and metastases are common. In recent years, there has been an increased incidence of spontaneous hibernomas in rat carcinogenicity studies, but overall the occurrence remains relatively low and highly variable across studies. There have only been four reported examples of pharmaceutical-induced hibernoma in rat carcinogenicity studies. These include phentolamine, an alpha-adrenergic antagonist; varenicline, a nicotine partial agonist; tofacitinib, a Janus kinase (JAK) inhibitor; and hydromorphone, an opiod analgesic. Potential non-genotoxic mechanisms that may contribute to the pathogenesis of BAT activation/proliferation and/or subsequent hibernoma development in rats include: (1) physiological stimuli, (2) sympathetic stimulation, (3) peroxisome proliferator-activated receptor (PPAR) agonism, and/or (4) interference or inhibition of JAK/Signal Transducer and Activator of Transcription (JAK/STAT) signaling. The evaluation of an apparent increase of hibernoma in rats from 2-year carcinogenicity studies of novel pharmaceutical therapeutics and its relevance to human safety risk assessment is complex. One should consider: the genotoxicity of the test article, dose/exposure and safety margins, and pathophysiologic and morphologic differences and similarities of hibernoma between rats and humans. Hibernomas observed to date in carcinogenicity studies of pharmaceutical agents do not appear to be relevant for human risk at therapeutic dosages.

Topics: Animals; Benzazepines; Carcinogenicity Tests; Disease Models, Animal; Humans; Hydromorphone; Lipoma; Mutagenicity Tests; Neoplasms; Phentolamine; Piperidines; Pyrimidines; Pyrroles; Quinoxalines; Rats; Risk Assessment; Varenicline

Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient's mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer's drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction.

Topics: Antineoplastic Agents; Central Nervous System Stimulants; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Humans; Indans; Memantine; Neoplasms; Piperidines

IL-15 has a pivotal role in life and death of natural killer (NK) and CD8 memory T cells. IL-15 signals through a heterotrimeric receptor involving the common gamma chain (γc) shared with IL-2, IL-4, IL-7, IL-9, and IL-21, IL-2/IL-15 receptor β (IL-15Rβ) shared with IL-2 and a private IL-15Rα subunit. IFN- or CD40 ligand-stimulated dendritic cells coordinately express IL-15 and IL-15Rα. Cell surface IL-15Rα presents IL-15 in trans to cells that express IL-2/IL-15Rβ and γc. IL-15 is being used to treat patients with metastatic malignancy. However, IL-15 is an inflammatory cytokine involved in immunological memory including that to self, thereby playing a role in autoimmune diseases. These insights provide the scientific basis for clinical strategies directed toward diminishing IL-15 action. Dysregulated IL-15 expression was demonstrated in patients with rheumatoid arthritis, inflammatory bowel disease, psoriasis, celiac disease, and alopecia areata. The monoclonal antibody Hu-Mik-β-1 targets the cytokine receptor subunit IL-2/IL-15Rβ (CD122), blocks IL-15 transpresentation, and is being used in clinical trials in patients with autoimmune diseases. In parallel, clinical trials have been initiated involving the Jak2/3 (Janus kinase-2/3) inhibitor tofacitinib and Jak1/2 inhibitor ruxolitinib to block IL-15 signaling.

Topics: Alopecia Areata; Animals; Antibodies, Monoclonal; Autoimmune Diseases; Humans; Interleukin-15; Leukemia-Lymphoma, Adult T-Cell; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Receptors, Interleukin-15; Signal Transduction

To perform a systematic review and meta-analysis of published clinical trials to determine incidence rate and overall risk of hypertension with vandetanib in cancer patients.. A comprehensive literature search for studies published up to March 2012 was performed. Summary incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials.. A total of 11 trials with 3154 patients were included for the meta-analysis. The summary incidences of all-grade and high-grade hypertension in patients with cancer were 24.2% [95% confidence interval (CI), 18.1-30.2%] and 6.4% (95% CI, 3.3-9.5%), respectively. Subgroup analysis demonstrated that the pooled incidences of all-grade and high-grade hypertension were 21.8% [95% CI, 15-30.5%] and 7.6% (95% CI, 2.8-18.8%), respectively, among non-small-cell lung cancer (NSCLC) patients, and 32.1% (95% CI: 27.3-37.3%) and 8.8% (5.9%-12.9%), respectively, among MTC patients, and 15.4 (95% CI: 3.2-33.7%) and 3.4% (95% CI: 1%-11.1%) respectively, among non-MTC/NSCLC tumors patients. Furthermore, vandetanib was associated with a significant increased risk of all-grade hypertension (RR 5.1, 95% CI: 3.76-6.92, P = 0.000) and high-grade hypertension (RR 8.06, 95% CI: 3.41-19.04, P = 0.000) in comparison with controls.. There is a significant risk of developing hypertension in cancer patients receiving vandetanib. Appropriate monitoring and treatment is strongly recommended to prevent cardiovascular complications.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Hypertension; Incidence; Neoplasms; Piperidines; Publication Bias; Quinazolines; Risk

The REarranged during Transfection (RET) proto-oncogene and its activated signalling pathways have been shown to play an important role in cancer. RET genetic alterations including germline, somatic mutations and gene rearrangements have been demonstrated in several solid tumours, and numerous clinical trials using multikinase inhibitors containing RET as a target have shown significant activity against RET. Sorafenib and sunitinib have been approved for the treatment of renal, hepatocellular, gastrointestinal and pancreatic neuoendocrine carcinomas. Vandetanib has recently been approved for the treatment of unresectable locally advanced or metastatic medullary thyroid carcinomas. Novel genomic rearrangements and RET signalling interactions are now being studied in a variety of tumours and will provide the basis for new therapeutic strategies. Combination or sequential targeted therapies that are based on solid preclinical data regarding the inhibition of RET-mediated parallel or different -signalling pathways will likely be more effective.

Topics: Animals; Antineoplastic Agents; Drug Design; Humans; Indoles; Molecular Targeted Therapy; Neoplasms; Niacinamide; Phenylurea Compounds; Piperidines; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Pyrroles; Quinazolines; Signal Transduction; Sorafenib; Sunitinib

Vandetanib is a multikinase inhibitor that is under assessment for the treatment of various cancers. QTc interval prolongation is one of the major adverse effects of this drug, but the reported incidence varies substantially among clinical trials. We performed a systematic review and meta-analysis to obtain a better understanding in the risk of QTc interval prolongation among cancer patients administered vandetanib.. Eligible studies were phase II and III prospective clinical trials that involved cancer patients who were prescribed vandetanib 300 mg/d and that included data on QTc interval prolongation. The overall incidence and risk of QTc interval prolongation were calculated using random-effects or fixed-effects models, depending on the heterogeneity of the included studies. Nine trials with 2,188 patients were included for the meta-analysis. The overall incidence of all-grade and high-grade QTc interval prolongation was 16.4% (95% CI, 8.1-30.4%) and 3.7% (8.1-30.4%), respectively, among non-thyroid cancer patients, and 18.0% (10.7-28.6%) and 12.0% (4.5-28.0%), respectively, among thyroid cancer patients. Patients with thyroid cancer who had longer treatment duration also had a higher incidence of high-grade events, with a relative risk of 3.24 (1.57-6.71), than patients who had non-thyroid cancer. Vandetanib was associated with a significantly increased risk of all-grade QTc interval prolongation with overall Peto odds ratios of 7.26 (4.36-12.09) and 5.70 (3.09-10.53) among patients with non-thyroid cancer and thyroid cancer, respectively, compared to the controls.. Treatment with vandetanib is associated with a significant increase in the overall incidence and risk of QTc interval prolongation. Different cancer types and treatment durations may affect the risk of developing high-grade QTc interval prolongation.

Topics: Clinical Trials as Topic; Electrocardiography; Humans; Incidence; Middle Aged; Neoplasms; Odds Ratio; Piperidines; Quinazolines; Risk Factors

Functional blood vasculature is essential for tumor progression. The main signalization pathways that play a key role in the survival and growth of tumor vessels originate from the VEGF-, PDGF- and FGF tyrosine kinase receptors. In the past decade, significant results have been published on receptor tyrosine kinase inhibitors (RTKIs). In this paper, the mechanisms of action and the results so far available of experimental and clinical studies on multi-target antiangiogenic TKIs are discussed. On the one hand, notable achievements have been made recently and these drugs are already used in clinical practice in some patient populations. On the other hand, the optimal combination and dosage of these drugs, selection of the apropriate biomarker and better understanding of the conflicting role of PDGFR and FGFR signaling in angiogenesis remain future challenges.

Topics: Angiogenesis Inhibitors; Animals; Axitinib; Benzenesulfonates; Humans; Imidazoles; Indazoles; Indoles; Neoplasms; Neovascularization, Pathologic; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Sunitinib

Lonafarnib is a non-peptidomimetic inhibitor of farnesyl transferase, an enzyme responsible for the post-translational lipid modification of a wide variety of cellular proteins that are involved in the pathogenic pathways of various diseases including cancer and progeria. Although extensive clinical research indicates limited activity of lonafarnib in solid tumors, there is recent interest in combinations of farnesyl transferase inhibitors with imatinib or bortezomib in hematological malignancies and to investigate the role of lonafarnib in progeria.. This review examines the in vitro and in vivo pharmacology of lonafarnib and the available clinical data for lonafarnib monotherapy and combination therapy in the treatment of solid and hematological malignancies as well as progeria, using studies identified from the PubMed database supplemented by computerized search of relevant abstracts from major cancer and hematology conferences.. There is no evidence to support the use of lonafarnib in solid tumors. There is ongoing interest to explore lonafarnib for progeria and to investigate other farnesyl transferase inhibitors for chronic and acute leukemias.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Neoplasms; Piperidines; Progeria; Protein Prenylation; Pyridines; Treatment Outcome; Xenograft Model Antitumor Assays

The addition of vandetanib to chemotherapy has been shown to have a marked effect on patients with advanced cancers who had failed previous chemotherapy. We carried out a meta-analysis to determine the efficacy and safety of vandetanib compared with chemotherapy in patients with advanced cancers. For this meta-analysis, we selected randomized clinical trials that compared vandetanib-based therapy (VBT) with the matched chemotherapy or placebo alone in patients with advanced cancers. The outcomes included overall survival (OS), progression-free survival (PFS), the objective response rate, and toxicities. Hazard ratios (HRs) and odds ratios were reported with 95% confidence intervals (CIs). A total of 14 eligible trials were included for the meta-analysis, with 2995 patients in the VBT group and 2479 patients in the control group. A significant improvement was observed in PFS (HR 0.76, 95% CI 0.68-0.86 in all cancers, HR 0.80, 95% CI 0.70-0.90 in lung cancer, HR 0.54, 95% CI 0.40-0.74 in thyroid cancer) and in objective response rate (odds ratio 2.09, 95% CI 1.42-3.07) in the VBT group. However, no significant difference was found in OS (HR 0.96, 95% CI 0.90-1.03). The subgroups of patients with non-small-cell lung cancer who benefited from vandetanib therapy were identified as those with a history of smoking (HR 0.87, 95% CI 0.80-0.95) and an adenocarcinoma histology (HR 0.85, 95% CI 0.77-0.94). In addition, patients who received VBT had an increased incidence of adverse events such as rash, diarrhea, and neutropenia. The addition of vandetanib to chemotherapy significantly improves PFS in patients with locally advanced or metastatic cancers, especially lung and thyroid cancer.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Humans; Lung Neoplasms; Neoplasms; Piperidines; Quinazolines; Thyroid Neoplasms; Treatment Outcome

Tyrosine kinases (TKs) are key mediators of signalling pathways in cells. Located at the surface of the cell, within the cytoplasm or in the nucleous, TKs have been showed to be involved in regulation of normal cellular processes and also play an important role in the development, progression and spread of several types of cancer. Seventy percent of TK's are Receptor Tyrosine Kinases and these have become key targets for cancer therapy. This short synopsis is intended to give the reader an introduction to this area of targeted therapy for cancer as a prelude to this special edition of Veterinary and Comparative Oncology.

Topics: Animals; Antineoplastic Agents; Benzamides; Drug Therapy, Combination; Humans; Indoles; Neoplasms; Piperidines; Pyridines; Pyrroles; Receptor Protein-Tyrosine Kinases; Thiazoles

The addition of neurokinin-1 receptor (NK1R) antagonists to antiemetic regimens has substantially reduced chemotherapy-induced nausea and vomiting (CINV). We sought to systematically review the overall impact of NK1R antagonists on CINV prevention.. We systematically searched the MEDLINE, EMBASE, and CENTRAL databases, and meeting proceedings for randomized controlled trials (RCTs) that evaluated NK1R antagonists plus standard antiemetic therapy for CINV prevention. Complete response (CR) to therapy was defined as the absence of emesis and the absence of rescue therapy. The endpoints were defined as CR in the overall phase (during the first 120 hours of chemotherapy), CR in the acute phase (first 24 hours), and the delayed phase (24-120 hours) after chemotherapy, nausea, and toxicity. Subgroup analyses evaluated the type of NK1R antagonist used, the emetogenic potential of the chemotherapy regimen, and prolonged use of 5-HT3 (serotonin) receptor antagonists, a class of standard antiemetic agents. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates and publication bias were two-sided.. Seventeen trials (8740 patients) were included in this analysis. NK1R antagonists increased the CR rate in the overall phase from 54% to 72% (OR = 0.51, 95% CI = 0.46 to 0.57, P < .001). CR and nausea were improved in all phases and subgroups. The expected side effects from NK1R antagonists did not statistically significantly differ from previous reports; however, this analysis suggests that the incidence of severe infection increased from 2% to 6% in the NK1R antagonist group (three RCTs with a total of 1480 patients; OR = 3.10; 95% CI = 1.69 to 5.67, P < .001).. NK1R antagonists increased CINV control in the acute, delayed, and overall phases. They are effective for both moderately and highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rates; however, additional appraisal of specific data from RCTs is needed.

Topics: Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Confidence Intervals; Humans; Infections; Morpholines; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Odds Ratio; Piperazines; Piperidines; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Antagonists; Vomiting

Angiogenesis is essential for tumor growth and metastasis. The main regulators of the process are the signaling cascades of VEGF-, PDGF- and FGF receptors. Inhibition of these pathways holds potential therapeutic benefit not only for cancer patients, but also for the treatment of other diseases. This paper summarizes the experimental and clinical results of studies available so far on the multi-target tyrosine kinase inhibitor nintedanib (BIBF 1120). According to these studies, nintedanib effectively inhibits VEGFR-, PDGFR- and FGFR signalization and thus the proliferation and survival of cell types which highly express these receptors (i.e. endothelial and smooth muscle cells and pericytes). In vitro studies and in vivo xenograft experiments have provided promising results. In the clinical setting, BIBF 1120 seems to be effective and well tolerated in various tumor types, such as lung, prostate, colorectal and hepatocellular carcinoma, as well as in gynecological tumors. The main adverse events are gastrointestinal toxicities and the reversible elevation of liver enzyme levels. Nintedanib might also be combined with paclitaxel, carboplatin, pemetrexed and docetaxel. There are several ongoing clinical trials testing the efficacy of BIBF 1120.

Topics: Animals; Antineoplastic Agents; Axitinib; Benzenesulfonates; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colorectal Neoplasms; Digestive System; Enzyme Inhibitors; Female; Genital Neoplasms, Female; Humans; Imidazoles; Indazoles; Indoles; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Prostatic Neoplasms; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinazolines; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Xenograft Model Antitumor Assays

The development of a carrier for the delivery of siRNA is a factor in the realization of RNA interference (RNAi) therapeutics. Modification of siRNA carriers with polyethylene glycol, i.e., PEGylation, is a general strategy for stabilizing a particle in the blood stream and delivering it to tissue or cells. However, it is well-known that, when a carrier is modified by PEGylation, it results in a significant inhibition of both cellular uptake and the endosomal escape process. In a previous study, we reported on the development of a multifunctional envelope-type nano device (MEND) for delivering siRNA and peptide-based functional devices for overcoming the effects conferred by PEGylation and succeeded in the delivery of siRNA to tumor tissue. In this study, we noticed that the pH-sensitive property, changing from neutral to cationic in response to a decrease in pH, could avoid the inhibition caused by PEGylation and succeeded in synthesizing a pH-sensitive cationic lipid, YSK05. The YSK05-MEND had a higher fusogenicity and potency for endosomal escape than other MENDs containing conventional cationic lipids. The PEGylated YSK05-MEND induced efficient gene silencing and avoided the inhibition of endosomal escape caused by PEGylation followed by optimization of the lipid composition. Furthermore, the intratumoral injection of the PEGylated YSK05-MEND resulted in a more efficient gene silencing compared with MENDs containing conventional cationic lipids. Thus, the YSK05-MEND is a promising siRNA carrier for avoiding the inhibition in intracellular trafficking caused by PEGylation both in vitro and in vivo.

Topics: Animals; Cations; Drug Delivery Systems; Drug Discovery; Endosomes; Gene Silencing; Humans; Hydrogen-Ion Concentration; Injections, Intralesional; Lipids; Nanostructures; Neoplasms; Piperidines; Polyethylene Glycols; RNA, Small Interfering

The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anticancer drugs targeting cancer stem cells. Naturally occurring dietary compounds have received increasing attention in cancer chemoprevention. The anticancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine and vitamin D(3), are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor-initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival.

Topics: Alkaloids; Animals; Anticarcinogenic Agents; Benzodioxoles; beta Catenin; Carotenoids; Catechin; Cell Differentiation; Cell Proliferation; Cholecalciferol; Curcumin; Diet; Humans; Isoflavones; Isothiocyanates; Lycopene; Neoplasms; Neoplastic Stem Cells; Piperidines; Polyunsaturated Alkamides; Resveratrol; Signal Transduction; Stilbenes; Sulfoxides; Thiocyanates; Wnt Proteins

The receptor tyrosine kinases (RTKs) play a critical role, controlling cell proliferation, survival, and differentiation of normal cells. Their pivotal function has been firmly established in the pathogenesis of many cancers as well. The anaplastic lymphoma kinase (ALK), a transmembrane RTK, originally identified in the nucleophosmin (NPM)-ALK chimera of anaplastic large cell lymphoma, has emerged as a novel tumorigenic player in several human cancers. In this review, we describe the expression of the ALK-RTK, its related fusion proteins, and their molecular mechanisms of activation. Novel tailored strategies are briefly illustrated for the treatment of ALK-positive neoplasms.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Crizotinib; CSK Tyrosine-Protein Kinase; Humans; Intracellular Signaling Peptides and Proteins; Lymphoma; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Phospholipase C gamma; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Signal Transduction; src-Family Kinases; Transcriptional Activation; Translocation, Genetic; Up-Regulation

Natural products are an abundant source of anti cancer agents. They act as cytotoxic drugs, and inhibitors of apoptosis, transcription, cell proliferation and angiogenesis. While pathways targeted by natural products have been well studied, there is paucity of information about the in vivo molecular target/s of these compounds. This review summarizes some of the natural compounds for which the molecular targets, mechanism of action and structural basis of specificity have been well documented. These examples illustrate that 'off target' binding can be explained on the basis of diversity inherent to biomolecular interactions. There is enough evidence to suggest that natural compounds are potent and versatile warheads that can be optimized for a multi targeted therapeutic intervention in cancer.

Topics: Antineoplastic Agents; Benzamides; Biological Products; Cyclohexanes; Epoxy Compounds; Fatty Acids, Unsaturated; Flavonoids; Humans; Imatinib Mesylate; Macrolides; Neoplasms; Piperazines; Piperidines; Proteins; Pyrimidines; Sesquiterpenes

Nampt/PBEF/visfatin is the rate-limiting enzyme that catalyzes the first step in NAD biosynthesis from nicotinamide and regulates growth, apoptosis and angiogenesis of mammalian cells. This enzyme was originally cloned as a putative cytokine shown to enhance the B cell precursor maturation in the presence of IL-7 and stem cell factor. A number of cancers have increased expression of Nampt/PBEF/visfatin, which regulates a variety of different signaling pathways such as PI3K/Akt, ERK1/2 and STAT3. FK866/APO866 and CHS828/GMX1777 are two known inhibitors of Nampt/PBEF/visfatin and have been evaluated as anticancer agents in the clinic. This review will focus on its role in carcinogenesis and cancer progression and its inhibitors as therapeutic target for cancer treatment.

Topics: Acrylamides; Cytokines; Disease Progression; Humans; NAD; Neoplasms; Nicotinamide Phosphoribosyltransferase; Piperidines; Signal Transduction

The Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase first identified as the product of a gene rearrangement in Anaplastic Large Cell Lymphoma. ALK has subsequently been found to be rearranged, mutated, or amplified in a further series of tumours including neuroblastoma, and Non-Small Cell Lung Cancer. There is strong preclinical evidence that ALK is a driving force for oncogenesis in these cases, and that inhibition of ALK kinase activity results in anti-tumoural efficacy. These observations have sparked the development of small molecule kinase inhibitors, the most advanced of which is currently in clinical testing and which has shown promising preliminary activity in the subset of lung cancer patients whose tumours harbour activated ALK. In this review, we describe the various oncogenic forms of ALK, relevant clinical settings, and give a detailed overview of current drug discovery efforts in the field.

Topics: Anaplastic Lymphoma Kinase; Animals; Crizotinib; Genetic Predisposition to Disease; Humans; Molecular Structure; Mutation; Neoplasms; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Receptor Protein-Tyrosine Kinases

Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR) and Ret tyrosine kinases involved in tumor growth, progression and angiogenesis. Phase I studies indicated that the recommended dose of vandetanib as a single agent is 300 mg/day. Rash, diarrhea, hypertension and asymptomatic Q-Tc prolongation were the most common adverse events. Four randomized phase III clinical trials evaluated the efficacy of vandetanib in non-small cell lung cancer (NSCLC) in combination with docetaxel (ZODIAC), pemetrexed (ZEAL) or as a single agent (ZEST and ZEPHYR). Only the ZODIAC trial met its primary endpoint (progression-free survival [PFS]), while no study showed an advantage in overall survival with vandetanib. No significant antitumor activity has been observed in small cell lung cancer, advanced ovarian, colorectal, breast, prostate cancer and multiple myeloma. In advanced metastatic medullary thyroid cancer, one randomized phase III clinical trial has demonstrated that vandetanib can significantly improve response rate, PFS and time to worsening of pain. Several key questions remain to be addressed regarding the identification of clinical or molecular biomarkers predictive of response, the choice of the optimal dose or schedule of vandetanib and the safety of long-term administration. The results of ongoing trials in untreated patients with advanced NSCLC and other tumors should better define the optimal clinical application of vandetanib.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Lung Neoplasms; Neoplasms; Piperidines; Quinazolines

The cell cycle is the series of events necessary for the division and duplication of a cell. The dysregulation of the cell cycle can promote the development of cancer. A group of proteins, cyclin-dependent kinases (CDKs), that control the cell cycle, provide new targets for treating cancer. As a result, cyclin-dependent kinase inhibitors (CDKIs) represent a novel class of chemotherapeutic agents. Of these, flavopiridol, a semisynthetic flavonoidal alkaloid, emerged as the first CDKI to enter clinical trials. Preclinical data indicate that flavopiridol could block the proliferation of neoplastic cells and induce programmed cell death as a single agent. Furthermore, recent emerging data revealed that flavopiridol can potentiate, generally in a dose- and sequence-dependent manner, the anti-tumor effects of many established chemotherapeutic agents. This review is primarily focused on the role of flavopiridol in combination with various therapeutic agents that are in or near clinical development.

Topics: Antineoplastic Agents; Cell Proliferation; Clinical Trials, Phase I as Topic; Cyclin-Dependent Kinases; Drug Design; Drug Synergism; Drug Therapy, Combination; Flavonoids; Humans; Neoplasms; Piperidines

Current cancer chemotherapy relies heavily on cytotoxic agents, such as the taxanes and Vinca alkaloids, that interfere with the cellular machinery required for cell division and divert the cell down a pathway of programmed cell death. These antimitotic agents, or spindle poisons, target the mitotic spindle by binding to tubulin, a protein required not only for mitosis but also for structural integrity and proper function of healthy, terminally differentiated cells. To avoid side effects attributed to this nonselective mechanism of action, new targets in the mitotic pathway that act only in dividing cells were sought and a leading candidate to emerge from these efforts was kinesin spindle protein (KSP or HsEg5). KSP is a molecular motor protein that is expressed only during mitosis and controls the formation of a functional mitotic spindle. Inhibition of KSP causes mitotic arrest followed by cell death in malignant cells and thus has the potential to become a novel chemotherapeutic strategy with the potential for reduced toxicity. This article summarizes efforts carried out at Merck to discover potent, selective and water soluble KSP inhibitors that culminated in the discovery of MK-0731, the second KSP inhibitor to enter clinical trials. Of special focus in this article is how an HTS lead was optimized in apparently divergent directions, but these disparate leads converged in the design of compounds that overcame P-glycoprotein efflux and hERG channel activity, two issues that required considerable optimization within our program.

Topics: Allosteric Regulation; Antineoplastic Agents; Drug Discovery; Humans; Kinesins; Neoplasms; Piperidines; Pyrroles; Taxoids

The effective treatment of emetic complications of cancer therapies has remained a challenging task for cancer patients and their cancer care providers. Despite striking advances in antiemetic interventions, the need for more personalized targeted treatments in those who fail to response to the currently available antiemetic agents are yet to be met. Casopitant, a potent selective inhibitor of neurokinin-1 receptors, is a product of the increasingly heightened interest in this particular subset of cancer patients. The current review examines the emerging data about the benefits and safety of casopitant for treatment of chemotherapy-induced acute and delayed emesis, as well as the postoperative nausea/vomiting. Although preclinical studies promoted the notion of a potential superiority of casopitant over the already approved aprepitant in enhancing food and fluid intake, the limited comparison in clinical settings have yet to affirm a demonstratable meaningful superiority. The prevailing view from the published prospective studies supports a single 100 or 150 mg dose schedule of casopitant, orally or intravenously, as an effective and safe prophylaxis for acute and delayed emesis. The relative inferior outcomes of "nausea" control, as compared to a more impressive "vomiting" prevention, are similarly shared by both casopitant and aprepitant. This repeated and disappointing observation has challenged the precision and accuracy of our current understandings about the exact fabric of the "emesis axis." The future efforts should be directed to identify more effective agents for managing nausea and anticipatory emesis equally in both genders.

Topics: Antiemetics; Antineoplastic Agents; Humans; Nausea; Neoplasms; Piperazines; Piperidines; Vomiting

The endothelins and their G protein-coupled receptors A and B have been implicated in numerous diseases and have recently emerged as pivotal players in a variety of malignancies. Tumors overexpress the endothelin 1 (ET-1) ligand and the endothelin-A-receptor (ET(A)R). Their interaction induces tumor growth and metastasis by promoting tumor cell survival and proliferation, angiogenesis, and tissue remodeling. On the basis of results from xenograft models, drug development efforts have focused on antagonizing the autocrine-paracrine effects mediated by ET-1/ET(A)R. In this review, we discuss a novel role of the endothelin-B-receptor (ET(B)R) in tumorigenesis and the effect of its blockade during cancer immune therapy. We highlight key characteristics of the B receptor such as its specific overexpression in the tumor compartment; and specifically, in the tumor endothelium, where its activation by ET-1 suppresses T-cell adhesion and homing to tumors. We also review our recent findings on the effects of ET(B)R-specific blockade in increasing T-cell homing to tumors and enhancing the efficacy of otherwise ineffective immunotherapy.

Topics: Animals; Endothelin B Receptor Antagonists; Endothelium, Vascular; Humans; Immunotherapy; Intercellular Adhesion Molecule-1; Models, Biological; Neoplasms; Oligopeptides; Piperidines; Receptor, Endothelin B; T-Lymphocytes

Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy which acts on all dividing cells generating toxic effects and damage of normal tissues, targeted drugs allow to hit, in a more specific manner, subpopulations of cells directly involved in tumor progression. Molecules controlling cell proliferation and death, such as Tyrosine Kinase Receptors (RTKs) for growth factors, are among the best targets for this type of therapeutic approach. Two classes of compounds targeting RTKs are currently used in clinical practice: monoclonal antibodies and tyrosine kinase inhibitors. The era of targeted therapy began with the approval of Trastuzumab, a monoclonal antibody against HER2, for treatment of metastatic breast cancer, and Imatinib, a small tyrosine kinase inhibitor targeting BCR-Abl, in Chronic Myeloid Leukemia. Despite the initial enthusiasm for the efficacy of these treatments, clinicians had to face soon the problem of relapse, as almost invariably cancer patients developed drug resistance, often due to the activation of alternative RTKs pathways. In this view, the rationale at the basis of targeting drugs is radically shifting. In the past, the main effort was aimed at developing highly specific inhibitors acting on single RTKs. Now, there is a general agreement that molecules interfering simultaneously with multiple RTKs might be more effective than single target agents. With the recent approval by FDA of Sorafenib and Sunitinib--targeting VEGFR, PDGFR, FLT-3 and c-Kit--a different scenario has been emerging, where a new generation of anti-cancer drugs, able to inhibit more than one pathway, would probably play a major role.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Benzenesulfonates; Bevacizumab; Cetuximab; Clinical Trials as Topic; Enzyme Inhibitors; Erlotinib Hydrochloride; Gefitinib; Humans; Imatinib Mesylate; Indoles; Lapatinib; Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Piperazines; Piperidines; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Sorafenib; Sunitinib; Trastuzumab

Nicotinamide adenine dinucleotide (NAD(+)) has crucial roles in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Enzymes involved in NAD(+) metabolism are attractive targets for drug discovery against a variety of human diseases, including cancer, multiple sclerosis, neurodegeneration and Huntington's disease. A small-molecule inhibitor of nicotinamide phosphoribosyltransferase, an enzyme in the salvage pathway of NAD(+) biosynthesis, is presently in clinical trials against cancer. An analog of a kynurenine pathway intermediate is efficacious against multiple sclerosis in an animal model. Indoleamine 2,3-dioxygenase plays an important role in immune evasion by cancer cells and other disease processes. Inhibitors against kynurenine 3-hydroxylase can reduce the production of neurotoxic metabolites while increasing the production of neuroprotective compounds. This review summarizes the existing knowledge on NAD(+) metabolic enzymes, with emphasis on their relevance for drug discovery.

Topics: Acrylamides; Adenosine Diphosphate Ribose; Aging; Animals; Antineoplastic Agents; Autoimmune Diseases; Clinical Trials, Phase II as Topic; Cyclic ADP-Ribose; DNA Damage; Drug Design; Enzyme Inhibitors; Humans; Kynurenine; Mice; NAD; Neoplasms; Neurodegenerative Diseases; Neuroprotective Agents; Piperidines; Poly Adenosine Diphosphate Ribose; Signal Transduction; Sirtuins; Tryptophan

Cancer-related constipation is common and a significant detractor from patient quality of life. It has many possible causes and is still not well understood. Information is lacking on therapies for cancer-related constipation among current medications approved by the US Food and Drug Administration (FDA). Most agents have only been formally tested in comparison with placebo in chronic idiopathic constipation if at all. Few comparative studies of laxatives have been performed to establish superiority or synergy. As we understand more about the physiology of the gastrointestinal tract, new targeted therapies have become available. These include a selective chloride channel activator, lubiprostone, and a selective 5HT4 serotonin receptor agonist, tegaserod, both of which have been FDA approved for chronic idiopathic constipation. The role of these agents in cancer-related constipation remains to be seen. On the horizon are two investigational peripherally acting opioid receptor antagonists, alvimopan and methylnaltrexone. Preliminary results in cancer-related constipation suggest that these agents may be important additions to our treatment repertoire.

Topics: Alprostadil; Constipation; Fatty Acids; Gastrointestinal Agents; Humans; Indoles; Lubiprostone; Naltrexone; Narcotic Antagonists; Neoplasms; Piperidines; Quaternary Ammonium Compounds; Serotonin Receptor Agonists

Angiogenesis does not initiate malignancy but promotes tumor progression and metastasis. Inhibiting angiogenesis is now a validated strategy for treatment of cancer. In order to do it, different ways are under investigation from cellular therapy to oral agents. Nowadays targeting angiogenesis with small molecules mainly concern inhibition of the VEGF receptors tyrosine kinase activity. Five molecules are currently in phase III trials and two of them (sunitinib and sorafenib) have been approved by the FDA for the treatment of advanced renal cancer. Despite those encouraging results, numerous points remain unclear. The toxicity profile seems to be favourable but long term effects could be problematic. Indeed, clinical trials have pointed out the role of VEGF pathway in the maintenance of numerous physiological functions. Moreover, none of the agents are specifically anti-angiogenic and the respective parts of the "off target" effects are difficult to evaluate. Simple and reliable surrogate markers of toxicity and efficacy are still lacking.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Asthenia; Axitinib; Benzenesulfonates; Humans; Hypertension; Imidazoles; Indazoles; Indoles; Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Phthalazines; Piperidines; Proteinuria; Pyridines; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cyclin-Dependent Kinases; Cyclins; Flavonoids; Humans; Neoplasms; Piperidines; Purines; Roscovitine; Staurosporine

The inhibition of cyclin-dependent kinases (CDKs) represents a novel approach to the therapy of human malignancies. Already in clinical trials, recently developed CDK inhibitors very efficiently target the rapidly proliferating cancer cells and inhibit their cell-cycle progression. Interestingly, some CDK inhibitors additionally affect the stability and activity of the tumour-suppressor protein p53, thereby enhancing their antiproliferative action towards cancer cells. Considering the fact that the p53 protein is mutated or inactivated in approximately 50% of all human cancers, the efficacy of CDK inhibitor therapy could differ between cancer cells depending on their p53 status. Moreover, recent reports demonstrating that some cancer cells can proliferate despite CDK2 inhibition questioned the central role of CDK2 in the cell-cycle control and suitability of CDK2 as a therapeutic target; however, the p53 activation that is mediated by CDK inhibitors could be essential for the efficacy of CDK inhibitors in therapy of CDK2-independent cancers. Furthermore, there is also reason to believe that CDK2 inhibitors could be used for another purpose, to protect normal cells from the effects of chemotherapy.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Proliferation; Clinical Trials as Topic; Cyclin-Dependent Kinase Inhibitor Proteins; Cyclin-Dependent Kinases; Drug Evaluation, Preclinical; Flavonoids; Gene Expression Regulation; Humans; Mutation; Neoplasms; Piperidines; Protein Kinase Inhibitors; Purines; Roscovitine; Transcription, Genetic; Tumor Suppressor Protein p53

In clinical trials thus far, single-targeted kinase inhibitors have shown only limited success in demonstrating survival benefits in cancer. This has led to the development of multitargeted kinase inhibitors capable of disrupting various mitogenic pathways in both cancer cells and associated vasculature. Vandetanib is a novel multitargeted kinase inhibitor exhibiting potent activity against vascular endothelial growth factor receptor-2 (VEGFR-2; kinase insert domain-containing receptor [KDR]) and, to a lesser extent, epidermal growth factor receptor (EGFR) and RET kinase. Vascular endothelial growth factor (VEGF) and VEGFR-2 play a pivotal role in regulating angiogenesis and vascular permeability in cancers. In addition to its antiangiogenic effects, vandetanib acts against EGFR, which is overexpressed or mutated in several solid tumors. Furthermore, vandetanib exerts activity against oncogenic RET kinase, the overexpression of which is common in medullary and papillary thyroid carcinomas. Therefore, the multitargeted kinase inhibitor vandetanib represents a new approach, targeting both tumor cells and tumor-associated endothelial cells. Preclinical studies of vandetanib have demonstrated antitumor efficacy against multiple human cancer xenografts in subcutaneous, orthotopic and metastatic models. Phase I clinical trials have demonstrated that vandetanib is well tolerated. Common adverse events included rash, diarrhea and asymptomatic QTc prolongation. Phase II clinical studies in patients with non-small-cell lung cancer have shown promising results, employing vandetanib as both monotherapy and in combination with docetaxel. Phase II studies in other cancers have likewise been initiated. This review summarizes preclinical and clinical studies of vandetanib for the treatment of cancers.

Topics: Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Molecular Structure; Neoplasms; Piperidines; Quinazolines; Receptor Protein-Tyrosine Kinases; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2

Cell proliferation, differentiation, and survival are regulated by a number of extracellular hormones, growth factors, and cytokines in complex organisms. The transduction of the signals by these factors from the outside to the nucleus often requires the presence of small intracellular proteins (i.e. ras and other small G proteins) that are linked to the plasma membrane through a isoprenyl residue that functions as hydrophobic anchor. Isoprenylation is a complex process regulated by different enzymatic steps that could represent potential molecular targets for anti-cancer strategies. In the present paper the different transduction pathways regulated by some isoprenylated proteins such as ras and other small G proteins are described. Moreover, the molecular mechanisms of the isoprenylation process and the mode of action of the different isoprenylation inhibitors are discussed with attention to statins, farnesyltransferase inhibitors (FTI) and aminobisphosphonates. The role of different candidate targets in the determination of anti-tumour effects by FTIs is also described in order to define potential molecular markers predictor of clinical response. On the basis of several preclinical data, new strategies based on multi-step enzyme inhibition or on target prioritization are proposed in order to enhance the anti-tumour activity of agents inhibiting isoprenylation. Finally, a summary of the principal data on clinical trials based on the use of FTIs and statins is given. In conclusion, the inhibition of isoprenylation is an attractive, but still not completely investigated therapeutic alternative that requires optimization for the translation in the current treatment of neoplasms.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Benzodiazepines; Farnesyltranstransferase; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazoles; Mevalonic Acid; Neoplasms; Phosphatidylinositol 3-Kinases; Piperidines; Protein Prenylation; Protein Processing, Post-Translational; Pyridines; Quinolones; ras Proteins

Cell cycle kinases are comprised of cyclin-dependent kinases (Cdks), non-Cdk kinases such as Plk-1 and Aurora and checkpoint proteins such as Chk1 and Chk2. Though ubiquitous to dividing cells, many cell cycle kinases are amplified or over-expressed in malignancy and are potential targets for anti-cancer therapies. Cdk inhibiting drugs (such as flavopiridol, UCN-01, E7070, R-Roscovitine and BMS-387032) have shown preclinical and clinical anticancer activity. However, many of these agents are promiscuous and undiscerning, targeting other non-cell cycle kinases and affecting normal cells, thereby causing significant toxicity. To overcome this, a new generation of Cdk inhibitors are in development with greater target specificity, as well as others that inhibit non-Cdk cell cycle kinases, both directly and indirectly. The outcome of early clinical trials involving these agents is awaited, but these certainly represent a promising new area of anticancer drug development.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Binding Sites; Cyclin-Dependent Kinases; Flavonoids; Humans; Neoplasms; Oxazoles; Piperidines; Protein Kinase Inhibitors; Purines; Roscovitine; Staurosporine; Sulfonamides; Thiazoles

Angiogenesis is crucial for maintaining the supply of oxygen and nutrients required to support solid tumour growth. Inhibitors of tumour blood vessel formation are therefore being sought, in particular, inhibitors of vascular endothelial growth factor-A (VEGF)-signalling, which has a pivotal role in stimulating neovascular growth and survival. ZD6474 is an orally bioavailable inhibitor of VEGF receptor-2 tyrosine kinase activity that in preclinical studies has been shown to inhibit both VEGF-induced signalling in endothelial cells and tumour-induced angiogenesis. Consistent with inhibition of angiogenesis, once-daily oral dosing of ZD6474 produced significant broad-spectrum antitumour activity in a panel of histologically diverse human tumour xenografts. In addition to its antiangiogenic properties, ZD6474 also has activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, which could impart a direct inhibitory effect on tumour cell growth and survival. This may be particularly relevant in tumours with a dependency upon EGFR signalling, for example in certain tumours harbouring activating mutations in EGFR. RET kinase has also been identified as a third target for ZD6474. This review summarises preclinical studies with this unique agent and considers its future direction in cancer treatment.

Topics: Administration, Oral; Biological Availability; Cell Survival; Drug Administration Schedule; ErbB Receptors; Humans; Neoplasms; Neovascularization, Pathologic; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Signal Transduction

Topics: Animals; Antineoplastic Agents; Cyclin-Dependent Kinases; Flavonoids; Humans; Neoplasms; Piperidines

A number of therapeutic agents have been developed which have anti-angiogenic potential. Here we present the most recent data from clinical trials with some of the promising inhibitors of angiogenesis.. Agents that target the vascular endothelial growth factor signaling pathway are the furthest along in clinical development. The last year has brought US Food and Drug Administration approval of bevacizumab (Avastin), a recombinant humanized anti-vascular endothelial growth factor monoclonal antibody. Bevacizumab has demonstrated a survival advantage in combination with chemotherapy for patients with metastatic colorectal cancer. Other agents with early promising results include PTK787/ZK 222584 (Vatalanib), ZD6474, and BAY 43-9006 (Sorafenib).. Angiogenesis inhibitors show promise, but evaluation for optimal efficacy has been a problem, given that the mechanisms of action of these agents differ from conventional cytotoxic agents and surrogate markers for inhibition of angiogenesis are not available.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Bevacizumab; Colorectal Neoplasms; Humans; Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Phthalazines; Piperidines; Pyridines; Quinazolines; Randomized Controlled Trials as Topic; Signal Transduction; Sorafenib; Vascular Endothelial Growth Factor A

Most human malignancies have an aberration in the Rb pathway due to 'cdk hyperactivation'. Several small-molecule cdk modulators are being discovered and tested in the clinic. The first ATP-competitive cdk inhibitors tested in clinical trials, flavopiridol and UCN-01, have shown promising results with evidence of antitumor activity and plasma concentrations sufficient to inhibit cdk-related functions. The best schedule to be administered, combination with standard chemotherapeutic agents, best tumor types to be targeted, and demonstration of cdk modulation from tumor samples from patients in these trials are important issues that need to be answered to advance these agents to the clinical arena.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinases; Flavonoids; Humans; Neoplasms; Piperidines; Protein Kinase Inhibitors; Staurosporine

Eukaryotic organisms depend on an intricate and evolutionary conserved cell cycle to control cell division. The cell cycle is regulated by a number of important protein families which are common targets for mutational inactivation or overexpression in human tumours. The cyclin D and E families and their cyclin-dependent kinase partners initiate the phosphorylation of the retinoblastoma tumour suppressor protein and subsequent transition through the cell cycle. Cyclin/cdk activity and therefore control of cell division is restrained by two families of cyclin dependent kinase inhibitors. A greater understanding of the cell cycle has led to the development of a number of compounds with the potential to restore control of cell division in human cancers. This review will introduce the protein families that regulate the cell cycle, their aberrations in malignant progression and pharmacological strategies targeting this important process.

Topics: Animals; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Enzyme Inhibitors; Flavonoids; Humans; Neoplasms; Piperidines; Staurosporine

Based on presentations on the basic concepts and scientific rationale of anti-angiogenic approaches to cancer therapy and the possible applications in the area of prostate cancer, gastrointestinal cancer, lung cancer and breast cancer it is easy to conclude that development of anti-angiogenic approaches into clinical therapies is extremely challenging. It is now well established that cancer growth is increased by angiogenic factors and that inhibition of angiogenesis decreases growth and metastatic potential. Anti-angiogenic effect can be obtained through interference with multiple targets. Further development of new strategies involving such novel cancer therapies requires wide reaching development of translational research abilities. However, for moving new therapies into the clinic same rigorous criteria need to be applied as is done for traditional therapies. Angiogenesis appear to be a critical factor for development of prostate, gastric, lung and breast cancers. Development of new anti-angiogenic treatment modalities might become very important in these diseases. A critical requirement for the successful clinical development will be the development of imaging techniques that can help evaluate the effect on blood vessel functionality. Such surrogate markers of anti-angiogenic effect will be essential for optimising molecules and doses.

Topics: Angiogenesis Inhibitors; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Cyclooxygenase 2; Female; Humans; Isoenzymes; Lung Neoplasms; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase Inhibitors; Membrane Proteins; Neoplasms; Neovascularization, Pathologic; Piperidines; Prostaglandin-Endoperoxide Synthases; Prostatic Neoplasms; Quinazolines; Research Design; Thalidomide; Vascular Endothelial Growth Factor A

Flavopiridol has potent anti-proliferative properties due to its direct action of binding to the ATP-binding pocket of cyclin-dependent kinases (cdks), and due to its indirect action reducing levels of other cyclins and cdk inhibitors, contributing to its pleiotropic effects. Flavopiridol is a potent apoptotic agent due to its ability to cause cell death in cycling as well as non-cycling tumor cells; to down-regulate important cell survival proteins, such as survivin, through inhibition of the phosphorylation of Thr34; to increase sensitivity for S phase cells to drug treatment by modulating E2F-1 transcription factor activity in tumor cells; to induce both caspase-dependent and -independent mitochondrial cell death pathways; and to inhibit the activation of p-Akt which in turn inhibits activation of NF-kappaB. Flavopiridol possesses several important anti-angiogenic activities including induction of apoptosis of endothelial cells; inhibition of the hypoxic induction of vascular endothelial growth factor and/or its production under hypoxic conditions through inhibition of HIF-1alpha transcription; and decreased secretion of matrix metalloproteinases that is linked with significant inhibition of invasive potential in Matrigel assays. Taken together, the anti-proliferative and anti-angiogenic properties of flavopiridol may contribute to its anti-tumor activities observed in several preclinical animal models of human cancers including prostate, lymphoid, head and neck, colon, and glioma. These promising preclinical observations opened the way for phase I and II clinical trials. Given the low toxicity profile of flavopiridol used as a single agent in patients, combination therapy now offers numerous opportunities in the near future to improve the efficacy of flavopiridol in the treatment of refractory cancers.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Clinical Trials as Topic; Flavonoids; Humans; Neoplasms; Piperidines

Flavopiridol is the first potent inhibitor of cyclin-dependent kinases (cdks) to reach clinical trial. In the majority of solid tumor cell lines and xenografts, flavopiridol induces cell cycle arrest and tumor growth inhibition. This is reflected in clinical outcomes: across multiple Phase II trials there are subsets of patients with prolonged stable disease, although few responses have been observed. Flavopiridol displays sequence-dependent cytotoxic synergy with chemotherapy agents. These effects are most marked when chemotherapy precedes flavopiridol. In the case of DNA-damaging agents that impose S-phase delay, flavopiridol-mediated cdk inhibition disrupts the phosphorylation of E2F-1, leading to inappropriate persistence of its activity, inducing apoptotic pathways. This mechanism has been exploited in a Phase I trial of sequential gemcitabine and flavopiridol that has produced promising results. Flavopiridol is also synergistic with taxanes. Inhibition of cyclin B-cdk1 by flavopiridol accelerates exit from an abnormal mitosis associated with taxane-induced cell death and reduces the phosphorylation of survivin, preventing its stabilization and the cellular protection it affords after taxane exposure. The sequential combination of docetaxel and flavopiridol has been investigated in a Phase I trial in patients with advanced non-small cell lung cancer, and a randomized Phase II study is under way. Initial schedules of flavopiridol used prolonged continuous infusions that produced nanomolar levels of drug thought to be capable of achieving cdk inhibition based on results in tumor cell lines. Recently, it has been discovered that micromolar concentrations are likely to be more effective, and shorter infusions that achieve a higher C(max) have now been adopted. Loading followed by maintenance infusions are also under development, designed to achieve sustained micromolar drug levels. Clinical trials remain complicated by the absence of pharmacodynamic end points to confirm target inhibition.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinases; Drug Administration Schedule; Flavonoids; Humans; Neoplasms; Piperidines; Tumor Cells, Cultured

Ras mutation is observed in 20-30% of human malignancies. Ras proteins belong to the family of G-proteins, which are able to bind and hydrolyze guanosine triphosphate reversibly. They are responsible for signal transduction within cell. Ras undergoes several steps of posttranslational modification, but only farmesylation is necessary for its biologic activity. The crucial enzyme of farnesylation - farnesyltransferase (FT-ase) has become a major target for the development of new anticancer agents--farnesyltransferase inhibitors (FTI). Mutation of Ras results in the abrogation of its normal GTP-ase activity and subsequently it causes a permanent activation of Ras with uncontrolled growth and proliferation of cells. Recently published trials revealed, that FTI are highly effective in several malignant disorders, including myeloid leukemias. FTI are bioavailable after oral administration and have an acceptable toxicity profile. No enhanced myelosuppression effect was noted. It was observed, that FTI may increase cytotoxic effect of some antineoplastic drugs and radiotherapy. It seems that these agents are an interesting and promising therapeutic option for patients, who were resistant to conventional chemotherapy. The benefits of ambulatory drug administration may improve the quality of life in oncological patients. The II phase trials with FTI are under way and we hope, that these agents will find an unquestionable position in treatment of patients with malignancies.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Farnesyltranstransferase; Genes, ras; GTP-Binding Proteins; Guanosine Triphosphate; Humans; Imidazoles; Neoplasms; Piperidines; Point Mutation; Pyridines; Quinolones; Signal Transduction

Farnesyl Protein Transferase as a target for therapeutic intervention is currently under investigation in human clinical trials. Sch-66336 (sarasar), a benzocycloheptapyridyl Farnesyl Transferase Inhibitor (FTI), has been found to be effective in cellular proliferation assays and in in vivo oncology models both as a single agent and in combination with other anti-cancer agents. Clinically, early evidence is being generated that suggests efficacy in humans, particularly in patients with leukemia. Herein, we review the biology of FPT, the discovery of Sch-66336 and other benzocycloheptapyridyl FTIs, and the clinical evaluation of Sch-66336 for the treatment of leukemia and solid tumors.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Binding Sites; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Molecular Structure; Neoplasms; Piperidines; Protein Conformation; Pyridines

Abnormalities in the cell cycle are responsible for the majority of human neoplasias. Most abnormalities occur due to hyperphosphorylation of the tumor suppressor gene Rb by the key regulators of the cell cycle, the cyclin-dependent kinases (CDKs). Thus, a pharmacological CDK inhibitor may be useful in the prevention and/or treatment of human neoplasms. Flavopiridol is a flavonoid with interesting preclinical properties: (1) potent CDK inhibitory activity; (2) it depletes cyclin D1 and vascular endothelial growth factor mRNA by transcriptional and posttranscriptional mechanisms, respectively; (3) it inhibits positive elongation factor B, leading to transcription "halt"; and (4) it induces apoptosis in several preclinical models. The first phase I trial of a CDK inhibitor, flavopiridol, has been completed. Dose-limiting toxicities included secretory diarrhea and proinflammatory syndrome. Antitumor activity was observed in some patients with non-Hodgkin's lymphoma and renal, colon, and prostate cancers. Concentrations between 300 and 500 n M-necessary to inhibit CDK-were achieved safely. Phase II trials with infusional flavopiridol and phase I infusional trials in combination with standard chemotherapy are being completed with encouraging results. A novel phase I trial of 1-h flavopiridol administration was recently completed. The maximum tolerated doses using flavopiridol daily for 5, 3, and 1 consecutive days are 37.5, 50, and 62.5 mg/m(2) per day. Dose-limiting toxicities include vomiting, neutropenia, proinflammatory syndrome, and diarrhea. Plasma flavopiridol concentrations achieved were in the range 1.5-3.5 MICRO M. Phase II/III trials using this 1-h schedule in several tumor types including non-small-cell lung cancer, chronic lymphocytic leukemia, mantle cell lymphoma, and head and neck cancer are being conducted worldwide. UCN-01, the second CDK modulator that has entered clinical trials, has unique preclinical properties: (1) it inhibits protein kinase C (PKC) activity; (2) it promotes cell-cycle arrest by accumulation in p21/p27; (3) it induces apoptosis in several preclinical models; and (4) it abrogates the G(2) checkpoint by inhibition of chk1. The last of these represents a novel strategy to combine UCN-01 with DNA-damaging agents. In the initial UCN-01 clinical trial (continuous infusion for 72 h), a prolonged half-life of about 600 h (100 times longer than in preclinical models) was observed. The maximum tolerated dose was 42.5 mg/m(2) per d

Topics: Alkaloids; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinases; Enzyme Inhibitors; Flavonoids; Humans; Neoplasms; Piperidines; Staurosporine; Tumor Cells, Cultured

Cell-cycle dysregulation is one of the cardinal characteristics of neoplastic cells. For this reason, small molecule inhibitors targeting cyclin-dependent kinases (CDKs), of which flavopiridol is a prototype, have been the focus of extensive interest in cancer therapy. In addition to inhibiting cell-cycle progression, these agents exhibit a variety of other activities, including the induction of cell death. Recently, several novel mechanisms of action have been ascribed to the CDK inhibitor flavopiridol, including interference with transcription, most likely through disruption of P-TEFb (i.e. the CDK9/cyclin T complex), and induction of apoptosis, possibly a consequence of downregulation of various anti-apoptotic proteins. It has also been observed that combining CDK inhibitors with either conventional cytotoxic drugs or novel signal transduction modulators dramatically promotes neoplastic cell death in a variety of preclinical models. Efforts are underway to uncover inhibitors that selectively target specific CDKs and to develop these as a new generation of antitumour drugs. For all of these reasons, it is likely that interest in CDK inhibitors as antineoplastic agents will continue for the foreseeable future.

Topics: Animals; Antineoplastic Agents; Apoptosis; Clinical Trials as Topic; Cyclin-Dependent Kinases; Drug Resistance, Neoplasm; Drug Synergism; Flavonoids; Humans; Neoplasms; Piperidines; Transcription, Genetic

Arzoxifene is a benzothiophene second-generation selective estrogen receptor modulator (SERM) under development by Eli Lilly & Co as a potential treatment for cancer.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drugs, Investigational; Humans; Neoplasms; Piperidines; Technology, Pharmaceutical; Thiophenes

Recent progress in molecular biology and cancer biology has revealed that many molecules, which are heavily involved in the un-limited growth, anti-apoptotic effects and invasion of tumors, would be targets of cancer therapy. Part of the drugs which inhibit these molecules have shown clinical response as well as clinical benefits. In this review article, the summary of mechanism based drug screening for cancer as well as recent status of new molecular target drugs for cancer, are described.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Benzamides; Boronic Acids; Bortezomib; Drug Delivery Systems; Drug Screening Assays, Antitumor; Gefitinib; Heat-Shock Proteins; Humans; Imatinib Mesylate; Indoles; Lactones; Mice; Neoplasms; Phthalazines; Piperazines; Piperidines; Pyrazines; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Sunitinib

ZD-6474, one of a series of inhibitors of vascular endothelial growth factor receptor tyrosine kinase, which also has activity against the epidermal growth factor receptor tyrosine kinase, is under development by AstraZeneca for the potential treatment of solid tumors. Phase II trials in non-small-cell lung cancer, small-cell lung cancer and myeloma were ongoing in January 2003.

Topics: Animals; Clinical Trials as Topic; Drugs, Investigational; Enzyme Inhibitors; Humans; Neoplasms; Piperidines; Quinazolines; Technology, Pharmaceutical

Many tumor types are associated with genetic changes in the retinoblastoma pathway, leading to hyperactivation of cyclin-dependent kinases and incorrect progression through the cell cycle. Small-molecule cyclin-dependent kinase inhibitors are being developed as therapeutic agents. Of these, flavopiridol and UCN-01 are being explored in cancer patients in phase I and phase II clinical trials, both as single agents and in combination with conventional chemotherapeutic agents. The present article discusses the mechanisms of action of flavopiridol and UCN-01 as well as the outcome of clinical trials with these novel agents.

Topics: Alkaloids; Animals; Antineoplastic Agents; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinases; Enzyme Inhibitors; Flavonoids; Humans; Neoplasms; Piperidines; Staurosporine

Protein farnesylation catalysed by the enzyme farnesyl protein transferase involves the addition of a 15-carbon farnesyl group to conserved amino acid residues at the carboxyl terminus of certain proteins. Protein substrates of farnesyl transferase include several G-proteins, which are critical intermediates of cell signalling and cytoskeletal organisation such as Ras, Rho, PxF and lamins A and B. Activated Ras proteins trigger a cascade of phosphorylation events through sequential activation of the PI3 kinase/AKT pathway, which is critical for cell survival, and the Raf/Mek/Erk kinase pathway that has been implicated in cell proliferation. Ras mutations which encode for constitutively activated proteins are found in 30% of human cancers. Because farnesylation of Ras is required for its transforming and proliferative activity, the farnesyl protein transferase inhibitors were designed as anticancer agents to abrogate Ras function. However, current evidence suggests that the anticancer activity of the farnesyl transferase inhibitors may not be simply due to Ras inhibition. This review will discuss available clinical data on three of these agents that are currently undergoing clinical trials.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Benzodiazepines; Cell Division; Clinical Trials as Topic; Combined Modality Therapy; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Humans; Imidazoles; Neoplasms; Piperidines; Pyridines; Quinolones; Tumor Cells, Cultured

The inhibitors of VEGF-mediated signaling continue to wind their way through extensive preclinical and clinical development paths. Whereas the first phase III trial did not meet its endpoints, one hopes that the others will. As we learn more about the VEGF pathways in the laboratory and the clinic, we can interpret with greater certainty what role these drugs or their successors will have in the treatment of human cancers.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Clinical Trials as Topic; Colorectal Neoplasms; Drug Design; Drug Screening Assays, Antitumor; Endothelial Growth Factors; Enzyme Inhibitors; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Lymphokines; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Phthalazines; Piperidines; Pyridines; Pyrroles; Quinazolines; Recombinant Proteins; RNA, Catalytic; Treatment Failure; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors

Based on the frequent aberration in cell cycle regulatory pathways in human cancer by cdk hyperactivation, novel ATP competitive cdk inhibitors are being developed. The first two tested in clinical trials, flavopiridol and UCN-01, showed promising results with evidence of antitumor activity and plasma concentrations sufficient to inhibit cdk-related functions. Best schedule to be administered, combination with standard chemotherapeutic agents, best tumor types to be targeted, and demonstration of cdk modulation from tumor samples from patients in these trials are important questions that need to be answered to advance these agents to the clinic.

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Differentiation; Clinical Trials, Phase I as Topic; Cyclin-Dependent Kinases; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Flavonoids; Humans; Neoplasm Proteins; Neoplasms; Piperidines; Signal Transduction; Staurosporine; Transcription, Genetic

To review preclinical and clinical information on flavopiridol, an inhibitor of cyclin-dependent kinases (CDKs), tested as an antitumor agent.. Primary and review articles were identified by MEDLINE search (1990-June 2001). Abstracts from recent meetings were also used as source materials.. Flavopiridol was reviewed with regard to its mechanisms, preclinical and clinical results, pharmacokinetics, and metabolism.. Flavopiridol is an inhibitor of several CDKs and displays unique anticancer properties. In addition to direct CDK inhibition, flavopiridol also exhibited other features such as inducing apoptosis in many cancer cell lines, decreasing cyclin D1 concentration, and inhibiting angiogenesis. Preclinical xenograft models showed significant antitumor activity for flavopiridol. The regimen using 72-hour continuous infusion every 2 weeks has been most extensively applied in clinical trials, with a 1-hour infusion currently being explored to achieve higher peak concentrations. Several Phase I and II trials have been reported, with some evidence of antitumor activity noted. Further Phase I and II trials using flavopiridol as a single agent and in combination with standard chemotherapeutic regimens and various tumor types are ongoing.. Flavopiridol is the first CDK inhibitor to enter clinical trials. Several Phase I and Phase II clinical trials with different regimens (72-h or 1-h infusion) have been completed. Initial clinical trials have been intriguing, but many questions remain: What is the best regimen (< or =72-h infusion)? Does optimal future development of this drug depend on the combination with other chemotherapy? What is the best combination of flavopiridol with other chemotherapy?

Topics: Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colonic Neoplasms; Cyclin-Dependent Kinases; Diarrhea; Drug Evaluation, Preclinical; Drug Therapy, Combination; Fatigue; Flavonoids; Humans; Infusion Pumps; Kidney Neoplasms; Lymphoma, Non-Hodgkin; Neoplasms; Neutropenia; Piperidines

Modulation of P glycoprotein (Pgp) in clinical oncology has had limited success. Contributing factors have included the limitation in our understanding of the tumours in which Pgp overexpression is mechanistically important in clinical drug resistance; the failure to prove that concentrations of modulators achieved in patients were sufficient to inhibit Pgp; and the inability to conclusively prove that Pgp modulation was occurring in tumours in patients. New approaches are needed to determine the clinical settings in which Pgp overexpression plays a major role in resistance. (Clinical trials with third generation modulators are ongoing, including trials with the compounds LY335979, R101933 and XR9576. Using the Pgp substrate Tc-99m Sestamibi as an imaging agent, increased uptake has been seen in normal liver and kidney after administration of PSC 833, VX710 and XR9576. These studies confirm that the concentrations of modulator achieved in patients are able to increase uptake of a Pgp substrate. Furthermore, CD56+ cells obtained from patients treated with PSC 833 demonstrate enhanced rhodamine retention in an ex vivo assay after administration of the antagonist. Finally, a subset of patients treated with Pgp antagonists show enhanced Sestamibi retention in imaged tumours. These results suggest that Pgp modulators can increase drug accumulation in Pgp-expressing tumours and normal tissues in patients. Using third generation Pgp antagonists and properly designed clinical trials, it should be possible to determine the contribution of modulators to the reversal of clinical drug resistance.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzazepines; Clinical Trials as Topic; Cyclosporins; Dibenzocycloheptenes; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Inhibitors; Fluorescent Dyes; Gene Expression Regulation, Neoplastic; Genes, MDR; Humans; Mice; Mice, Knockout; Neoplasm Proteins; Neoplasms; Piperidines; Pyridines; Quinolines; Radionuclide Imaging; Radiopharmaceuticals; Rhodamines; Technetium Tc 99m Sestamibi; Tissue Distribution; Tumor Cells, Cultured

Vertex is developing biricodar as a chemosensitizing agent designed to restore the effectiveness of chemotherapeutic agents in tumor multidrug resistance. By November 1998, phase II trials had commenced for biricodar, in combination with chemotherapy, for five common cancer indications: breast, ovarian, soft-tissue sarcomas, small cell lung cancer and prostate cancer. Phase II trials were ongoing in January 2002. By March 2000, Vertex was the sole developer of biricodar, as an agreement made in 1996 with BioChem Pharma (now Shire Pharmaceuticals), for the development and marketing of biricodar in Canada was terminated. Biricodar is the free base compound, which also has a citrate salt analog known as VX-710-3. Vertex has published three patents, WO-09615101, WO-09636630 and WO-09736869, disclosing derivatives of biricodar that are claimed for the treatment of multidrug resistant protein and P-glycoprotein-mediated multidrug resistant tumors. In January 2002, a Banc of America analyst report forecast that biricodar had a 30% chance of reaching the market with a launch date in the second half of 2005, with peak sales estimated at $250 million.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Piperidines; Pyridines; Structure-Activity Relationship

Farnesyl protein transferase (FPT) inhibition is an interesting and promising approach to non-cytotoxic anticancer therapy. Research in this area has resulted in several orally active compounds that are currently in clinical evaluation. This review focuses on FPT inhibitors in clinical trials and concentrates on the benzocycloheptapyridine class, with details on the discovery and development of SCH 66336, currently in Phase II clinical trials.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Binding Sites; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Molecular Structure; Neoplasms; Piperidines; Protein Conformation; Pyridines

Farnesyltransferase inhibitors represent a new class of agents that target signal transduction pathways responsible for the proliferation and survival of diverse malignant cell types. Although these agents were developed to prevent a processing step necessary for membrane attachment and maturation of Ras proteins, recent studies suggest that farnesyltransferase inhibitors block the farnesylation of additional cellular polypeptides, thereby exerting antitumor effects independent of the presence of activating ras gene mutations. Clinical trials of two farnesyltransferase inhibitors--the tricyclic SCH66336 and the methylquinolone R115777--as single agents have demonstrated disease stabilization or objective responses in 10 to 15% of patients with refractory malignancies. Combinations of farnesyltransferase inhibitors with cytotoxic chemotherapies are yielding complete and partial responses in patients with advanced solid tumors. A phase I trial of R115777 in refractory and relapsed acute leukemias induced responses in 8 (32%) of 25 patients with acute myelogenous leukemia (including two complete remissions) and in two of three with chronic myelogenous leukemia in blast crisis. In patients with solid tumors, accessible normal tissues such as peripheral blood lymphocytes or, perhaps more germane to epithelial malignancies, buccal mucosa have provided surrogate tissues that allow confirmation that farnesyltransferase is inhibited in vivo at clinically achievable drug doses. In conjunction with the R115777 acute leukemia trial, serial measurements provided evidence of farnesyltransferase enzyme inhibition, interference with farnesyltransferase function ( ie, protein processing), and blockade of signal transduction pathways in leukemic bone marrow cells. Preclinical studies of farnesyltransferase inhibitor resistance and clinical trials of farnesyltransferase inhibitors in combination with other agents currently are in progress.

Topics: Alkyl and Aryl Transferases; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Leukemia; Neoplasms; Piperidines; Pyridines; Quinolones; Signal Transduction

Flavopiridol is a synthetic flavonoid inhibitor of cyclin-dependent kinases, which is under development by Aventis Pharma (formerly Hoechst Marion Roussel) and the National Cancer Institute (NCI) for the potential treatment of cancer and proliferative disorders. By May 2001, the product was in phase IIa trials and had achieved proof-of-concept in phase I/IIa trials as a monotherapy. At this time, Aventis expected a global submission to take place in 2003 [409257]. By July 1999, the compound had entered phase II trials for gastric cancer and leukemia, and phase I/II trials for esophageal tumor and non-small cell lung cancer (NSCLC) [277372], [325929], [331850]. Phase II trials for colon and renal cancer [411684], [411769] and phase I trials for prostate cancer [279466] have also been reported. Analysts Merrill Lynch predicted in September and November 2000 that the product would be launched by 2003, with sales of EUR 50 million in that year, rising to EUR 100 million in 2004 [383742], [391426]. In April 1999, ABN Amro predicted annual sales of DM 100 million in 2002 [328676].

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Flavonoids; Humans; Neoplasms; Piperidines; Structure-Activity Relationship

In the last decade, the discovery and cloning of the cyclin-dependent kinases (cdks), key regulators of cell cycle progression, have led to the identification of novel modulators of cdk activity. Initial experimental results demonstrated that these cdk modulators are able to block cell cycle progression, induce apoptotic cell death, promote differentiation, inhibit angiogenesis, and modulate transcription. Alteration of cdk activity may occur indirectly by affecting upstream pathways that regulate cdk activity or directly by targeting the cdk holoenzyme. Two direct cdk modulators, flavopiridol and UCN-01, are showing promising results in early clinical trials, in which the drugs reach plasma concentrations that can alter cdk activity in vitro. Although modulation of cdk activity is a well-grounded concept and new cdk modulators are being assessed for clinical testing, important scientific questions remain to be addressed. These questions include whether one or more cdks should be inhibited, how cdk inhibitors should be combined with other chemotherapy agents, and which cdk substrates should be used to assess the biologic effects of these drugs in patients. Thus, modulation of cdk activity is an attractive target for cancer chemotherapy, and several agents that modulate cdk activity are in or are approaching entry into clinical trials.

Topics: Alkaloids; Animals; Antineoplastic Agents; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinases; Enzyme Inhibitors; Flavonoids; Humans; Neoplasms; Piperidines; Staurosporine

Four most widely investigated flavonoids, flavopiridol, catechins, genistein and quercetin are reviewed in this article. Flavopiridol is a novel semisynthetic flavone analogue of rohitukine, a leading anticancer compound from an Indian tree. Flavopiridol inhibits most cyclin-dependent kinases and displays unique anticancer properties. It is the first cyclin-dependent kinase inhibitor to be tested in Phase II clinical trials. Catechin and its gallate are major ingredients in green tea and their anti-oxidant and cancer preventive effects have been widely investigated. A Phase I study of green tea extract GTE-TP91 has been conducted in adult patients with solid tumours. Similarly, genistein is a major ingredient in soybean and has been shown to prevent cancer and have antitumour, anti-oxidant and anti-inflammatory effects. Two antibody-genistein conjugates, B43-genistein and EGF-genistein, are currently in clinical development for the treatment of acute lymphoblastic leukaemia and breast cancer, respectively. Finally, most recent updates of quercetin are briefly described.

Topics: Adult; Animals; Antineoplastic Agents; Catechin; Clinical Trials as Topic; Dietary Supplements; Drug Screening Assays, Antitumor; Flavonoids; Genistein; Humans; Neoplasms; Piperidines; Quercetin

Topics: Antineoplastic Agents; Apoptosis; Cell Division; Clinical Trials as Topic; Cyclin-Dependent Kinases; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Flavonoids; Humans; Neoplasms; Piperidines; Structure-Activity Relationship; Tumor Cells, Cultured

This review focuses on the clinical development of the prototype broad spectrum inhibitor of cyclin-dependent kinases (CDKs), flavopiridol, now undergoing Phase II single-agent trials and Phase I combination trials (with paclitaxel and cisplatin). Preclinically, flavopiridol is a potent inhibitor of CDKs 1, 2 and 4 in cell-free assays (IC(50)in the region of 100 nM) and tumour cell growth in vitro (typical IC(50)in the region of 100 nM). The drug showed in vivo antitumour activity (using iv., ip. or oral dosing) against a variety of human tumour xenografts, especially when administered on a regular daily, rather than weekly, schedule and most notably against prostate carcinoma, head and neck cancer, non-Hodgkin's lymphoma and leukaemia. The major toxicities observed in rodents were on the bone marrow and gastrointestinal tract. Pharmacokinetics were linear with dose and with a bi-exponential decline both in rodents and man. Oral bioavailability in rodents is in the region of 20%. Glucuronidation appears to be the major route of metabolism. Single-agent clinical trials have mainly used a 72 h continuous infusion schedule. Dose-limiting toxicities were diarrhoea and hypotension. Plasma concentrations in excess of those required for in vitro enzyme or cell growth inhibition are achievable. While there has been some evidence of single-agent antitumour activity (partial responses in a patient with renal cancer and another with gastric cancer), ongoing combination studies, especially with paclitaxel, where preclinical synergistic antitumour effects are observed, are promising. Doubt as to whether CDKs are the sole target responsible for the drug's antitumour effects have been raised by preclinical observations of apoptosis of non-cycling cells, effects on endothelial cells and non-CDK proteins, such as aldehyde dehydrogenase and glycogen phosphorylase, potent effects on PTEFb and transcription and its ability to directly interact with DNA.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Cyclin-Dependent Kinases; Flavonoids; Humans; Neoplasms; Piperidines

The shortening of the telomeric DNA sequences at the ends of chromosomes is thought to play a critical role in regulating the lifespan of human cells. Since all dividing cells are subject to the loss of telomeric sequences, cells with long proliferative lifespans need mechanisms to maintain telomere integrity. It appears that the activation of the enzyme telomerase is the major mechanism by which these cells maintain their telomeres. The proposal that a critical step in the process of the malignant transformation of cells is the upregulation of expression of telomerase has made this enzyme a potentially useful prognostic and diagnostic marker for cancer, as well as a new target for therapeutic intervention for the treatment of patients with cancer. It is now clear that simply inhibiting telomerase may not result in the anticancer effects that were originally hypothesized. While telomerase may not be the universal target for cancer therapy, we certainly believe that targeting the telomere maintenance mechanisms will be important in future research aimed toward a successful strategy for curing cancer.

Topics: Animals; Anthracenes; Antineoplastic Agents; Drug Delivery Systems; Drug Design; Glycoside Hydrolases; Humans; Neoplasms; Oligonucleotides, Antisense; Perylene; Piperidines; Poly(ADP-ribose) Polymerases; Reverse Transcriptase Inhibitors; RNA; RNA, Long Noncoding; RNA, Untranslated; Tankyrases; Telomerase; Telomere

The discovery and cloning of the cyclin-dependent kinases (cdks), main regulators of cell cycle progression, allowed several investigators to design novel modulators of cdk activity. Flavopiridol (HMR 1275, L86-8275), a flavonoid derived from an indigenous plant from India, demonstrated potent and specific in vitro inhibition of all cdks tested (cdks 1, 2, 4 and 7) with clear block in cell cycle progression at the G1/S and G2/M boundaries. Moreover, preclinical studies demonstrated the capacity of flavopiridol to induce programmed cell death, promote differentiation, inhibit angiogenic processes and modulate transcriptional events. The relationship between the latter effects and cdk inhibition is still unclear. Initial testing in early clinical human trials with infusional flavopiridol showed activity in some patients with non-Hodgkin's lymphoma, renal, prostate, colon and gastric carcinomas. Main side effects were secretory diarrhea and a pro-inflammatory syndrome associated with hypotension. Biologically active plasma concentrations of flavopiridol (approximately 300-500 nM) are easily achievable in patients receiving infusional flavopiridol. Phase 2 trials with infusional flavopiridol in several tumor types, other schedules and combination with standard chemotherapies are being assessed. In conclusion, flavopiridol is the first cdk inhibitor to be tested in clinical trials. Although important questions remain to be answered, this positive experience will stimulate the development of novel cdk modulators for cancer therapy.

Topics: Antineoplastic Agents; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinases; Enzyme Inhibitors; Flavonoids; Humans; Neoplasms; Piperidines

Topics: Benzeneacetamides; Humans; Neoplasms; Peptides; Piperidines; Piperidones

Increases in lipid levels and cancers with tofacitinib prompted a trial of major adverse cardiovascular events (MACE) and cancers in patients with rheumatoid arthritis receiving tofacitinib as compared with a tumor necrosis factor (TNF) inhibitor.. We conducted a randomized, open-label, noninferiority, postauthorization, safety end-point trial involving patients with active rheumatoid arthritis despite methotrexate treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor. Patients were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a TNF inhibitor. The coprimary end points were adjudicated MACE and cancers, excluding nonmelanoma skin cancer. The noninferiority of tofacitinib would be shown if the upper boundary of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor.. A total of 1455 patients received tofacitinib at a dose of 5 mg twice daily, 1456 received tofacitinib at a dose of 10 mg twice daily, and 1451 received a TNF inhibitor. During a median follow-up of 4.0 years, the incidences of MACE and cancer were higher with the combined tofacitinib doses (3.4% [98 patients] and 4.2% [122 patients], respectively) than with a TNF inhibitor (2.5% [37 patients] and 2.9% [42 patients]). The hazard ratios were 1.33 (95% confidence interval [CI], 0.91 to 1.94) for MACE and 1.48 (95% CI, 1.04 to 2.09) for cancers; the noninferiority of tofacitinib was not shown. The incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor. Efficacy was similar in all three groups, with improvements from month 2 that were sustained through trial completion.. In this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk-enriched population, risks of MACE and cancers were higher with tofacitinib and did not meet noninferiority criteria. Several adverse events were more common with tofacitinib. (Funded by Pfizer; ORAL Surveillance ClinicalTrials.gov number, NCT02092467.).

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Cardiovascular Diseases; Female; Heart Disease Risk Factors; Humans; Incidence; Janus Kinase Inhibitors; Male; Middle Aged; Neoplasms; Piperidines; Pyrimidines

Doublet combination therapies targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unknown if rational triplet combinations will be well tolerated and associated with improved antitumor activity. The objective of this trial was to determine the recommended phase 2 doses (RP2Ds) and to assess the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor dostarlimab in combination with (1) the poly(ADP-ribose) polymerase inhibitor niraparib with or without vascular endothelial growth factor inhibitor bevacizumab or (2) carboplatin-paclitaxel chemotherapy with or without bevacizumab, in patients with advanced cancer.. IOLite is a multicenter, open-label, multi-arm clinical trial. Patients with advanced solid tumors were enrolled. Patients received dostarlimab in combination with niraparib with or without bevacizumab or in combination with carboplatin-paclitaxel with or without bevacizumab until disease progression, unacceptable toxicity, or withdrawal from the study. Prespecified endpoints in all parts were to evaluate the dose-limiting toxicities (DLTs), RP2Ds, pharmacokinetics (PKs), and preliminary efficacy for each combination.. A total of 55 patients were enrolled; patients received dostarlimab and: (1) niraparib in part A (n=22); (2) carboplatin-paclitaxel in part B (n=14); (3) niraparib plus bevacizumab in part C (n=13); (4) carboplatin-paclitaxel plus bevacizumab in part D (n=6). The RP2Ds of all combinations were determined. All combinations were safe and tolerable, with no new safety signals observed. DLTs were reported in 2, 1, 2, and 0 patients, in parts A-D, respectively. Preliminary antitumor activity was observed, with confirmed Response Evaluation Criteria in Solid Tumors v1.1 complete/partial responses reported in 4 of 22 patients (18.2%), 6 of 14 patients (42.9%), 4 of 13 patients (30.8%), and 3 of 6 (50.0%) patients, in parts A-D, respectively. Disease control rates were 40.9%, 57.1%, 84.6%, and 83.3%, in parts A-D, respectively. Dostarlimab PK was unaffected by any combinations tested. Coadministration of bevacizumab showed no impact on niraparib PKs. The overall mean PD-1 receptor occupancy was 99.0%.. Dostarlimab was well tolerated in both doublet and triplet regimens tested, with promising antitumor activity observed with all combinations. We observed higher disease control rates in the triplet regimens than in doublet regimens.. NCT03307785.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Humans; Indazoles; Neoplasms; Paclitaxel; Piperidines; Vascular Endothelial Growth Factor A

Results of the ORAL Surveillance safety trial have indicated that there is an increased risk for the development of malignancies with tofacitinib therapy when compared to treatment with tumor necrosis factor inhibitors (TNFi). This study was undertaken to further examine this safety concern in rheumatoid arthritis (RA) patients in a real-world setting.. Using US insurance claims data from Optum Clinformatics (2012-2020), IBM MarketScan Research Databases (2012-2018), and Medicare (parts A, B, and D, 2012-2017), we created 2 cohorts of RA patients who had initiated treatment with tofacitinib or TNFi. The first cohort, designated the real-world evidence (RWE) cohort, included RA patients from routine care. For the second cohort, designated the randomized controlled trial (RCT)-duplicate cohort, we emulated the inclusion and exclusion criteria that were applied in the ORAL Surveillance trial of tofacitinib, which allowed us to assess the comparability of our results with the results of that trial. Cox proportional hazards models with propensity score fine-stratification weighting were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the risk of any malignancy (excluding nonmelanoma skin cancer). Database-specific estimates were meta-analyzed using fixed-effects models with inverse-variance weighting.. The RWE cohort consisted of 83,295 patients, including 10,504 patients (12.6%) who received treatment with tofacitinib. The pooled weighted HR for the primary outcome of any malignancy associated with tofacitinib treatment compared to any malignancy associated with TNFi therapy was 1.01 (95% CI 0.83, 1.22) in the RWE cohort and 1.17 (95% CI 0.85, 1.62) in the RCT-duplicate cohort (compared to the ORAL Surveillance trial HR of 1.48 [95% CI 1.04, 2.09]).. We did not find evidence of an increased risk of malignancy development with tofacitinib therapy, in comparison with TNFi therapy, in RA patients treated in a real-world setting. However, our results cannot rule out the possibility of an increase in risk that may accrue with a longer duration of treatment with tofacitinib.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Neoplasms; Piperidines; Pyrimidines; Tumor Necrosis Factor Inhibitors

The MAPK pathway is an emerging target across a number of adult and pediatric tumors. Targeting the downstream effector of MAPK, MEK1, is a proposed strategy to control the growth of MAPK-dependent tumors.. iMATRIX-cobi assessed the safety, pharmacokinetics, and anti-tumor activity of cobimetinib, a highly selective MEK inhibitor, in children and young adults with relapsed/refractory solid tumors.. This multicenter Phase I/II study enrolled patients aged 6 months to < 30 years with solid tumors with known/expected MAPK pathway involvement. Patients received cobimetinib tablet or suspension formulation on Days 1-21 of a 28-day cycle. Dose escalation followed a rolling 6 design. The primary endpoint was safety; secondary endpoints were pharmacokinetics and anti-tumor activity.. The safety profile of cobimetinib in pediatrics was similar to that reported in adults. Clinical activity was observed in LGG patients with known/suspected MAPK pathway activation. Cobimetinib combination regimens may be required to improve response rates in this pediatric population.. ClinicalTrials.gov NCT02639546, registered December 24, 2015.

Topics: Adolescent; Adult; Azetidines; Child; Child, Preschool; Enzyme Inhibitors; Glioma; Humans; Maximum Tolerated Dose; Neoplasm Recurrence, Local; Neoplasms; Pediatrics; Piperidines; Tablets; Young Adult

This Phase Ib study explored combination dosing of the allosteric MEK1/2 inhibitor cobimetinib and the ATP-competitive pan-AKT inhibitor ipatasertib.. Patients with advanced solid tumors were enrolled to two dose escalation arms, each using a 3 + 3 design in 28-day cycles. In Arm A, patients received concurrent cobimetinib and ipatasertib on days 1-21. In Arm B, cobimetinib was administered intermittently with ipatasertib for 21 days. Primary objectives evaluated dose-limiting toxicities (DLTs), maximum tolerated doses (MTD), and the recommended Phase II dose (RP2D). Secondary objectives included analysis of pharmacokinetic parameters, MAPK and PI3K pathway alterations, changes in tissue biomarkers, and preliminary anti-tumor efficacy. Expansion cohorts included patients with PTEN-deficient triple-negative breast cancer and endometrial cancer.. Among 66 patients who received ≥1 dose of study drug, all experienced an adverse event (AE). Although no DLTs were reported, 6 patients experienced Cycle 1 DLT-equivalent AEs. The most common treatment-related AEs were diarrhea, nausea, vomiting, dermatitis acneiform, and fatigue. Thirty-five (53%) patients experienced drug-related AEs of ≥ grade 3 severity. Cobimetinb/ipatasertib MTDs were 60/200 mg on Arm A and 150/300 mg on Arm B; the latter was chosen as the RP2D. No pharmacokinetic interactions were identified. Biomarker analyses indicated pathway blockade and increases in IFNγ and PD-L1 gene expression following the combination. Three patients with endometrial or ovarian cancer achieved partial response, all with PTEN-low disease and two with tumor also harboring KRAS mutation.. There was limited tolerability and efficacy for this MEK and AKT inhibitor combination. Nonetheless, pharmacodynamic analyses indicated target engagement and suggest rationale for further exploration of cobimetinib or ipatasertib in combination with other anticancer agents. ClinicalTrials.gov identifier: NCT01562275.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mitogen-Activated Protein Kinases; Neoplasms; Phosphatidylinositol 3-Kinases; Piperazines; Piperidines; Pyrimidines

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Background Aurora A kinase (AurA) overexpression likely contributes to tumorigenesis and therefore represents an attractive target for cancer therapeutics. This phase 1 study aimed to determine the safety, pharmacokinetics, and antitumor activity of LY3295668 erbumine, an AurA inhibitor, in patients with locally advanced or metastatic solid tumors. Methods Patients with locally advanced or metastatic solid tumors, Eastern Cooperative Oncology Group performance status 0-1, and disease progression after one to four prior treatment regimens were enrolled. Primary objective was to determine maximum tolerated dose (MTD); secondary objectives included evaluation of the tolerability and safety profile and pharmacokinetics of LY3295668. All patients received twice-daily (BID) oral LY3295668 in 21-day cycles in an ascending-dose schedule. Results Twelve patients were enrolled in phase 1 (25 mg, n = 8; 50 mg, n = 2; 75 mg, n = 2) and one patient was enrolled after. Overall, four patients experienced dose-limiting toxicities (DLTs) within the first cycle (75 mg: Grade 3 diarrhea [one patient], Grade 4 mucositis and Grade 3 corneal deposits [one patient]; 50 mg: mucositis and diarrhea [both Grade 3, one patient]; 25 mg: Grade 3 mucositis [one patient]). Patients exhibiting DLTs had the highest model-predicted exposures at steady state. Mucositis was the most common adverse event (67%), followed by diarrhea, fatigue, alopecia, anorexia, constipation, and nausea. Nine patients had best response of stable disease; the disease control rate was 69%. Conclusions MTD of LY3295668 was 25 mg BID. LY3295668 had a manageable toxicity profile and demonstrated activity in some patients with locally advanced or metastatic solid tumors.Trial registration ClinicalTrials.gov, NCT03092934. Registered March 22, 2017. https://clinicaltrials.gov/ct2/show/NCT03092934 .

Topics: Adult; Aged; Aurora Kinase A; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Treatment Outcome

Niraparib is the only poly (adenosine diphosphate-ribose)-polymerase (PARP) inhibitor available as oral monotherapy for maintenance, regardless of BRCA mutational status.. This phase I, open-label, non-randomized, dose-escalation study was conducted in Japan using a 3 + 3 design. Adults (≥20 years) with metastatic or locally advanced solid tumours were enrolled. Niraparib 200 mg (cohort 1) or 300 mg (cohort 2) was administered once daily in 21-day cycles (no drug holiday between cycles) until progressive disease (PD) or unacceptable toxicity. The primary objective was to evaluate the safety and tolerability of niraparib in Japanese patients with advanced solid tumours. The number of patients with dose-limiting toxicities in cycle 1 and number with treatment-emergent adverse events were primary endpoints. Secondary endpoints were pharmacokinetics and tumour response.. There were three patients in cohort 1 and six patients in cohort 2. Only one patient, in cohort 2, developed a dose-limiting toxicity (grade 4 platelet count decreased). All patients in both cohorts developed treatment-emergent adverse events. The most common treatment-related treatment-emergent adverse events were decreased appetite (n = 2) in cohort 1, and platelet count decreased as well as aspartate aminotransferase increased (both n = 5) in cohort 2. Mean Cmax and AUC0-24 of niraparib increased dose-proportionally after multiple doses (accumulation ratio of between 1.64 and 3.65); median tmax was 3-4 h. Two patients, both in cohort 2, had a partial response to treatment.. Niraparib (200 or 300 mg/day) was tolerable and had a favourable pharmacokinetic profile in Japanese patients with advanced solid tumours.

Topics: Adult; Aged; Cohort Studies; Female; Humans; Indazoles; Japan; Male; Middle Aged; Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of VAN + EV in patients with advanced solid cancers and the effect of combination therapy on cancer cell proliferation and intracellular pathways.. Patients with refractory solid tumors were enrolled in a phase I dose-escalation trial testing VAN (100-300 mg orally daily) + EV (2.5-10 mg orally daily). Objective responses were evaluated using RECIST v1.1. RET mutant cancer cell lines were used in cell-based studies.. Among 80 patients enrolled, 72 (90%) patients were evaluable: 7 achieved partial response (PR) (10%) and 37 had stable disease (SD) (51%; duration range: 1-27 cycles). Clinical benefit (SD or PR ≥ 6 months) was observed in 26 evaluable patients [36%, 95% confidence intervals (CI) (25% to 49%)]. In 80 patients, median overall survival (OS) was 10.5 months [95% CI (8.5-16.1)] and median progression-free survival (PFS) 4.1 months [95% CI (3.4-7.3)]. Six patients (7.5%) experienced DLTs and 20 (25%) required dose modifications. VAN + EV was safe, with fatigue, rash, diarrhea, and mucositis being the most common toxicities. In cell-based studies, combination therapy was superior to monotherapy at inhibiting cancer cell proliferation and intracellular signaling.. The MTDs and RP2Ds of VAN + EV are 300 mg and 10 mg, respectively. VAN + EV combination is safe and active in refractory solid tumors. Further investigation is warranted in RET pathway aberrant tumors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Everolimus; Humans; Neoplasms; Piperidines; Proto-Oncogene Mas; Quinazolines; Vascular Endothelial Growth Factor A

TAS0728 is an oral covalent binding inhibitor of human epidermal growth factor receptor 2 (HER2). A first-in-human open-label, dose-escalation, phase I study (NCT03410927) was initiated to investigate the safety and dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of TAS0728 in adults with advanced solid tumors with HER2 or HER3 overexpression, amplification or mutation. In total, 19 patients received TAS0728 at escalating doses from 50 to 200 mg BID for 21-day cycles. Following escalation of the dose to 200 mg BID, a total of two DLTs were observed, both cases of Grade 3 diarrhea (lasting >48 h and not responsive to aggressive antidiarrheal treatment). Following de-escalation of the dose to 150 mg BID, another DLT of Grade 3 diarrhea was observed in one patient. Additionally, at 150 mg BID, one patient had a fatal cardiac arrest after receiving 1 cycle (21 days) of TAS0728. The etiology of the cardiac arrest event was not clear, however causal relationship to TAS0728 could not be excluded due to the temporal association observed. Partial responses were observed in 2 of 14 patients evaluable for TAS0728 treatment response. The study was stopped due to unacceptable toxicity during the dose-escalation as the overall risk-benefit ratio no longer favored the dose level being tested, therefore the MTD was not determined. ClinicalTrials.gov registration number: https://clinicaltrials.gov/ct2/show/NCT03410927 ; registered on January 25, 2018.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Purines; Receptor, ErbB-2; Receptor, ErbB-3

Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).. Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.. One hundred and forty-nine patients received tepotinib (R1:. Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily.

Topics: Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Nausea; Neoplasms; Patient Safety; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridazines; Pyrimidines; Tissue Distribution; Treatment Outcome; Vomiting; Young Adult

To evaluate the efficacy of orvepitant (10 or 30 mg given once daily, orally for 4 weeks), a neurokinin-1 receptor antagonist, compared with placebo in reducing the intensity of epidermal growth factor receptor inhibitor (EGFRI)-induced intense pruritus.. Randomised, double-blind, placebo-controlled clinical trial.. 15 hospitals in Italy and five hospitals in the UK.. 44 patients aged ≥18 years receiving an EGFRI for a histologically confirmed malignant solid tumour and experiencing moderate or intense pruritus after EGFRI treatment.. 30 or 10 mg orvepitant or placebo tablets once daily for 4 weeks (randomised 1:1:1).. The primary endpoint was change from baseline in mean patient-recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary outcome measures were NRS score, verbal rating scale score, Skindex-16 and Leeds Sleep Evaluation Questionnaire at each study visit (baseline, weeks 1, 4, 8); rescue medication use; EGFRI dose reduction; and study withdrawal because of intense uncontrolled pruritus.. The trial was terminated early because of recruitment challenges; only 44 of the planned 90 patients were randomised. All patients were analysed for efficacy and safety. Mean NRS score change from baseline to week 4 was -2.78 (SD: 2.64) points in the 30 mg group, -3.04 (SD: 3.06) points in the 10 mg group and -3.21 (SD: 1.77) points in the placebo group; the difference between orvepitant and placebo was not statistically significant. No safety signal was detected. Adverse events related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of mild or moderate severity.. Orvepitant was safe and well tolerated. No difference in NRS score between the orvepitant and placebo groups was observed at the week 4 primary endpoint. A number of explanations for this outcome are possible.. EudraCT2013-002763-25.

Topics: Adult; Aged; Aged, 80 and over; Antidepressive Agents; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Double-Blind Method; Early Termination of Clinical Trials; Female; Humans; Italy; Male; Middle Aged; Neoplasms; Neurokinin-1 Receptor Antagonists; Piperidines; Pruritus; Severity of Illness Index; United Kingdom

Despite strong preclinical rationale, combined cobimetinib-mediated MEK inhibition and GDC-0994-mediated ERK inhibition was not tolerable on two 28-day dosing schedules in which GDC-0994 was given for 21 days continuously and cobimetinib administered over 21 days either continuously or intermittently. Adverse events were as expected for mitogen-activated protein kinase pathway inhibition, but overlapping and cumulative toxicities could not be managed on either dosing schedule. Pharmacokinetic parameters of cobimetinib and GDC-0994 given in combination were similar to those previously observed in monotherapy studies, so that there was no evidence of drug-drug interaction. Cycle 1 metabolic responses were observed by 18F-fluorodeoxyglucose-positron emission tomography but were not predictive of outcome measured by RECIST 1.1.. Simultaneous targeting of multiple nodes in the mitogen-activated protein kinase (MAPK) pathway offers the prospect of enhanced activity in RAS-RAF-mutant tumors. This phase Ib trial evaluated the combination of cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) in patients with locally advanced or metastatic solid tumors.. Cobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Arm A consisted of concurrent cobimetinib and GDC-0994 once daily for 21 days of a 28-day cycle; Arm B consisted of intermittent dosing of cobimetinib on a 28-day cycle concurrent with GDC-0994 daily for 21 days of a 28-day cycle.. In total, 24 patients were enrolled. For Arm A, owing to cumulative grade 1-2 toxicity, the dose of cobimetinib was decreased. For Arm B, dose increases of GDC-0994 and cobimetinib were intolerable with grade 3 dose-limiting toxicities of myocardial infarction and rash. Pharmacokinetic data did not show evidence of a drug-drug interaction. Overall, seven patients had a best overall response of stable disease (SD) and one patient with pancreatic adenocarcinoma had an unconfirmed partial response.. The safety profile of MEK and ERK inhibition demonstrated classic MAPK inhibitor-related adverse events (AEs). However, overlapping AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination.

Topics: Adenocarcinoma; Azetidines; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Pancreatic Neoplasms; Piperidines; Protein Kinase Inhibitors

Tepotinib (MSC2156119J) is an oral, potent and highly selective small molecule mesenchymal-epithelial transition factor (MET) inhibitor for which the recommended Phase II dose of 500 mg once daily has been defined, based on the first-in-man trial conducted in the USA and Europe. We carried out a multicenter Phase I trial with a classic `3 + 3' design to determine the recommended Phase II dose in Japanese patients with solid tumors (NCT01832506).. Patients aged ≥20 years with advanced solid tumors (refractory to standard therapy or for whom no effective standard therapy was available) received tepotinib at 215, 300 or 500 mg once daily in a 21-day cycle. Occurrence of dose-limiting toxicities during cycle 1 was used to determine the maximum tolerated dose. Efficacy, safety and pharmacokinetics were also evaluated to support the dose assessment.. Twelve patients were treated. Tepotinib was generally well tolerated with no observed dose-limiting toxicities; treatment-related adverse events were mainly grades 1-2. The tolerability profile of tepotinib was similar to that observed in non-Japanese populations. Pharmacokinetics in Japanese and Western patients was comparable. One patient with gastric cancer and one patient with urachal cancer had stable disease of ≥12 weeks in duration. The observed safety profile and pharmacokinetics are comparable with those in patients from the USA and Europe, and the recommended Phase II dose of tepotinib in Japanese patients was confirmed as 500 mg once daily.. These results, including initial signals of antitumor activity, support further development of tepotinib in Japanese patients with cancer.

Topics: Aged; Antineoplastic Agents; Asian People; Biomarkers, Tumor; Female; Humans; Japan; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridazines; Pyrimidines

Purpose We investigated the combination of the MEK inhibitor, cobimetinib, and the pan-PI3K inhibitor, pictilisib, in an open-label, phase Ib study. Experimental Design Patients with advanced solid tumors were enrolled in 3 dose escalation schedules: (1) both agents once-daily for 21-days-on 7-days-off ("21/7"); (2) intermittent cobimetinib and 21/7 pictilisib ("intermittent"); or (3) both agents once-daily for 7-days-on 7-days-off ("7/7"). Starting doses for the 21/7, intermittent, and 7/7 schedules were 20/80, 100/130, and 40/130 mg of cobimetinib/pictilisib, respectively. Nine indication-specific expansion cohorts interrogated the recommended phase II dose and schedule. Results Of 178 enrollees (dose escalation: n = 98), 177 patients were dosed. The maximum tolerated doses for cobimetinib/pictilisib (mg) were 40/100, 125/180, and not reached, for the 21/7, intermittent, and 7/7 schedules, respectively. Six dose-limiting toxicities included grade 3 (G3) elevated lipase, G4 elevated creatine phosphokinase, and G3 events including fatigue concurrent with a serious adverse event (SAE) of diarrhea, decreased appetite, and SAEs of hypersensitivity and dehydration. Common drug-related adverse events included nausea, fatigue, vomiting, decreased appetite, dysgeusia, rash, and stomatitis. Pharmacokinetic parameters of the drugs used in combination were unaltered compared to monotherapy exposures. Confirmed partial responses were observed in patients with BRAF-mutant melanoma (n = 1) and KRAS-mutant endometrioid adenocarcinoma (n = 1). Eighteen patients remained on study ≥6 months. Biomarker data established successful blockade of MAP kinase (MAPK) and PI3K pathways. The metabolic response rate documented by FDG-PET was similar to that observed with cobimetinib monotherapy. Conclusions Cobimetinib and pictilisib combination therapy in patients with solid tumors had limited tolerability and efficacy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Class I Phosphatidylinositol 3-Kinases; Female; GTP Phosphohydrolases; Humans; Indazoles; Male; Membrane Proteins; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Sulfonamides; Treatment Outcome; Young Adult

Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors.. This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival.. Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ≥1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n = 84), melanoma (n = 22), non-small-cell lung cancer (NSCLC; n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases.. Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study.. NCT01988896 (the investigators in the NCT01988896 study are listed in the supplementary Appendix, available at Annals of Oncology online).

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Piperidines; Prognosis; Survival Rate; Tissue Distribution; Young Adult

Final data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA).. Eligible patients had previously completed a phase 1, 2, or 3 qualifying index study of tofacitinib and received open-label tofacitinib 5 mg or 10 mg BID. Stable background therapy, including csDMARDs, was continued; adjustments to tofacitinib or background therapy were permitted at investigators' discretion. Assignment to dose groups (5 mg or 10 mg BID) was based on patients' average total daily dose. The primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy.. Between February 5, 2007, and November 30, 2016, 4481 patients were enrolled. Total tofacitinib exposure was 16,291 patient-years. Safety data are reported up to month 114 for all tofacitinib; efficacy data are reported up to month 96 for tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points). Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies. The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8. For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality. Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained.. Tofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions.. NCT00413699 , funded by Pfizer Inc (date of trial registration: December 20, 2006).

Topics: Administration, Oral; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Herpes Zoster; Humans; Male; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Time Factors; Treatment Outcome

Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers.. In this sequential, open-label, phase 1 trial (NCT02048488), patients received doses of 30 mg, escalated to 480 mg every 24 hours (Q24h), followed by an expansion cohort of patients with ALK-positive cancers. The primary objective was to evaluate safety and tolerability. Secondary objectives included pharmacokinetics.. TSR-011 320- and 480-mg Q24h doses exceeded the maximum tolerated dose. At the RP2D of 40 mg every 8 hours (Q8h), the most common grade 3-4 treatment-emergent adverse events occurred in 3.2-6.5% of patients. Of 14 ALK inhibitor-naive patients with ALK-positive NSCLC, 6 experienced partial responses and 8 had stable disease.. At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued.. NCT02048488.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Benzamides; Benzimidazoles; Electrocardiography; Female; Humans; Lymphoma; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors

Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors.. This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab.. The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%).. The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; B7-H1 Antigen; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neoplasms; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed.. In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000 mg/m2 (arm 2a) or 500 mg/m2 (arm 2b), followed by GDC-0575 (45 or 80 mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts.. Of 102 patients treated, 70% were female, the median age was 59 years (range 27-85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and half-life was ∼23 hours. No pharmacokinetic drug-drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2.. GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine.. NCT01564251.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Checkpoint Kinase 1; Deoxycytidine; Dose-Response Relationship, Drug; Drug Interactions; Fatigue; Female; Gemcitabine; Half-Life; Humans; Male; Maximum Tolerated Dose; Middle Aged; Nausea; Neoplasms; Neutropenia; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrroles; Thrombocytopenia; Treatment Outcome

This open-label, single-dose study was designed to characterize pharmacokinetics and safety profile of ibrutinib in hepatically impaired subjects. Each subject received single oral dose of ibrutinib (140 mg) following an overnight fast (hepatic impairment-mild [n = 6], moderate [n = 10], and severe [n = 8]; healthy control [n = 6]). Subjects with hepatic impairment showed significant increase in ibrutinib plasma exposures and fraction unbound ibrutinib. Compared to control group, mean exposure (AUC

Topics: Adenine; Adult; Aged; Area Under Curve; Biomarkers; Drug Monitoring; Female; Humans; Incidence; Liver Diseases; Liver Function Tests; Male; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Severity of Illness Index

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60-125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Azetidines; Class I Phosphatidylinositol 3-Kinases; Female; Genes, ras; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasms; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Treatment Outcome

AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks.. Patients with advanced refractory solid tumours or non-Hodgkin's lymphoma were enroled. Dose escalation occurred in a 3+3 manner based on toxicity assessment. Pharmacokinetic samples were collected after first AT7519 infusion, whereas pharmacodynamics (PD) samples were obtained in selected patients.. Thirty-four patients were enroled, and 32 received study treatments over 4 dose levels. Dose-limiting toxicities included mucositis, febrile neutropenia, rash, fatigue and hypokalemia. The recommended phase II dose (RP2D) was 27.0 mg m(-2). Ten of 19 patients evaluable for efficacy had stable disease as the best response (median duration: 3.3 months; range: 2.5 to 11.1 months). There was no clinically significant QTc prolongation. There was an apparent dose proportional increase in AT7519 exposure. The PD studies showed reduction in markers of CDK activity in selected patients' skin biopsies post treatment.. AT7519, when administered as an intravenous infusion on days 1, 4, 8 and 11, was well tolerated. The RP2D is 27.0 mg m(-2). At this dose level, plasma AT7519 concentrations were above the biologically active concentrations, and preliminary anti-cancer activity was observed in patients. This dosing schedule is being further evaluated in multiple phase II studies.

Topics: Adult; Aged; Cyclin-Dependent Kinases; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles

A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy.. Patients received fixed doses of P (200 mg/m(2)) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4-19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D).. The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia (n = 5), diarrhea (n = 4), pulmonary embolism (n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia (n = 2). BMS-690514-related AEs included diarrhea (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), and anorexia (30 %). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease.. The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types.

Topics: Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Paclitaxel; Piperidines; Pyrroles; Treatment Outcome; Triazines

BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514.. In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD.. In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (≥4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways.. This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Diarrhea; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Exanthema; Female; Humans; Lung Neoplasms; Male; Metabolic Clearance Rate; Middle Aged; Neoplasm Metastasis; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrroles; Quinazolines; Receptor, ErbB-2; Treatment Outcome; Triazines; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-3

Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib.. In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502.. Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8-46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19-64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7-93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer.. A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer.. Merck Sharp and Dohme.

Topics: Adult; Aged; BRCA1 Protein; BRCA2 Protein; Cohort Studies; Female; Follow-Up Studies; Heterozygote; Humans; Indazoles; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasms; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Prostatic Neoplasms; Tissue Distribution

Based on the promising activity and tolerability of flavopiridol administered with a pharmacokinetically-derived dosing schedule in chronic lymphocytic leukemia (CLL), we conducted a phase I study using this schedule in patients with advanced solid tumors.. Flavopiridol was given IV as a 30-min loading dose followed by a 4-hr infusion weekly for 4 weeks repeated every 6 weeks. Dose-escalation was in cohorts of three patients using the standard 3+3 phase I study design. Blood samples were obtained for pharmacokinetic and pharmacodynamic studies.. Thirty-four eligible patients with advanced solid tumors received a total of 208 doses (median 7, range 1-24). Total doses ranged from 40 to 105 mg/m(2). The primary dose limiting toxicity was cytokine release syndrome (CKRS). No antitumor responses were observed. The mean peak plasma concentration across all doses was 1.65 ± 0.86 μM. Area under the concentration-versus-time curve ([Formula: see text]) ranged from 4.31 to 32.2 μM[Symbol: see text]hr with an overall mean of 13.6 ± 7.0 μM[Symbol: see text]hr. Plasma flavopiridol concentrations and AUC increased proportionally with dose. There was no correlation between cytokine levels and clinical outcomes.. The maximum-tolerated dose of flavopiridol is 20 mg/m(2) bolus followed by 20 mg/m(2) infusion over 4 h given weekly for 4 weeks on a 6-week cycle in patients with advanced solid tumors. Flavopiridol PK was notably different, and there was a higher frequency of CKRS, despite prophylactic steroids, seen in this patient group compared to previous studies with CLL using a similar dosing schedule.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Cytokines; Female; Flavonoids; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Ohio; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

The kinesin spindle protein (KSP) is essential for separation of spindle poles during mitosis. Its inhibition results in mitotic arrest. This phase I trial examined safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic parameters, and anti-tumor activity of MK-0731, a potent inhibitor of KSP.. In part 1, patients with advanced solid tumors received MK-0731 intravenously over 24 h every 21 days starting at 6 mg/m(2), escalating until MTD was reached. In part 2, patients with taxane-resistant tumors received the MTD. Plasma samples were collected to analyze the pharmacokinetics of MK-0731. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0.. In part 1, 21 patients (median age 63 years) were treated with MK-0731 at doses ranging from 6 to 48 mg/m(2)/24 h for median four cycles. The dose-limiting toxicity was neutropenia and the MTD was 17 mg/m(2)/24 h. At the MTD, AUC (±SD) was 10.5 (±7.3) μM × hour, clearance (±SD) was 153 mL/min (±84), and t(1/2) was 5.9 h. In part 2, 22 patients received the MTD and there were no DLTs. Although there were no objective tumor responses, four patients (with cervical, non-small cell lung, and ovarian cancers) had prolonged stable disease.. MK-0731 at the MTD of 17 mg/m(2)/day every 21 days in patients with solid tumors had few grade 3 and 4 toxicities with the major DLTs at higher doses being myelosuppression. Anti-tumor efficacy was suggested by the length of stable disease in selected patients with taxane-resistant tumors.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Female; Humans; Infusions, Intravenous; Kinesins; Leukocyte Count; Male; Middle Aged; Neoplasms; Piperidines; Pyrroles; Young Adult

E7974, a synthetic analog of hemiasterlin, interacts with the tubulin molecule and overcomes resistance to other antitubulin drugs (taxanes and vinca alkaloids).. In a phase 1 study, E7974 was given intravenously over a 2- to 5-minute infusion on day 1 of every 21-day cycle. Adult patients with advanced refractory solid tumors who had adequate organ function and Eastern Cooperative Oncology Group performance status 0 to 2 were eligible for this study. A modified Fibonacci schema was used. The maximal tolerated dose (MTD) was the dose where <2 of 6 patients developed a dose-limiting toxicity (DLT).. Twenty-eight patients (19 men and 9 women; median age, 64 years) treated at different cohort dose levels (0.18 mg/m(2) , 0.27 mg/m(2) , 0.36 mg/m(2) , 0.45 mg/m(2) , and 0.56 mg/m(2) ) received a total of 66 courses of E7974. The MTD was established at 0.45 mg/m(2) , where 1 of 6 patients experienced DLT (grade 4 febrile neutropenia). Of the 17 refractory colon cancer patients with a median of 3 prior treatments, stable disease was seen in 7 patients (41%). There were no tumor responses. Median progression-free survival was 1.2 months, and median overall survival was 6.7 months. In pharmacokinetic analysis, E7974 was characterized by a fast and moderately large distribution (37.95-147.93 L), slow clearance (2.23-7.15 L/h), and moderate to slow elimination (time to half-life, 10.4-30.5 hours).. This study shows that E7974 once every 21-day cycle shows antitumor activity in patients with refractory solid tumors. The recommended phase 2 dose is 0.45 mg/m(2).

Topics: Adult; Aged; Aged, 80 and over; Antimitotic Agents; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Oligopeptides; Piperidines; Treatment Outcome

BMS-690514 is a novel oral tyrosine kinase inhibitor of ErbB and vascular endothelial growth factor receptor. This open-label phase I dose-escalation study (ClinicalTrials.gov Identifier: NCT00516451) aimed to assess the safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics of BMS-690514 in Japanese patients with advanced or metastatic solid tumors.. Patients with advanced or metastatic solid tumors received oral BMS-690514 once daily continuously until disease progression or intolerable toxicity occurred. Dose-limiting toxicity (DLT) was evaluated from the first dose to Day 29. Dose levels at 100 and 200 mg were investigated. Assessments included adverse events, tumor response, pharmacokinetics, pharmacodynamics, 2 [18F] fluoro-2-deoxyglucose positron-emitting tomography, and epidermal growth factor receptor and K-ras mutations.. BMS-690514 at the dose of 100 mg (n = 3) or 200 mg (n = 3) was administered once daily to totally nine patients and was well tolerated up to 200 mg. No treatment-related serious adverse events or DLTs were reported. Frequently observed treatment-related AEs were acne, diarrhea, dry skin, hypertension, stomatitis, blood fibrinogen increased, hemoglobin decreased, pruritus, and hypoalbuminemia. These were generally reported as Grade 1 and 2. Five of 9 patients (56 %) had stable disease. Plasma concentrations of BMS-690514 reached Cmax within 3 h and declined with an effective half-life of approximately 10 and 12 h at 100 and 200 mg, respectively.. Oral BMS-690514 was well tolerated in Japanese patients with advanced or metastatic solid tumors up to 200 mg.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Piperidines; Positron-Emission Tomography; Pyrroles; Triazines

Vorinostat (V) at levels >2.5 µM enhances chemotherapy in vitro. Yet the approved oral dose of 400 mg inconsistently achieves this level in patients. We developed an intermittent oral pulse-dose schedule of V to increase serum levels. We combined V with the cyclin dependent kinase inhibitor flavopiridol (F) which increases V-induced apoptosis.. One week before combination treatment, V alone was given daily for 3d (cycle -1). Then V was given on d1-3 and d8-10, and F on d2 and d9, every 21-d. Due to neutropenia, this was modified to V on d1-3 and d15-17, and F on d2 and d16, every 28-d. Bolus and split-dose F schedules were studied.. 34 patients were treated. On the 21-d schedule, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m(2) bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m(2) over 30 min and 30 mg/m(2) over 4 h. V C(max) at the 800 mg dose was 4.8 µM (± 2.8). V C(max) ≥ 2.5 µM was achieved in 86% of patients at the MTD. F increased the C(max) of V by 27% (95% CI 11%-43%). F C(max) of ≥ 2 µM was achieved in 90% of patients. 8 patients had stable disease for on average 5.5 m (range 1.6-13.2 m).. Intermittent high dose oral V in combination with F is feasible and achieves target serum levels >2.5 µM. V concentrations higher than previously reported with oral dosing were achieved.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Dose-Response Relationship, Drug; Female; Flavonoids; Humans; Hydroxamic Acids; Male; Middle Aged; Neoplasms; Piperidines; Vorinostat

The neurokinin-1 receptor antagonist, casopitant, is a weak-to-moderate inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A) and has the potential to inhibit the metabolism of CYP3A substrates such as docetaxel.. Fourteen cancer patients were enrolled in this phase 1, open-label, randomized, two-period crossover study. Intravenous (i.v.) docetaxel was coadministered with oral ondansetron and dexamethasone with (Regimen B) or without (Regimen A) 150 mg single-dose oral casopitant.. The geometric least-squares mean Regimen B: Regimen A ratios (90% confidence interval) for docetaxel maximum plasma concentration and area under the concentration-time curve from time 0 extrapolated to infinity were 0.97 (0.83, 1.12) and 1.06 (0.94, 1.19), respectively. Coadministration of casopitant and docetaxel was well tolerated, with adverse event profiles and absolute neutrophil count nadirs similar for both treatments.. C(max) and AUC of docetaxel were similar when given as monotherapy or when given in combination with casopitant. Likewise, absolute neutrophil count nadirs were similar for docetaxel alone or docetaxel with casopitant.

Topics: Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dexamethasone; Docetaxel; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Least-Squares Analysis; Leukocyte Count; Male; Middle Aged; Neoplasms; Neurokinin-1 Receptor Antagonists; Neutrophils; Ondansetron; Piperazines; Piperidines; Taxoids

This phase I study was performed to determine the safety profile, maximum tolerated dose (MTD) and biological activity of lonafarnib (SCH 66336). Single-dose and multi-dose pharmacokinetics were conducted.. Twenty-one patients with advanced solid tumors were enrolled. Each patient received single-dose administration on day 1, cycle 1 then switched to a twice daily (BID) dosing regimen on days 2-14 of a 28-day cycle; subsequent cycles continued BID dosing on days 1-14. Dose-limiting toxicity (DLT) was assessed during the cycle one; toxicity evaluation was closely monitored throughout the treatment. Radiographic scans were completed to assess tumor response. Blood and urine pharmacokinetics were evaluated on days 1 and 14 in cycle 1. SCH 66336- induced farnesylation inhibition was assessed via conversion of prelamin A to lamin in buccal mucosa.. DLT and most common adverse events were diarrhea, fatigue, nausea and anorexia. No grade 3 or 4 hematological toxicities were observed. Nineteen of 21 patients were evaluable for response; short-term stable disease was observed in 5 patients. SCH 66336 systemic exposure increased with dose; however, drug accumulation was higher than projected. Renal excretion of parent drug was negligible. Farnesyl transferase inhibition was detected at the 200 and 300 mg BID doses.. The MTD and recommended phase II dose is 200 mg BID on days 1-14 of a 28-day dosing regimen. The plasma concentration profile suggests the pharmacokinetics of SCH 66336 is dose and time dependent. Farnesyl transferase target inhibition was observed at doses of lonafarnib recommended for further study.

Topics: Adult; Aged; Alkyl and Aryl Transferases; Antineoplastic Agents; Area Under Curve; Enzyme Inhibitors; Female; Humans; Lamin Type A; Male; Maximum Tolerated Dose; Middle Aged; Mouth Mucosa; Neoplasms; Nuclear Proteins; Piperidines; Protein Precursors; Pyridines; Treatment Outcome

Inhibition of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways may result in synergistic antitumour activity. We designed a phase I study to evaluate the combination of vandetanib, an investigational agent with activity against EGF receptor and VEGF receptor 2, and bevacizumab, a monoclonal antibody against VEGF.. Patients with advanced solid tumours and lymphomas were enrolled. Objectives were to determine the safety and maximum tolerated dose of the combination, characterise pharmacokinetics, measure angiogenic marker changes in blood, and assess tumour blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Vandetanib was given orally once daily and bevacizumab intravenously once in every 3 weeks in 21-day cycles utilising a standard dose-escalation design.. Fifteen patients were enrolled, and a total of 94 cycles of therapy were administered. No protocol-defined dose-limiting toxicities were observed; due to toxicities associated with chronic dosing, hypertension, proteinuria, diarrhoea and anorexia, dose escalation was stopped at the second dose level. We observed one partial response and one minor response; 9 patients experienced stable disease. There were significant changes in plasma VEGF and placental-derived growth factor levels, and decreases in K(trans) and k(ep) were observed by DCE-MRI.. In this trial, we safely combined two targeted agents that cause dual blockade of the VEGF pathway, demonstrated preliminary evidence of clinical activity, and conducted correlative studies demonstrating anti-angiogenic effect. The recommended phase II dose was established as vandetanib 200 mg daily and bevacizumab 7.5 mg/kg every 3 weeks.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Biomarkers, Tumor; Contrast Media; Epidermal Growth Factor; Female; Humans; Lymphoma; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasms; Piperidines; Quinazolines; Signal Transduction; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD).. AT7519 was administered in a '3 + 3' dose- escalation scheme on 5 consecutive days every 3 weeks to patients with advanced, refractory solid tumors. Samples to monitor AT7519 PK and PD were obtained.. Twenty-eight patients were treated at seven dose levels (1.8-40 mg/m(2)/day). At 40 mg/m(2)/day, one patient developed hypotension and ST segment elevation. At 34 mg/m(2)/day, dose-limiting toxic effects (DLTs) were QTc prolongation with one death (grade 5), fatigue (grade 4) and mucositis (grade 3). Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. Four patients exhibited stable disease for >6 months and one had a prolonged partial response. PK profile revealed modest interpatient variation with linear exposure at increasing doses. Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity at a dose of 28 mg/m(2).. AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cyclin-Dependent Kinases; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles

Lonafarnib (LNF) is a protein farnesyl transferase (FTase) inhibitor that has shown synergistic activity with taxanes in preclinical models and early stage clinical trials. Preclinical findings suggested tubulin acetylation and FTase expression levels may be important determinants of drug sensitivity that would help identify patient populations more likely to benefit from this regimen. This pilot study evaluated the biological effects of LNF and docetaxel (DTX) combination therapy in refractory solid tumors by comparing pretreatment and post-treatment tumor biopsies.. Patients with histologically confirmed locally advanced or metastatic solid malignancies refractory to standard therapies or with no effective therapies available were eligible. Patients were randomized to 1 of 4 dosing cohorts: 1) 30 mg/m², 100 mg; 2) 36 mg/m², 100 mg; 3) 30 mg/m², 150 mg; or 4) 36 mg/m², 150 mg of DTX intravenously weekly, LNF orally twice daily, respectively.. Of the 38 patients enrolled, 36 were treated, and 29 were evaluable for toxicity and response assessment. The combination of LNF and DTX was tolerated in all cohorts with the exception of a 28% incidence of grade 3/4 diarrhea, which was manageable with aggressive antidiarrheal regimens. Seven patients derived clinically meaningful benefit from this combination treatment; these patients had significantly lower basal FTase-beta mRNA expression levels than the mean study population level (P < .05). Correlation of clinical benefit with tubulin acetylation content as well as basal acetyl-tubulin content were evaluated. However, no significant correlation was found.. Despite the small number of patients, these findings support our preclinical mechanistic studies and warrant further clinical investigations using FTase-beta mRNA expression as a potential predictive biomarker to select for an enriched patient population to study the effects of taxane and FTase inhibitor combination therapies.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Enzyme Inhibitors; Farnesyltranstransferase; Female; Humans; Male; Middle Aged; Neoplasms; Pilot Projects; Piperidines; Pyridines; Taxoids

Vandetanib (ZD6474) is an orally available inhibitor of 3 signaling pathways important in tumor progression: vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinase activity. Current development of vandetanib is focused on the treatment of non-small-cell lung cancer and other tumor types, including thyroid cancer. This study was conducted as a requirement for regulatory submission for vandetanib in China.. To determine the pharmacokinetics of vandetanib in Chinese patients with advanced, solid, malignant tumors and to compare these with data obtained in Japanese and Western populations.. Phase I consisted of a nonrandomized, open-label, single-center study conducted in Guangzhou, China. Adult patients (12 per treatment) who had tumors refractory to standard treatments or for whom no appropriate therapies existed received oral vandetanib (100 mg every other day, 100 mg once daily, or 300 mg once daily) until disease progression or discontinuation in the study. The initial cohort was dosed at 100 mg every other day. Once at least 3 patients had received this dose of vandetanib for 28 days without experiencing dose-limiting toxicity, a second cohort at 100 mg once daily was started. Following the same criteria, the third cohort received 300 mg once daily. Pharmacokinetics, tolerability, and tumor response were assessed. The pharmacokinetics of vandetanib in Chinese, Western, and Japanese patients were compared through a combined population pharmacokinetic model. Tolerability was assessed by recording adverse events and monitoring physical examination, body weight, performance status, vital signs, urinalysis, biochemistry, hematology, and 12-lead electrocardiogram.. Thirty-six patients were enrolled (age range 21-82 years, 56% male, body mass index range 17.6-33.0 kg/m(2)). Thirty-three of 36 patients (92%) were World Health Organization performance status 0-1. Vandetanib pharmacokinetics were linear over the dose range studied with AUC(ss) for the 300 mg once daily group (38611 ng/h/mL) being 3.6-fold higher than that for the 100 mg once daily group (10826 ng/h/mL). Absorption was relatively slow following a single 100- or 300-mg dose, with T(max) ranging from 2 to 10 hours. Interpatient variability in C(max SS) and AUC(SS) was relatively high, with the coefficient of variation ranging from 29.1% to 40.6%. Vandetanib plasma clearance was slow (7.8-9.2 L/h) and was independent of dose. The most common drug-related adverse events were rash (42%) and diarrhea (39%). No QT(C) prolongation was observed. Hypertension was reported as an adverse event in 3 patients. There were no clinically relevant changes in hematology, urinalysis, or World Health Organization performance status. Elevation of alanine aminotransferase was reported as an adverse event in 1 patient. One patient with medullary thyroid cancer showed a partial tumor response. Population pharmacokinetic analysis suggests that vandetanib pharmacokinetics appear to be comparable in Chinese, Western, and Japanese patients.. The pharmacokinetic properties of vandetanib in these Chinese patients were characterized by low plasma clearance of approximately 8 L/h, a long half-life of approximately 8 to 10 days, and an accumulation of approximately 8-fold to 15-fold on multiple dosing. In these Chinese patients, the pharmacokinetic profile of vandetanib appeared to be comparable with that observed in Japanese and Western populations. Oral doses up to 300 mg once daily appeared to be well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; China; Cohort Studies; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Piperidines; Quinazolines; Young Adult

We conducted a phase I study to assess safety, pharmacokinetics, pharmacodynamics, and activity of lonafarnib plus gemcitabine. Subjects received oral lonafarnib twice daily and gemcitabine on days 1, 8, and 15 every 28 days; multiple dose levels were explored. Lonafarnib had no apparent effect on gemcitabine PK. Mean lonafarnib half-life ranged from 4 to 7 hr; median T(max) values ranged from 4 to 8 hr. Two patients had partial response; seven patients had stable disease at least 6 months. Oral lonafarnib at 150 mg a.m./100 mg p.m. plus gemcitabine at 1,000 mg/m(2) is the maximum tolerated dose with acceptable safety and tolerability.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Piperidines; Pyridines

Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials.. A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy.. Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials.. Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low.

Topics: Acrylamides; Aged; Clinical Trials, Phase I as Topic; Cyanides; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Guanidines; Humans; Male; Meta-Analysis as Topic; Middle Aged; NAD; Nausea; Neoplasms; Nicotinamide Phosphoribosyltransferase; Piperidines; Thrombocytopenia; Treatment Outcome; Vomiting

The control of chemotherapy-induced nausea and vomiting (CINV) is critical in preventing poor health outcomes and increasing patient quality of life. The objective of this study was to evaluate the impact of the addition of casopitant to dual-combination therapy of dexamethasone and ondansetron on quality of life in patients receiving highly emetogenic chemotherapy (HEC).. In a multicenter, double-blind, randomized, placebo-controlled, add-on trial (N = 810), patients were randomized to intravenous (IV) ondansetron/dexamethasone alone (control) or in combination with either a single 150-mg oral dose of casopitant or 3-day IV/oral casopitant. Quality of life was assessed as impact of nausea and vomiting on daily life using the Functional Living Index Emesis (FLIE) questionnaire. Patients completed the FLIE questionnaire at baseline prior to receiving chemotherapy and after completion of the first cycle of HEC.. Patients in the single oral dose and 3-day IV/oral casopitant groups scored higher mean total FLIE scores (115.7 and 114.0, respectively; p ≤ 0.0332) than patients in the control group (107.5), indicating that casopitant patients experienced less impact from nausea and vomiting on daily life. The overall absolute difference in the proportion of patients reporting CINV with no impact on daily life between the single oral casopitant group and the control group was 13%; the difference between the 3-day IV/oral casopitant group and the control group was 14%.. The addition of casopitant to ondansetron and dexamethasone in patients receiving HEC was significantly more effective in reducing the impact of nausea and vomiting on all daily life activities as assessed by the FLIE compared with ondansetron/dexamethasone dual therapy.

Topics: Activities of Daily Living; Administration, Oral; Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Nausea; Neoplasms; Ondansetron; Piperazines; Piperidines; Quality of Life; Surveys and Questionnaires; Vomiting; Young Adult

The cyclin-dependent kinase inhibitor flavopiridol increases irinotecan- and fluorouracil-induced apoptosis. We conducted a phase I trial of FOLFIRI + flavopiridol in patients with advanced solid tumors.. FOLFIRI + flavopiridol were administered every 2 weeks. Based on sequence-dependent inhibition, flavopiridol was given 3 h after irinotecan but before 5-FU. Two maximum tolerated doses were determined, one with flavopiridol administered over 1 h, and one with flavopiridol split as a 30-min bolus followed by a 4-h infusion.. A total of 74 patients were enrolled and 63 were evaluable. The MTD with FOLFIRI was flavopiridol 80 mg/m(2) over 1 h or 35 mg/m(2) bolus + 35 mg/m(2) over 4 h. Dose-limiting toxicities were diarrhea, fatigue, neutropenia, and neuropathy. Clinical activity included 2 partial responses in small bowel cancer and bladder cancer and 1 complete response in mucosal melanoma. Stable disease was seen in 22 patients. Pharmacokinetic studies showed increasing C(max) with increasing flavopiridol dose. Clinical benefit was correlated with the presence of wild-type p53. Of 25 patients with colorectal cancer, 11 had as best response SD for >3 m (median 6 m, range 4.2-15.4 m), despite failing ≥1 irinotecan-containing regimen.. Treatment with flavopiridol and FOLFIRI is a safe and effective regimen. Concentrations of flavopiridol that enhance the effects of FOLFIRI can be achieved. Clinical activity is encouraging and includes prolonged stable disease in patients with irinotecan-refractory colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Flavonoids; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

Chemotherapy-induced nausea and vomiting (CINV) remains a clinical management problem after treatment with highly emetogenic chemotherapy (HEC). We therefore designed and carried out a multicentre, randomised, double-blind, placebo-controlled trial to assess whether a three-drug antiemetic regimen of ondansetron, dexamethasone, and the neurokinin-1-receptor antagonist casopitant mesylate was able to prevent acute and delayed CINV events in patients naive to chemotherapy with a malignant solid tumour who were scheduled to receive cisplatin-based HEC regimens.. The study was done between Nov 6, 2006, and Oct 9, 2007, in 77 participating centres in 22 countries. All 810 patients enrolled in the trial received dexamethasone and ondansetron. Patients were randomly assigned to also receive placebo (n=269), single oral dose of casopitant mesylate (150 mg oral, n=271), or 3-day intravenous plus oral casopitant mesylate (90 mg intravenous on day 1 plus 50 mg oral on days 2 and 3, n=270). Randomisation was done using a central telephone system at the study level, because some centres were expected to recruit only a few patients during the study period. The primary endpoint was the proportion of patients achieving complete response (no vomiting, retching, or use of rescue medications) in the first 120 h after receiving HEC. Efficacy analysis was done on the modified intention-to-treat population (n=800), which included all patients who received placebo or study drug and HEC (n=265 control, n=266 single-dose oral casopitant mesylate, n=269 3-day intravenous and oral casopitant mesylate). Safety was reported in 802 patients who received either placebo or study medication. This study is registered with ClinicalTrials.gov, NCT00431236.. Significantly more patients in each casopitant group achieved complete response in cycle 1 of HEC treatment than did those in the control group (175 [66%] patients in the control group, 228 [86%] in the single-dose oral casopitant mesylate group [p<0.0001 vs control], and 214 [80%] in the 3-day intravenous plus oral casopitant mesylate group (p=0.0004 vs control]). This improvement was sustained over multiple cycles of HEC. Adverse events occurred in 205 (77%) patients in the single-dose oral casopitant mesylate group and 203 (75%) patients in the 3-day intravenous and oral casopitant mesylate group compared with 194 (73%) of patients in the control group. The most common serious adverse events were neutropenia (n=5 [3%] in the control group, n=3 [1%] in the single-dose oral casopitant mesylate group, and n=11 [4%] in the 3-day intravenous plus oral casopitant mesylate group), febrile neutropenia (n=1 [<1%] in the control group, n=4 [1%] in the single-dose oral casopitant mesylate group, and n=6 [2%] in the 3-day intravenous plus oral casopitant mesylate group), and dehydration (n=4 [2%] in the control group, n=2 [<1%] in the single-dose oral casopitant mesylate group, and n=1 [<1%] in the 3-day intravenous plus oral casopitant mesylate group).. A three-drug regimen including a single oral dose or 3-day intravenous plus oral regimen of casopitant mesylate plus dexamethasone and ondansetron significantly reduced CINV events in patients receiving HEC compared with a two-drug regimen of dexamethasone and ondansetron.. GlaxoSmithKline.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Cisplatin; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Infusion Pumps; Male; Middle Aged; Molecular Structure; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Vomiting; Young Adult

Casopitant mesylate is a novel, oral neurokinin-1 receptor antagonist with demonstrated antiemetic efficacy. We conducted a randomized, double-blind, controlled phase II trial to evaluate three casopitant doses as part of a triple-therapy regimen for the prevention of nausea and vomiting associated with high-dose cisplatin. The aim of the study was to detect a dose response.. A total of 493 patients with solid tumors receiving a first cycle of cisplatin > or =70 mg/m(2) were randomly assigned among six treatment arms. The primary analysis compared a control arm [ondansetron/dexamethasone (Ond/Dex)] with three investigational treatments (Ond/Dex plus oral casopitant 50, 100, or 150 mg administered daily for 3 days). Two exploratory arms were included: one evaluating a single oral casopitant dose of 150 mg added to standard Ond/Dex and another with 3-day oral aprepitant-based therapy (Ond/Dex plus aprepitant 125 mg day 1, 80 mg days 2-3).. The complete response (CR) rate (defined as no vomiting, retching, rescue therapy, or premature discontinuation) was significantly increased in each casopitant arm relative to control over the 120-h evaluation period: 76% (50 mg), 86% (100 mg), 77% (150 mg), and 60% with control (P = 0.0036). The CR rate for the single oral dose regimen was similar to the CR rate reported for the 3-day regimens. No differences were observed in the incidence of nausea or significant nausea among groups in the primary analysis. The most common adverse events related to treatment included headache (n = 10) and hiccups (n = 14).. All doses of oral casopitant as a 3-day regimen (and likely as a 150-mg single oral dose) in combination with Ond/Dex provided significant improvement in the prevention of cisplatin-induced emesis.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Cisplatin; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Ondansetron; Piperazines; Piperidines; Receptors, Neurokinin-1; Vomiting

This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596.. Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups.. Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased gamma-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months).. CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzimidazoles; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptors, Platelet-Derived Growth Factor; Young Adult

The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic chemotherapy (MEC).. Predominantly female patients (98%) diagnosed with breast cancer (96%) who were chemotherapy-naïve and scheduled to receive an anthracycline and cyclophosphamide (AC) -based regimen were enrolled onto this multinational, randomized, double-blind, parallel-group, placebo-controlled clinical trial. All patients received dexamethasone 8 mg intravenously (IV) on day 1 and oral ondansetron 8 mg twice daily on days 1 to 3. Patients were randomly assigned to a control arm (placebo), a single oral dose casopitant arm (150 mg orally [PO] on day 1), a 3-day oral casopitant arm (150 mg PO on day 1 plus 50 mg PO on days 2 to 3), or a 3-day IV/oral casopitant arm (90 mg IV on day 1 plus 50 mg PO on days 2 to 3). The primary end point was the proportion of patients achieving complete response (no vomiting/retching or rescue medications) in the first 120 hours after the initiation of MEC.. A significantly greater proportion of patients in the single-dose oral casopitant arm, 3-day oral casopitant arm, and 3-day IV/oral casopitant arm achieved complete response (73%, 73%, and 74%, respectively) versus control (59%; P < .0001). The study did not demonstrate a reduced proportion of patients with nausea or significant nausea in those receiving casopitant. Adverse events were balanced among study arms.. All casopitant regimens studied were more effective than the control regimen. Casopitant was generally well tolerated.

Topics: Administration, Oral; Alopecia; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Constipation; Cyclophosphamide; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Headache; Humans; Injections, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Neutropenia; Ondansetron; Piperazines; Piperidines; Treatment Outcome; Vomiting

Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner.. We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and oxaliplatin) for advanced solid tumors. Flavopiridol was administered every 2 weeks with oxaliplatin before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated.. Forty-eight patients were treated on study. With dose escalation of oxaliplatin (85 mg/m(2)) and 5FU (2,400 mg/m(2)), dose-limiting toxicities included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. Dose-limiting toxicities with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose was 70 mg/m(2) flavopiridol, 85 mg/m(2) oxaliplatin, and 1,800 mg/m(2) 5FU continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors: 3 of 9 (33%) evaluable patients showed a partial response on imaging and 7 of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the maximum tolerated dose, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for nonresponders.. Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory germ cell tumor population has prompted a phase II trial that is currently open for accrual.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cyclin-Dependent Kinases; Female; Flavonoids; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Piperidines; Tumor Suppressor Protein p53

FK866 is a potent inhibitor or NAD synthesis. This first-in-human study was performed to determine the maximum-tolerated dose, toxicity profile, and pharmacokinetics on a 96-h continuous infusion schedule.. Twenty four patients with advanced solid tumor malignancies refractory to standard therapies were treated with escalating doses of FK866 as a continuous, 96-h infusion given every 28 days. Serial plasma samples were collected to characterize the pharmacokinetics of FK866. Further blood samples were collected for the measurement of plasma VEGF levels.. There were 12 women and 12 men with a median age of 61 (range 34-78) and a median KPS of 80%, received a 4-day of infusion of FK866 at dose levels of 0.018 mg/m2/h (n=3), 0.036 mg/m2/h (n=3), 0.072 mg/m2/h (n=3), 0.108 mg/m2/h (n=4), 0.126 mg/m2/h (n=6), and 0.144 mg/m2/h (n=5). Thrombocytopenia was the dose limiting toxicity, observed in two patients at the highest dose level and one patient at the recommended phase II dose of 0.126 mg/m2/h No other hematologic toxicities were noted other than mild lymphopenia and anemia. There was mild fatigue and grade 3 nausea; the latter was controlled with antiemetics and was not a DLT. Css (the mean of the 72 and 96 h plasma concentrations) increased in relation to the dose escalation. The study drug did not significantly affect plasma concentrations of VEGF. There were no objective responses, although four patients had stable disease (on treatment for 3 months or greater).. The recommended phase II dose is 0.126 mg/m2/h given as a continuous 96-h infusion every 28 days. The dose limiting toxicity of FK866 is thrombocytopenia. Pharmacokinetic data suggest an increase in the plasma Css in relation to the escalation of FK866.

Topics: Acrylamides; Adult; Aged; Area Under Curve; Dose-Response Relationship, Drug; Fatigue; Female; Half-Life; Humans; Infusions, Intravenous; Male; Middle Aged; NAD; Nausea; Neoplasms; Neutropenia; Nicotinamide Phosphoribosyltransferase; Piperidines; Thrombocytopenia; Vascular Endothelial Growth Factor A; Vomiting

To establish the maximum tolerated dose of the farnesyltransferase inhibitor lonafarnib (Sarasar, Schering-Plough Corp., Kenilworth, NJ) in combination with weekly paclitaxel in patients with solid tumors. Tolerability, pharmacokinetics, safety, and dose-limiting toxicity were characterized.. Patients were enrolled from January 2000 to May 2001. Lonafarnib was administered continuously orally twice daily at doses of 100, 125, and 150 mg in combination with paclitaxel at doses of 40, 60, or 80 mg/m(2) i.v. over 1 h weekly in 28-day cycles in a phase I design. Plasma samples for determinations of lonafarnib and paclitaxel concentrations were collected at selected time points.. Twenty-seven patients were enrolled. The maximum tolerated dose (the dose level below where dose-limiting toxicity occurred and the recommended phase II dose) was lonafarnib 125 mg/m(2) twice daily and paclitaxel 80 mg/m(2) weekly. Dose-limiting toxicity was neutropenia with or without fever, which occurred in two of three patients treated at the lonafarnib 150 mg twice daily dose level. Diarrhea was a common side effect of lonafarnib but usually was mild to moderate in severity and could be controlled with standard medication without lonafarnib dose adjustment. Other reported adverse events included nausea, vomiting, fatigue, and taste changes. These adverse events were neither more frequent nor more severe than would be expected with paclitaxel alone. There were no apparent pharmacokinetic interactions between weekly paclitaxel and continuous twice-daily lonafarnib.. The recommended dose of lonafarnib for phase II trials is 125 mg orally twice daily when combined with weekly paclitaxel 80 mg/m(2). The dose-limiting toxicity was neutropenia.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Clinical Trials as Topic; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesyltranstransferase; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Paclitaxel; Piperidines; Pyridines; Time Factors

To evaluate the effectiveness of donepezil compared with placebo in cancer patients with fatigue as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F).. Patients with fatigue score >or= 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) for more than 1 week were included. Patients were randomly assigned to receive donepezil 5 mg or placebo orally every morning for 7 days. A research nurse contacted the patients by telephone daily to assess toxicity and fatigue level. All patients were offered open-label donepezil during the second week. FACIT-F and/or the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 11, and 15. The FACIT-F fatigue subscale score on day 8 was considered the primary end point.. Of 142 patients randomly assigned to treatment, 47 patients in the donepezil group and 56 in the placebo group were assessable for final analysis. Fatigue intensity improved significantly on day 8 in both donepezil and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .57) or ESAS (P = .18) between groups. In the open-label phase, fatigue intensity continued to be low as compared with baseline. No significant toxicities were observed.. Donepezil was not significantly superior to placebo in the treatment of cancer-related fatigue.

Topics: Aged; Disease Progression; Donepezil; Double-Blind Method; Fatigue; Female; Humans; Indans; Male; Middle Aged; Neoplasms; Nootropic Agents; Piperidines; Placebos; Telemedicine; Time Factors; Treatment Outcome

Flavopiridol is a cyclin-dependent kinase inhibitor that enhances docetaxel-induced apoptosis in a sequence-specific manner. In vivo, docetaxel must precede flavopiridol by at least 4 h to induce this effect. We conducted a phase I trial of weekly, sequential docetaxel followed 4 h later by flavopiridol in patients with advanced solid tumors.. Docetaxel at a fixed dose of 35 mg/m2 was administered over 30 min, followed 4 h later by escalating doses of flavopiridol, ranging from 20 to 80 mg/m2 in successive cohorts, administered weekly over 1 h. This schedule was repeated for 3 weeks of each 4-week cycle.. Twenty-seven evaluable patients were enrolled. The combination was well tolerated, with one dose-limiting toxicity occurring at flavopiridol 70 mg/m2 (grade 3 mucositis) and one dose-limiting toxicity at 80 mg/m2 (grade 4 neutropenia). We observed 1 complete response in a patient with pancreatic carcinoma and 4 partial responses in pancreatic (1), breast (2), and ovarian (1) cancer patients. Stable disease was seen in 10 patients. Pharmacokinetic studies showed Cmax ranging from 1.49 +/- 0.69 micromol/L (flavopiridol 20 mg/m2) to 4.54 +/- 0.08 micromol/L (flavopiridol 60 mg/m2) in cycle 1.. Treatment with weekly, sequential docetaxel followed by flavopiridol is an effective and safe regimen at all flavopiridol dose levels. The pharmacokinetic data indicate that concentrations of flavopiridol that enhance the effects of docetaxel both in vitro and in vivo can be achieved. Clinical activity is encouraging, even in patients who have received a prior taxane and in patients with gemcitabine-refractory metastatic pancreatic cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Synergism; Female; Flavonoids; Gemcitabine; Humans; Male; Middle Aged; Neoplasms; Piperidines; Taxoids; Treatment Outcome

The objective was to determine whether food affects the pharmacokinetics and safety of lonafanib, an orally bioavailable farnesyl transferase inhibitor that is under clinical evaluation for the treatment of various hematologic malignancies and solid tumors.. Two Phase 1 studies were conducted in separate patient populations. A single-dose study was performed in 12 healthy subjects who received lonafarnib 100 mg under fasted and fed conditions. Additionally, a multiple-dose study was performed in 19 patients with advanced cancer who received lonafarnib 200 mg Q 12 H for 28 days under fasted and fed conditions. Nine of the 19 patients completed both treatment cycles and were used for pharmacokinetic assessment. A 2-week washout period separated treatments in each study. Single-dose pharmacokinetics were assessed at various time points up to 48 hours postdose and multiple-dose pharmacokinetics were assessed at Day 15 for 24 hours postdose.. The pharmacokinetics of lonafarnib were affected by food during single-dose but not multiple-dose administration. Relative oral bioavailabilities (fed vs. fasted) based on log-transformed maximum plasma concentration (C(max)) and area under the concentration-time curve (AUC) were 48% and 77%, respectively, following single-dose administration, and 87% and 96%, respectively, following multiple-dose administration. Intrasubject variability in the pharmacokinetic parameters was less pronounced after multiple dosing (17%) than that after single dosing (33%) of lonafarnib. Intersubject variability was unaffected by food in either study. In the single-dose study, 7 of the 12 subjects (58%) reported treatment emergent adverse events, the most common being headache. No clinically significant differences in adverse events were seen between fasting and fed states after a single dose administration. Thus, single dose 100 mg lonafarnib was safe and generally well tolerated. In the multiple-dose study, all 19 subjects reported at least one treatment-emergent adverse event. General disorders including fatigue and anorexia, and gastrointestinal disorders including diarrhea, vomiting and nausea, were the most commonly reported adverse events after multiple doses. While gastrointestinal adverse events were reported with equal frequency under both fasting (82%, 14/17) and fed states (83%, 15/18), the incidence of severe gastrointestinal adverse events was higher in fasted (47%, 8/17) vs. fed subjects (22%, 4/18) after multiple-dose administration.. The administration of food does not affect the pharmacokinetics of lonafanib following multiple-dose administration. We recommend that multiple-dose lonafarnib should be administered with food to enhance tolerability.

Topics: Adult; Aged; Analysis of Variance; Area Under Curve; Biological Availability; Cross-Over Studies; Drug Administration Schedule; Enzyme Inhibitors; Farnesyltranstransferase; Female; Food-Drug Interactions; Humans; Male; Middle Aged; Neoplasms; Piperidines; Pyridines

Halofuginone (tempostatin) is a synthetic derivative of a quinazolinone alkaloid showing anti-angiogenic, anti-metastatic and anti-proliferative effects in preclinical studies. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to study the pharmacokinetics (PKs) of halofuginone when administered once or twice daily orally to patients with advanced solid tumours.. Patients were treated with escalating doses of halofuginone at doses ranging from 0.5 to 3.5 mg/day. For pharmacokinetic analysis plasma sampling was performed during the first and second course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection.. Twenty-four patients received a total of 106 courses. The 'acute' MTD was reached at 3.5 mg/day, with nausea, vomiting, and fatigue as DLT. The recommended dose for chronic administration was defined as 0.5mg/day with the requirement of 5HT3 antagonists to control nausea and vomiting considered as DLT. Several patients experienced bleeding complications on treatment with halofuginone in which a causal relationship could not be excluded. The PKs of halofuginone were linear over the dose range studied with a large interpatient variability.. In this study the DLT of halofuginone was nausea, vomiting, and fatigue. The recommended dose for phase II studies of halofuginone is 0.5mg administered orally, once daily.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Fatigue; Humans; Maximum Tolerated Dose; Middle Aged; Nausea; Neoplasms; Piperidines; Quinazolines; Quinazolinones; Vomiting

Anesthesia techniques in children undergoing short painful oncology procedures should allow rapid recovery without side effects. We compared the recovery characteristics of two anesthetic techniques: propofol with sevoflurane and nitrous oxide and a total IV technique using propofol and remifentanil. Twenty-one children, undergoing two similar painful procedures within 2 wk were studied in a single-blind manner within patient comparison. The order of the techniques was randomized. Propofol and remifentanil involved bolus doses of both propofol 3-5 mg/kg and remifentanil 1-4 microg/kg. Propofol with sevoflurane and nitrous oxide involved propofol 3-5 mg/kg with 2%-8% sevoflurane and 70% nitrous oxide. The primary outcome variable was the time taken to achieve recovery discharge criteria; other recovery characteristics were also noted. The mean age of the children was 6.5 yr (range, 2.5-9.8 yr). Nineteen had lymphoblastic leukemia and two had lymphoma. All children had intrathecal chemotherapy and one had bone marrow aspiration. Most procedures lasted <4 min. The mean time to achieve recovery discharge criteria was appreciably shorter after propofol and remifentanil than propofol with sevoflurane and nitrous oxide by nearly 19 min (P = 0.001). All other time comparisons had similar trends and statistical differences. Seven parents expressed a preference for the propofol and remifentanil technique compared with one preferring propofol with sevoflurane and nitrous oxide. Children are apneic during the procedure and require respiratory support from an anesthesiologist. Discharge readiness from the recovery ward was achieved on average 19 min earlier after propofol with remifentanil compared with the combination of propofol, sevoflurane and nitrous oxide. Parents more often preferred propofol with remifentanil.

Topics: Anesthesia Recovery Period; Anesthesia, Inhalation; Anesthesia, Intravenous; Anesthetics, Inhalation; Anesthetics, Intravenous; Child; Child, Preschool; Female; Hemodynamics; Humans; Male; Methyl Ethers; Neoplasms; Nitrous Oxide; Piperidines; Propofol; Remifentanil; Sevoflurane; Treatment Outcome

Flavopiridol potently enhances the effect of irinotecan with cures in colorectal cancer xenografts, and is associated with modulation of several molecular targets, including p21, Differentiation-related gene 1 (Drg1), and p53. We initiated a phase I trial of the sequential combination of irinotecan followed by flavopiridol to determine the maximal tolerated dose of this combination therapy.. Forty-five patients with advanced solid tumors were enrolled. Irinotecan was administered first (100 or 125 mg/m(2)) followed 7 hours later by escalating flavopiridol (10-70 mg/m(2)) given weekly over 1 hour for 4 of 6 weeks. At the maximal tolerated dose, the pharmacokinetic analysis was expanded and pre- and posttreatment tumor biopsies were done.. At irinotecan 100 mg/m(2), dose-limiting diarrhea and myelosuppression were observed with flavopiridol 70 mg/m(2). At irinotecan 125 mg/m(2), we observed dose-limiting hyperbilirubinemia, fatigue, and myelosuppression at flavopiridol 60 mg/m(2). Peak flavopiridol concentrations of >/=2 mumol/L were achieved above flavopiridol 50 mg/m(2). No significant pharmacokinetic interactions with irinotecan were noted. Baseline serum bilirubin significantly predicted cycle 1 dose-limiting toxicity and neutropenia. We observed partial responses in three patients and prolonged stable disease (i.e., >6 months) in 36% of patients including adrenocortical cancer and hepatocellular cancer. Patients with wild-type p53 and either no change or low posttreatment biopsy p21 and a decrease in Drg1 expression showed stable or responsive disease to the combination therapy.. The recommended phase II dose with irinotecan 100 mg/m(2) is flavopiridol 60 mg/m(2) and with irinotecan 125 mg/m(2) is flavopiridol 50 mg/m(2). Toxicity can be predicted by baseline bilirubin. Clinical activity is encouraging and may correlate to changes in p21 and Drg1 levels in patients with wild type p53 tumors following therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bilirubin; Camptothecin; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p21; Drug Administration Schedule; Drug Interactions; Female; Flavonoids; Humans; Intracellular Signaling Peptides and Proteins; Irinotecan; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Piperidines; Treatment Outcome; Tumor Suppressor Protein p53

ZD6474 selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor and epidermal growth factor receptor. The safety, tolerability and pharmacokinetics of ZD6474 were assessed in a phase I dose-escalation study of patients with advanced solid tumors.. Adult patients with tumors refractory to standard treatments received once-daily oral ZD6474 (50-600 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed.. Seventy-seven patients were treated at doses of 50 mg (n=9), 100 mg (n=19), 200 mg (n=8), 300 mg (n=25), 500 mg (n=8), and 600 mg (n=8). Adverse events were generally mild, and the most common dose-limiting toxicities (DLT) were diarrhea (n=4), hypertension (n=4), and rash (n=3). The incidence of most adverse events appeared to be dose-dependant. In the 500 mg/day cohort, 3/8 patients experienced DLT and this dose was therefore considered to exceed the maximum tolerated dose. Pharmacokinetic analysis confirmed that ZD6474 was suitable for once-daily oral dosing.. Once-daily oral dosing of ZD6474 at 300 mg/day is generally well tolerated in patients with advanced solid tumors, and this dose is being investigated in phase II trials.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; ErbB Receptors; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor

Flavopiridol, a cyclin-dependent kinase inhibitor, transcription inhibitor, and DNA-interacting agent, was combined with cisplatin or carboplatin to establish toxicities, evaluate pharmacokinetics, and examine its effects on patient cancers and levels of selected polypeptides in patient peripheral blood mononuclear cells (PBMC).. Therapy was given every 3 weeks. Stage I: cisplatin was fixed at 30 mg/m2 with escalating flavopiridol. Stage II: flavopiridol was fixed at the stage I maximum tolerated dose (MTD) with escalation of cisplatin. Stage III: flavopiridol was fixed at the stage I MTD with escalation of carboplatin.. Thirty-nine patients were treated with 136 cycles of chemotherapy. Neutropenia was seen in only 11% of patients. Grade 3 flavopiridol/CDDP toxicities were nausea (30%), vomiting (19%), diarrhea (15%), dehydration (15%), and neutropenia (10%). Flavopiridol combined with carboplatin resulted in unexpectedly high toxicities and one treatment-related death. Stable disease (>3 months) was seen in 34% of treated patients, but there were no objective responses. The stage II MTD was 60 mg/m2 cisplatin and 100 mg/m2/24 hours flavopiridol. As given, CDDP did not alter flavopiridol pharmacokinetics. Flavopiridol induced increased p53 and pSTAT3 levels in patient PBMCs but had no effects on cyclin D1, phosphoRNA polymerase II, or Mcl-1.. Flavopiridol and cisplatin can be safely combined in the treatment of cancer patients. Unexpected toxicity in flavopiridol/carboplatin-treated patients attenuates enthusiasm for this alternative combination. Analysis of polypeptide levels in patient PBMCs suggests that flavopiridol may be affecting some, but not all, of its known in vitro molecular targets in vivo.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Cell Line, Tumor; Cisplatin; Cohort Studies; Diarrhea; Dose-Response Relationship, Drug; Female; Flavonoids; Humans; Immunoblotting; Leukocytes, Mononuclear; Male; Middle Aged; Nausea; Neoplasms; Piperidines; Proto-Oncogene Proteins c-bcl-2; STAT3 Transcription Factor; Treatment Outcome; Tumor Suppressor Protein p53

To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) when administered as a 1-hour infusion over 3 consecutive days to children with recurrent or refractory solid tumors.. Flavopiridol was administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days, or when hematologic toxicity or any grade 2 or greater nonhematologic toxicity resolved. The starting dose was 37.5 mg/m2/d. Dose escalation was in cohorts of three patients in a standard fashion until dose-limiting toxicity and the maximum-tolerated dose were determined. Flavopiridol levels were measured on days 1, 2, and 3.. Twenty-five children received flavopiridol at doses of 37.5 to 80 mg/m2/day over 3 consecutive days. The maximum-tolerated dose was 62.5 mg/m2/d. The primary dose-limiting toxicities were neutropenia and diarrhea. No antitumor effect was observed in this population. Mean peak plasma concentrations of 3.71 and 9.11 micromol/L were achieved at the end of the 1-hour infusion, following dose escalation from 37.5 mg/m2 to 80 mg/m2, respectively. The median flavopiridol plasma clearance was 8.0 L/h/m2 (range, 2.6 to 17.1 L/h/m2).. The maximum-tolerated dose of flavopiridol in children, and the recommended phase II dose for pediatric studies, was 62.5 mg/m2/day when administered as a 1-hour infusion for 3 consecutive days. Dose-limiting toxicities of neutropenia and diarrhea were similar to those in adult studies.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Child, Preschool; Diarrhea; Female; Flavonoids; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Neoplasms; Neutropenia; Piperidines

To establish the maximum tolerated dose of lonafarnib, a novel farnesyltransferase inhibitor, in combination with paclitaxel in patients with solid tumors and to characterize the safety, tolerability, dose-limiting toxicity, and pharmacokinetics of this combination regimen.. In a Phase I trial, lonafarnib was administered p.o., twice daily (b.i.d.) on continuously scheduled doses of 100 mg, 125 mg, and 150 mg in combination with i.v. paclitaxel at doses of 135 mg/m(2) or 175 mg/m(2) administered over 3 h on day 8 of every 21-day cycle. Plasma paclitaxel and lonafarnib concentrations were collected at selected time points from each patient.. Twenty-four patients were enrolled; 21 patients were evaluable. The principal grade 3/4 toxicity was diarrhea (5 of 21 patients), which was most likely due to lonafarnib. dose-limiting toxicities included grade 3 hyperbilirubinemia at dose level 3 (100 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel); grade 4 diarrhea and grade 3 peripheral neuropathy at dose level 3A (125 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel); and grade 4 neutropenia with fever and grade 4 diarrhea at level 4 (150 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel). The maximum tolerated dose established by the continual reassessment method was lonafarnib 100 mg b.i.d. and paclitaxel 175 mg/m(2). Paclitaxel appeared to have no effect on the pharmacokinetics of lonafarnib. The median duration of therapy was eight cycles, including seven cycles with paclitaxel. Six of 15 previously treated patients had a durable partial response, including 3 patients who had previous taxane therapy. Notably, two of five patients with taxane-resistant metastatic non-small cell lung cancer had partial responses.. When combined with paclitaxel, the recommended dose of lonafarnib for Phase II trials is 100 mg p.o. twice daily with 175 mg/m(2) of paclitaxel i.v. every 3 weeks. Additional studies of lonafarnib in combination regimens appear warranted, particularly in patients with non-small cell lung cancer.

Topics: Adult; Aged; Alkyl and Aryl Transferases; Anemia; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Dose-Response Relationship, Drug; Farnesyltranstransferase; Fatigue; Female; Heart Arrest; Humans; Leukopenia; Male; Middle Aged; Neoplasms; Neutropenia; Paclitaxel; Piperidines; Pyridines; Treatment Outcome

A phase I trial of flavopiridol administered as a 1-h i.v. infusion schedule was explored. Fifty-five patients were treated with flavopiridol at doses ranging from 12 to 78 mg/m2 daily for 5, 3 and 1 day every 3 weeks. Pharmacokinetic and pharmacodynamic analysis was performed together with analysis of a promoter polymorphism of the UGT1A1 gene. Peak concentrations and areas under the time-concentration curve of flavopiridol were linear within the doses studied. Estimated clearance was 13.8+/-4.9 l/h/m2 (mean+/-SD), volume of distribution at steady-state was 64.9+/-43.4 l/m2 and elimination half-life was 5.2+/-4.9 h. Forty-nine of the 55 patients were genotyped for the promoter polymorphism. We found five (10%) homozygous and 11 (22%) heterozygous patients for UGT1A1*28, which alters the reference sequence (TA)6TAA to the variant (TA)7TAA by an extra TA dinucleotide insertion within the TATA box. One patient was heterozygous for the sequence of five TA repeats, (TA)5TAA. The remaining 32 patients did not have the UGT1A1*28 allele (homozygous for the reference sequence). Associations of the UGT1A1 promoter genotype with either the pharmacokinetic parameters or diarrhea (occurrence and severity) were not observed in this study. The pharmacogenetic analyses did not support that the UGT1A1 promoter polymorphism could affect flavopiridol pharmacokinetics and alter the incidence and severity of diarrhea induced by the drug.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Biological Availability; Cyclin-Dependent Kinases; Dose-Response Relationship, Drug; Female; Flavonoids; Genotype; Glucuronosyltransferase; Half-Life; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pharmacogenetics; Pharmacology, Clinical; Piperidines; Treatment Outcome

Flavopiridol is a flavonoid with antiproliferative effects mediated, in part, by inhibition of cyclin-dependent kinases. Clinical manifestations in a previous Phase I trial in patients with refractory malignancies treated with a 72-h flavopiridol infusion included a proinflammatory syndrome consisting of fever, fatigue, and "local" tumor pain with concomitant alterations in plasma acute-phase reactant proteins.. The aim of this study was to determine whether the proinflammatory syndrome observed in this trial was associated with modulation of plasma cytokines.. Patients receiving flavopiridol (n = 76) had serial plasma samples drawn preinfusion and during the infusion for evaluation of interleukin (IL)-6, IL-10, IL-12, granulocyte macrophage colony-stimulating factor, basic-fibroblast growth factor, transforming growth factor-beta, and tumor necrosis factor-alpha levels by standard ELISA assays. The Wilcoxon signed rank test was used to test the significance of the difference between the baseline (time 0) plasma cytokine levels compared with the values of each subsequent data collection time points (8, 24, 48, and 72 h).. There was a significant and sustained increase in plasma IL-6 levels at all time points when compared with baseline values. Paired values were used in the statistical analysis. Median plasma (interquartile range) values of IL-6 were elevated from 15.5 (9-52) pg/ml at baseline to 23 (4-48) pg/ml (P < 0.01) at 8 h; from 15 (2-48) pg/ml at baseline to 46 (21-105) pg/ml (P < 0.001) at 24 h; from 16 (9-52) pg/ml at baseline to 61 (32-170) pg/ml (P < 0.001) at 48 h; and from 15.5 (6-48) pg/ml to 68 (40-200) pg/ml (P < 0.001) at 72 h. Significance was maintained even when adjusted for multiple comparisons. The relative increase in IL-6 concentration was dose-dependent. Moreover, IL-6 elevation had a direct correlation with flavopiridol peak plasma concentration, flavopiridol area under the curve, and plasma C-Reactive protein levels. A significant decrease in plasma granulocyte macrophage colony-stimulating factor occurred at the 8-h sampling point: 50 pg/ml (interquartile range 10-205 pg/ml, P < 0.01) when compared with baseline plasma levels and 71 pg/ml (interquartile range 5-152 pg/ml, P < 0.01). No changes in the other pro or anti-inflammatory cytokines were observed. Immunohistochemistry studies in bone marrow aspirates from a prospective group of patients in this trial demonstrated approximately 4-fold induction of IL-6 (compared with baseline), mostly in non-T cells.. Biochemical analysis of plasma in patients undergoing infusional flavopiridol found a significant dose-dependent induction of IL-6. IL-6 elevation could be a marker for the process leading to the appearance of the proinflammatory syndrome observed in patients treated with infusional flavopiridol. The mechanism(s) underlying IL-6 induction and its significance are still unknown but may influence strategies to modulate flavopiridol's clinical effects.

Topics: Antineoplastic Agents; Bone Marrow; Cyclin-Dependent Kinases; Enzyme Inhibitors; Flavonoids; Humans; Inflammation; Infusions, Intravenous; Interleukin-6; Interleukins; Neoplasms; Piperidines

Flavopiridol, a novel flavone derivative, inhibits cyclin-dependent kinase-1. We initiated a Phase I trial in patients with refractory solid tumors to determine the maximum tolerated dose and characterize the adverse effect profile.. To characterize the clinical pharmacology of flavopiridol.. Serial plasma samples were collected and analyzed by HPLC using electrochemical detection. The pharmacokinetics were analyzed by noncompartmental analysis. Enterohepatic recirculation was studied by analyzing fecal samples, with an attempt to correlate cholecystokinin and post-infusional peak concentrations. The plasma protein binding was studied using equilibrium dialysis.. Seventy-six patients were treated with flavopiridol at 13 dose levels for a total of 504 cycles of treatment. The average steady-state concentration was 26.5 and 253 nM at 4 and 122.5 mg/m2, respectively. The clearance ranged from 49.9 to 2943 mL/min, with nonlinearity at doses >50 mg/m2/d. A post-infusional increase in plasma flavopiridol concentrations was noted in a subset of patients and generally occurred between 3 and 24 hours after the end of infusion. Flavopiridol was found in fecal matter, suggesting enterohepatic recirculation. There was nonsaturable plasma protein binding of flavopiridol (fu = 6%).. The dose-limiting toxicity for the Phase I trial of flavopiridol was secretory diarrhea. We failed to identify a clear relationship between dose or concentration and diarrhea. At 50 and 78 mg/m2/d, the mean steady-state plasma concentrations were 278 and 390 nM. These concentrations were well above those noted for in vitro antiproliferative activity. Nonlinear elimination was observed at doses above 50 mg/m2/d, and postinfusional peaks appear to be related to enterohepatic recirculation.

Topics: Adult; Aged; Diarrhea; Feces; Female; Flavonoids; Food; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pharmacology, Clinical; Piperidines; Protein Binding; Time Factors

Opioid-induced sedation is a major complication in patients with cancer pain. This study assessed the effectiveness of donepezil in opioid-induced sedation and related symptoms in patients with cancer pain. Twenty-seven patients who were receiving strong opioids for pain and reported sedation were enrolled. Donepezil 5 mg was given every morning for 7 days. Changes between baseline and Day 7 in sedation, pain, fatigue and other symptoms were evaluated using the Edmonton Symptom Assessment Scale. Fatigue was also measured using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). Overall usefulness of donepezil was measured by the patient at the end of the study. In 20 evaluable patients, sedation, fatigue, anxiety, well-being, depression, anorexia and problems with sleep were significantly improved. Side effects included nausea, vomiting, diarrhea, muscle and abdominal cramps, and anorexia. Overall, however, the treatment was well tolerated. Donepezil appears to improve sedation and fatigue in patients receiving opioids for cancer pain. Randomized controlled trials of this agent are justified.

Topics: Adult; Aged; Analgesics, Opioid; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neoplasms; Nootropic Agents; Pain; Pilot Projects; Piperidines; Prospective Studies; Sleep Stages

To define the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol administered as a daily 1-hour infusion every 3 weeks.. Fifty-five patients with advanced neoplasms were treated with flavopiridol at doses of 12, 17, 24, 30, 37.5, and 52.5 mg/m(2)/d for 5 days; doses of 50 and 62.5 mg/m(2)/d for 3 days; and doses of 62.5 and 78 mg/m(2)/d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of flavopiridol with these schedules.. Dose-limiting neutropenia developed at doses >/= 52.5 mg/m(2)/d. Nonhematologic toxicities included nausea, vomiting, diarrhea, hypotension, and a proinflammatory syndrome characterized by anorexia, fatigue, fever, and tumor pain. The median peak concentrations of flavopiridol achieved at the MTDs on the 5-day, 3-day, and 1-day schedule were 1.7 micro mol/L (range, 1.3 to 4.2 micro mol/L), 3.2 micro mol/L (range, 1.7 to 4.8 micro mol/L), and 3.9 micro mol/L (1.8 to 5.1 micro mol/L), respectively. Twelve patients had stable disease for >/= 3 months, with a median duration of 6 months (range, 3 to 11 months).. The recommended phase II doses of flavopiridol as a 1-hour infusion are 37.5 mg/m(2)/d for 5 days, 50 mg/m(2)/d for 3 days, and 62.5 mg/m(2)/d for 1 day. Flavopiridol as a daily 1-hour infusion can be safely administered and can achieve concentrations in the micromolar range, sufficient to inhibit cyclin-dependent kinases in preclinical models. Further studies to determine the optimal schedule of flavopiridol as a single agent and in combination with chemotherapeutic agents are underway.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Flavonoids; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Piperidines; Treatment Outcome

A single-agent dose-escalating phase I study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile and recommended dose for phase II studies. Plasma pharmacokinetics were determined as well as the SCH 66336-induced inhibition of farnesyl protein transferase in vivo. SCH 66336 was given orally once daily (OD) without interruption to patients with histologically-confirmed solid tumours. Routine antiemetics were not prescribed. 12 patients were enrolled into the study. Dose levels studied were 300 mg (6 patients) and 400 mg (6 patients) OD. Pharmacokinetic sampling was performed on days 1 and 15. Although at 400 mg OD only 1 patient had a grade 3 diarrhoea, 3 out of 6 patients interrupted treatment early due to a combination of various grade 1-3 toxicities (diarrhoea, uremiacreatinine, asthenia, vomiting, weight loss) indicating that this dose was not tolerable for a prolonged period of time. At 300 mg OD, the same pattern of toxicities was observed, but all were grade 1-2. Therefore, this dose can be recommended for phase II studies. Pharmacokinetic analysis showed that peak plasma concentrations as well as the AUCs were dose-related, with increased parameters at day 15 compared with day 1, indicating some accumulation upon multiple dosing. Plasma half-life ranged from 5 to 9 h and appeared to increase with increasing dose. Steady state plasma concentrations were attained by day 14. A large volume of distribution at steady state suggested extensive distribution outside the plasma compartment. There is evidence of inhibition of protein prenylation in some patients after OD oral administration of SCH 66336. SCH 66336 can be safely administered using a continuous oral OD dosing regimen. The recommended dose for phase II studies using this regimen is 300 mg OD.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Piperidines; Pyridines

Flavopiridol (NSC 649890) is a synthetic flavone possessing significant antitumor activity in preclinical models. Flavopiridol is capable of inducing cell cycle arrest and apoptosis, presumably through its potent, specific inhibition of cyclin-dependent kinases. We conducted a phase I trial and pharmacokinetic study of flavopiridol given as a 72-h continuous intravenous infusion repeated every 2 weeks.. A total of 38 patients were treated at dose levels of 8, 16, 26.6, 40, 50 and 56 mg/m(2)/24 h. During the first infusion, plasma was sampled at 24, 48 and 72 h to determine steady-state concentrations, and peripheral blood lymphocytes were assessed by flow cytometry for evidence of apoptosis. Additional postinfusion pharmacokinetic sampling was done at the 40 and 50 mg/m(2)/24 h dose levels.. Gastrointestinal toxicity was dose limiting, with diarrhea being the predominant symptom. Symptomatic orthostatic hypotension was also frequently noted. Several patients experienced tumor-specific pain during their infusions. The maximum tolerated dose (MTD) was determined to be 40 mg/m(2)/24 h. A patient with metastatic gastric cancer at this dose level had a complete response and remained disease-free for more than 48 months after completing therapy. Plasma concentrations at 24 h into the infusion were 94% of those achieved at steady state. Steady-state plasma flavopiridol concentrations at the MTD were 416.6+/-98.9 micro M. These concentrations are at or above those needed to see cell cycle arrest and apoptosis in vitro. The mean clearance of flavopiridol over the dose range was 11.3+/-3.9 l/h per m(2), similar to values obtained preclinically. Elimination was biphasic. The terminal half-life at the MTD was 26.0 h. No significant differences in pharmacokinetic parameters were noted between males and females. Patients taking cholestyramine to ameliorate flavopiridol-induced diarrhea had lower steady-state plasma concentrations. There was no significant change in the cell cycle parameters of peripheral blood lymphocytes analyzed by flow cytometry.. The MTD and recommended phase II dose of flavopiridol given by this schedule is 40 mg/m(2)/24 h. The manageable gastrointestinal toxicity, early signs of clinical activity and lack of hematologic toxicity make further exploration in combination trials warranted.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cyclin-Dependent Kinases; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Flavonoids; Flow Cytometry; Half-Life; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Metabolic Clearance Rate; Middle Aged; Neoplasms; Piperidines; Safety; Treatment Outcome

Preclinical studies indicate that the cyclin-dependent kinase inhibitor flavopiridol potentiates the induction of apoptosis by paclitaxel, provided paclitaxel is followed by flavopiridol. We therefore designed a phase I clinical trial of sequential paclitaxel and flavopiridol.. Paclitaxel was administered at a fixed dose, as either a 24- or 3-hour infusion on day 1, followed by a 24-hour infusion of flavopiridol on day 2. Doses of flavopiridol were escalated in successive cohorts according to a modified Fibonacci design. Flavopiridol pharmacokinetics were obtained on all patients.. Dose-limiting neutropenia developed with 24-hour paclitaxel doses of 135 and 100 mg/m(2) and flavopiridol doses of 10 and 20 mg/m(2), respectively. With 3-hour paclitaxel at 100 mg/m(2), flavopiridol could be escalated to 70 mg/m(2) without dose-limiting toxicity. With 3-hour paclitaxel next escalated to 135 mg/m(2), dose-limiting neutropenia and pulmonary toxicity occurred when flavopiridol was escalated to 94 mg/m(2). This did not correlate with any change in flavopiridol or paclitaxel pharmacokinetics. At a 3-hour paclitaxel dose of 175 mg/m(2), dose-limiting pulmonary toxicity occurred in only one patient at flavopiridol doses under 94 mg/m(2). Clinical activity was observed in patients with esophagus, lung, and prostate cancer, including patients who had progressed on paclitaxel.. The recommended phase II doses will be a 3-hour infusion of paclitaxel at 175 mg/m(2) on day 1 followed by a 24-hour infusion of flavopiridol at 70 mg/m(2) on day 2. Flavopiridol dose escalations to 80 mg/m(2) are possible. At these doses, toxicities are manageable and clinical activity is promising.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclin-Dependent Kinases; Female; Flavonoids; Humans; Male; Middle Aged; Neoplasms; Paclitaxel; Piperidines

This prospective randomized study was designed to evaluate the effects of adding remifentanil to the standard propofol-based technique in the setting of paediatric haematology-oncology outpatient clinic.. Eighty ASA III paediatric patients treated in the outpatient haematology-oncology clinic requiring bone marrow aspiration were randomly assigned either to the propofol (P) or the propofol/remifentanil (PR) group. The quality of anaesthesia and recovery were evaluated.. The total amount of propofol required to prevent patient movement was lower in the PR group. The time interval to eye opening and to home readiness was significantly lower in the PR group. Adverse respiratory events (RR < 10.min-1 or SpO2 < 90%) occurred significantly more in the propofol/remifentanil group.. The addition of remifentanil improved the conditions during the procedure and reduced the total amount of propofol, as well as the time to home readiness. However, the addition of remifentanil is associated with an increased risk of respiratory depression.

Topics: Adolescent; Analgesics, Opioid; Anesthesia, Intravenous; Anesthetics, Intravenous; Biopsy, Needle; Bone Marrow; Child; Female; Hematologic Neoplasms; Hemodynamics; Humans; Male; Neoplasms; Piperidines; Propofol; Prospective Studies; Remifentanil; Respiratory Mechanics

To evaluate the safety, tolerability, and pharmacokinetics of biricodar (VX-710), an inhibitor of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1), alone and with doxorubicin in patients with advanced malignancies. The effect of VX-710 on the tissue distribution of (99m)Tc-sestamibi, a P-gp and MRP1 substrate, was also evaluated.. Patients with solid malignancies refractory to standard therapy first received a 96-hour infusion of VX-710 alone at 20 to 160 mg/m(2)/h. After a 3-day washout, a second infusion of VX-710 was begun, on the second day of which doxorubicin 45 mg/m(2) was administered. Cycles were repeated every 21 to 28 days. (99m)Tc-sestamibi scans were performed before and during administration of VX-710 alone.. Of the 28 patients who enrolled, 25 patients were eligible for analysis. No dose-limiting toxicity (DLT) was observed in the nine assessable patients who received 120 mg/m(2)/h or less. Among seven patients receiving VX-710 160 mg/m(2)/h, two DLTs were seen: reversible CNS toxicity and febrile neutropenia. All other adverse events were mild to moderate and reversible. Plasma concentrations of VX-710 in patients who received at 120 and 160 mg/m(2)/h were two- to fourfold higher than concentrations required to fully reverse drug resistance in vitro. VX-710 exhibited linear pharmacokinetics with a harmonic mean half-life of 1.1 hours. VX-710 enhanced hepatic uptake and retention of (99m)Tc-sestamibi in all patients.. A 96-hour infusion of VX-710 at 120 mg/m(2)/h plus doxorubicin 45 mg/m(2) has acceptable toxicity in patients with refractory malignancies. The safety and pharmacokinetics of VX-710 plus doxorubicin warrant efficacy trials in malignancies expressing P-gp and/or MRP1.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; DNA-Binding Proteins; Dose-Response Relationship, Drug; Doxorubicin; Drug Interactions; Female; Half-Life; Humans; Infusions, Intravenous; Liver; Male; Maximum Tolerated Dose; Middle Aged; Multidrug Resistance-Associated Proteins; MutS Homolog 3 Protein; Neoplasms; Piperidines; Pyridines; Radionuclide Imaging; Radiopharmaceuticals; Technetium Tc 99m Sestamibi; Tissue Distribution

Farnesyl protein transferase (FT), an enzyme that catalyzes the first step in the posttranslational modification of ras and a number of other polypeptides, has emerged as an important target for the development of anticancer agents. SCH66336 is one of the first FT inhibitors to undergo clinical testing. We report a Phase I trial to assess the maximum tolerated dose, toxicities, and biological effectiveness of SCH66336 in inhibiting FT in vivo. Twenty patients with solid tumors received 92 courses of escalating SCH66336 doses given orally twice a day (b.i.d.) for 7 days out of every 3 weeks. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and fatigue were dose-limiting at 400 mg of SCH66336 b.i.d. Moderate reversible renal insufficiency, secondary to dehydration from gastrointestinal toxicity, was also seen. Inhibition of prelamin A farnesylation in buccal mucosa cells of patients treated with SCH66336 was demonstrated, confirming that SCH66336 inhibits protein farnesylation in vivo. One partial response was observed in a patient with previously treated metastatic non-small cell lung cancer, who remained on study for 14 months. This study not only establishes the dose for future testing on this schedule (350 mg b.i.d.) but also provides the first evidence of successful inhibition of FT in the clinical setting and the first hint of clinical activity for this class of agents.

Topics: Adult; Aged; Aged, 80 and over; Alkyl and Aryl Transferases; Antineoplastic Agents; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesyltranstransferase; Female; Humans; Lamin Type A; Lamins; Male; Middle Aged; Mouth Mucosa; Neoplasms; Nuclear Proteins; Piperidines; Protein Precursors; Pyridines

The objectives of this phase I study were to evaluate the toxic effects and the maximum tolerated dose (MTD) of S9788, a new modifier of multidrug resistance (MDR), when given alone and in combination with doxorubicin to patients with advanced solid tumors; to achieve a potentially active plasma concentration of S9788; and to study the pharmacokinetics of both drugs.. A total of 26 patients (median age 58 years) entered the study. S9788 was given alone as a 30-min infusion at day 1 and in combination with a 50-mg/m2 bolus of doxorubicin at days 8 and 29. Dose levels of S9788 were escalated from 8 to 96 mg/m2 according to the modified Fibonacci scheme. Plasma samples were taken predose as well as during and up to 48 h after the beginning of infusion for S9788 and doxorubicin quantitation. Fractionated urine samples were also collected for up to 24 h for S9788 determination.. The dose-limiting side effects of S9788 consisted of bradycardia, sometimes associated with faintness or dizziness. The MTD of S9788 was 96 mg/m2. No enhancement of doxorubicin toxicity was observed. One partial response (duration 140 days) was observed at 96 mg/m2 in a patient with multiple lung metastases from a refractory urothelial carcinoma. Pharmacokinetic studies were performed in 24 patients. Since the mean apparent elimination half-life of S9788 was 46 +/- 23 h and the last plasma sampling time was 48 h, only model-independent parameters were considered. Plasma levels of S9788 were below the limit of quantitation (4 x 10[-3] microM) before each drug administration. S9788 plasma levels of up to 3.7 microM could be obtained with this administration schedule. The urinary elimination of the unchanged drug was negligible, whatever the collection period. In spite of the large inter- and intraindividual variability, plasma pharmacokinetics of S9788 given as a 30-min i.v. infusion were linear up to 96 mg/m2 and were not modified by doxorubicin administration. Doxorubicin pharmacokinetic parameters did not seem to be influenced by S9788 coadministration.. The dose-limiting toxicity of S9788 consisted of bradycardia or clinical symptoms suggesting a vasovagal impact such as faintness or dizziness. The MTD of S9788 was 96 mg/m2. The pharmacokinetic parameters of doxorubicin in this study were close to those usually described and were not influenced by escalation of the S9788 dose. No pharmacokinetic interaction was observed between S9788 and doxorubicin. The clinical tolerability of the combined treatment is in good agreement with the pharmacokinetic findings, since no enhancement of doxorubicin toxicity was observed.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Bradycardia; Dose-Response Relationship, Drug; Doxorubicin; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Neoplasms; Piperidines; Triazines

To evaluate the feasibility of administering biricodar (VX-710; Incel, Vertex Pharmaceuticals Inc, Cambridge, MA), an agent that modulates multidrug resistance (MDR) conferred by overexpression of both the multidrug resistance gene product (MDR1) P-glycoprotein and the MDR-associated protein (MRP) in vitro, in combination with paclitaxel. The study also sought to determine the maximum-tolerated dose (MTD) of paclitaxel that could be administered with biologically relevant concentrations of VX-710 and characterize the toxicologic and pharmacologic profiles of the VX-710/ paclitaxel regimen.. Patients with solid malignancies were initially treated with VX-710 as a 24-hour infusion at doses that ranged from 10 to 120 mg/m2 per hour. After a 2-day washout period, patients were re-treated with VX-710 on an identical dose schedule followed 8 hours later by paclitaxel as a 3-hour infusion at doses that ranged from 20 to 80 mg/m2. The pharmacokinetics of both VX-710 and paclitaxel were studied during treatment with VX-710 alone and VX-710 and paclitaxel. Thereafter, patients received VX-710 and paclitaxel every 3 weeks.. VX-710 alone produced minimal toxicity. The toxicologic profile of the VX-710/paclitaxel regimen was similar to that reported with paclitaxel alone; neutropenia that was noncumulative was the principal dose-limiting toxicity (DLT). The MTD levels of VX-710/ paclitaxel were 120 mg/m2 per hour and 60 mg/m2, respectively, in heavily pretreated patients and 120/60 to 80 mg/m2 per hour in less heavily pretreated patients. At these dose levels, VX-710 steady-state plasma concentrations (Css) ranged from 2.68 to 4.89 microg/mL, which exceeded optimal VX-710 concentrations required for MDR reversal in vitro. The pharmacokinetics of VX-710 were dose independent and not influenced by paclitaxel. In contrast, VX-710 reduced paclitaxel clearance. At the two highest dose levels, which consisted of VX-710 120 mg/m2 per hour and paclitaxel 60 and 80 mg/m2, pertinent pharacokinetic determinants of paclitaxel effect were similar to those achieved with paclitaxel as a 3-hour infusion at doses of 135 and 175 mg/m2, respectively.. VX-710 alone is associated with minimal toxicity. In combination with paclitaxel, biologically relevant VX-710 plasma concentrations are achieved and sustained for 24 hours, which simulates optimal pharmacologic conditions required for MDR reversal in vitro. The acceptable toxicity profile of the VX-710/ paclitaxel combination and the demonstration that optimal pharmacologic conditions for MDR reversal are achievable support a rationale for further trials of VX710/paclitaxel in patients with malignancies that are associated with de novo or acquired resistance to paclitaxel caused by overexpression of MDR1 and/or MRP.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Resistance, Multiple; Female; Humans; Immunosuppressive Agents; Infusions, Intravenous; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Neoplasms; Paclitaxel; Piperidines; Pyridines

We conducted a phase I trial of the cyclin-dependent kinase inhibitor, flavopiridol (National Service Center [NSC] 649890), to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacology of flavopiridol given as a 72-hour infusion every 2 weeks.. Seventy-six patients with refractory malignancies with prior disease progression were treated with flavopiridol, with first-cycle pharmacokinetic sampling.. Forty-nine patients defined our first MTD, 50 mg/m2/d x 3 with dose-limiting toxicity (DLT) of secretory diarrhea at 62.5 mg/kg/d x 3. Subsequent patients received antidiarrheal prophylaxis (ADP) to define a second MTD, 78 mg/m2/d x 3 with DLT of hypotension at 98 mg/m2/d x 3. Other toxicities included a proinflammatory syndrome with alterations in acute-phase reactants, particularly at doses >50 mg/ m2/d x 3, which in some patients prevented chronic therapy every 2 weeks. In some patients, ADP was not successful, requiring dose-deescalation. Although approximately 70% of patients displayed predictable flavopiridol pharmacology, we observed unexpected interpatient variability and postinfusion peaks in approximately 30% of cases. At the two MTDs, we achieved a mean plasma flavopiridol concentration of 271 nM (50 mg/m2/d x 3) and 344 nM (78 mg/m2/d x 3), respectively. One partial response in a patient with renal cancer and minor responses (n=3) in patients with non-Hodgkin's lymphoma, colon, and renal cancer occurred.. The MTD of infusional flavopiridol is 50 mg/m2/d x 3 with dose-limiting secretory diarrhea at 62.5 mg/m2/d x 3. With ADP, 78 mg/m2/d x 3 was the MTD, with dose-limiting hypotension at 98 mg/m2/d x 3. Based on chronic tolerability, 50 mg/m2/d x 3 is the recommended phase II dose without ADP. Antitumor effect was observed in certain patients with renal, prostate, and colon cancer, and non-Hodgkin's lymphoma. Concentrations of flavopiridol (200 to 400 nM) needed for cyclin-dependent kinase inhibition in preclinical models were achieved safely.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cyclin-Dependent Kinases; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Female; Flavonoids; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Piperidines

The triazinoaminopiperidine derivative S 9788 is a new multidrug-resistance modulator that is currently being evaluated in phase I clinical trials. In this study, the reversal effect of S 9788 in comparison with verapamil was shown in vitro in human T-leukemic CCRF-CEM/VLB cells expressing the multidrug-resistance (MDR) phenotype. S 9788 increased in a dose-dependent manner the cytotoxic activity of doxorubicin or vinblastine, with complete reversal of resistance occurring at 2 microM for a concomitant continuous exposure (96 h) to the cytotoxic drugs. At respective concentrations equivalent to the IC10 value (the concentration inhibiting 10% of cell growth), S 9788 was 44 times more potent than verapamil in CCRF-CEM/VLB cells. S 9788 at 2 microM did not enhance the in vitro toxicity of doxorubicin or vinblastine in the human normal bone-marrow erythroid (BFU-E) and myeloid (CFU-GM) progenitors. The effect of exposure duration and concentrations on the synergistic action of modulator and cytotoxic agent closely depended on the cytotoxic agent studied. Post-incubations with S 9788 alone after a 1-h coadministration with vinblastine and S 9788 dramatically increased the reversal effect (4-41 times) in proportion to both the duration of postincubation and the concentration of S 9788. In contrast, for doxorubicin resistance, post-incubation with S 9788 alone induced a maximal 2-fold increase in the reversal effect that was not proportional to the post-incubation duration. In patients treated with S 9788 as a 30-min intravenous infusion during phase I trials, a good correlation was found between the serum levels of S 9788 and the ability to reverse MDR in CCRF-CEM/VLB cells. The reversal effect was dose-dependent and was effective beginning at a plasma concentration of 0.25 microM. These data form a basis for the design of phase II trials using a combination of a loading dose of S 9788 given before vinblastine or doxorubicin administration followed by a maintenance infusion of S 9788 alone for a period of 2-24 h.

Topics: Antineoplastic Agents; Bone Marrow Cells; Cell Division; Cell Line; Cell Survival; Culture Media; Doxorubicin; Drug Resistance, Multiple; Drug Synergism; Hematopoietic Stem Cells; Humans; Leukemia, T-Cell; Neoplasms; Phenotype; Piperidines; Reference Values; Triazines; Tumor Cells, Cultured; Verapamil; Vinblastine

Topics: Adolescent; Adult; Aged; Animals; Benzilates; Biliary Tract Diseases; Blood Circulation; Cardiovascular System; Cats; Central Nervous System; Child; Child, Preschool; Clinical Trials as Topic; Dogs; Female; Gastrointestinal Diseases; Genital Diseases, Female; Guinea Pigs; Humans; Infant; Infant, Newborn; Male; Mice; Middle Aged; Muscle Contraction; Muscles; Muscular Diseases; Neoplasms; Piperidines; Pupil; Rabbits; Rats; Respiration; Respiratory Tract Diseases; Salivation; Urologic Diseases

Topics: B-Lymphocytes; Humans; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles

Over-expressions of epidermal growth factor receptor and vascular endothelial growth factor receptor were frequently associated with the metastasis of solid tumors. Vandetanib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor and vascular endothelial growth factor receptor, was broadly effective in treating a variety of human solid tumors. The compelling evidence that hypoxia is involved in tumor resistance to cancer therapy. Hypoxia-inducible factor (HIF-1α), a major transcription factor in response to hypoxia, has been considered as a promising specific target for cancer therapy. We reported a stronger vandetanib derivative, compound 39, which was more potently decreased viability of A549, HT-29, MCF-7, HepG2, and HeLa cells than its parent compound vandetanib. Remarkable hypoxia-selectivity was observed in A549 cells (IC

Topics: Apoptosis; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; HeLa Cells; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A

Topics: Etanercept; Herpes Zoster; Herpesvirus 3, Human; Humans; Neoplasms; Piperidines; Pyrimidines; Pyrroles

Topics: Arthritis, Rheumatoid; Humans; Neoplasms; Piperidines; Pyrimidines

Topics: Arthritis, Rheumatoid; Humans; Neoplasms; Piperidines; Pyrimidines

Topics: Arthritis, Rheumatoid; Humans; Neoplasms; Piperidines; Pyrimidines

Topics: Arthritis, Rheumatoid; Humans; Neoplasms; Piperidines; Pyrimidines

Integrated theranostic nanoplatforms with multi-model imaging and therapeutic functions are attracting great attention in cancer treatments, while the design and preparation of such nanoplatforms remain an open challenge. Herein, we report hemoporfin@Cu

Topics: Animals; Cell Line, Tumor; Hematoporphyrins; Hydrogen Peroxide; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manganese Compounds; Mice; Nanoparticles; Neoplasms; Oxides; Piperidines

Tumorectomy followed by radiotherapy, hormone, and chemotherapy, are the current mainstays for breast cancer treatment. However, these strategies have systemic toxicities and limited treatment outcomes. Hence, there is a crucial need for a novel controlled release delivery system for implantation following tumor resection to effectively prevent recurrence. Here, we fabricated polycaprolactone (PCL)-based electrospun nanofibers containing piperine (PIP), known for chemopreventive and anticancer activities, and also evaluated the impact of collagen (Coll) incorporation into the matrices. In addition to physicochemical characterization such as morphology, hydrophilicity, drug content, release properties, and mechanical behaviors, fabricated nanofibers were investigated in terms of cytotoxicity and involved mechanisms in MCF-7 and 4T1 breast tumor cell lines. In vivo antitumor study was performed in 4T1 tumor-bearing mice. PIP-PCL

Topics: Alkaloids; Animals; Benzodioxoles; Collagen; Mice; Nanofibers; Neoplasms; Piperidines; Polyesters; Polyunsaturated Alkamides

In order to investigate the effect of remifentanil combined with propofol on awakening of craniotomy for tumor, a retrospective analysis is conducted. 86 patients who underwent craniotomy for brain tumor in our hospital from July 2020 to December 2021 are chosen to observe the quality of awakening, hemodynamic parameters, and the occurrence of adverse reactions. All patients are divided into group A (

Topics: Anesthetics, Intravenous; Craniotomy; Hemodynamics; Humans; Neoplasms; Piperidines; Propofol; Remifentanil; Retrospective Studies

Topics: Adenine; Humans; Neoplasms; Piperidines; Pyrazoles; Pyrimidines

Immune therapy has ushered in a new era of tumor treatment, at the expense of immune-related adverse events, including rare but fatal adverse cardiovascular events, such as myocarditis. Steroids remain the cornerstone of therapy for immune-related myocarditis, with no clear consensus on additional immunosuppressive treatment for steroid-refractory cases yet.. Here, we report a patient with stage IV nasopharyngeal carcinoma who developed immune-related myocarditis in the fourth course of therapy with immune checkpoint inhibitors. The patient presented with precordial discomfort with elevation of cardiac enzymes and interleukin-6, atypical electrocardiographic abnormalities, and reduced left ventricular ejection fraction. Coronary computed tomography angiography excluded the possibility of acute coronary syndrome. The therapy with tofacitinib targeting the Janus kinase-signal transducer and activator of transcription signal pathway was successfully conducted, since there was no significant improvement in troponin under high-dose steroid and intravenous immunoglobulin treatment. The patient recovered without major adverse cardiac events during hospitalization.. The safety and efficacy of tofacitinib in a patient with steroid-refractory immune-related myocarditis were investigated, hoping to provide a basis for prospective therapeutic strategies. Tofacitinib led to remarkable remissions in primary autoimmune disease by blocking the inflammatory cascade, indicating its potential therapeutic use in immune-related adverse events.

Topics: Humans; Immune Checkpoint Inhibitors; Immunoglobulins, Intravenous; Interleukin-6; Janus Kinases; Myocarditis; Neoplasms; Piperidines; Pyrimidines; Steroids; Stroke Volume; Troponin; Ventricular Function, Left

Canine histiocytic sarcoma (HS) is an aggressive and highly metastatic neoplasm. Mutations in src homology 2 domain-containing phosphatase 2 (SHP2; encoded by PTPN11), which recently have been identified in canine HS tumour cells, could be attractive therapeutic targets for SHP099, an allosteric inhibitor of SHP2. Here, molecular characteristics of wild-type SHP2 and four SHP2 mutants (p.Ala72Gly, p.Glu76Gln, p.Glu76Ala and p.Gly503Val), including one that was newly identified in the present study, were investigated. Furthermore, in vivo effects of SHP099 on a HS cell line carrying SHP2 p.Glu76Ala were examined using a xenograft mouse model. While SHP2 Glu76 mutant cell lines and SHP2 wild-type/Gly503 mutant cell lines are highly susceptible and non-susceptible to SHP099, respectively, a cell line carrying the newly identified SHP2 p.Ala72Gly mutation exhibited moderate susceptibility to SHP099. Among recombinant wild-type protein and four mutant SHP2 proteins, three mutants (SHP2 p.Ala72Gly, p.Glu76Gln, p.Glu76Ala) were constitutively activated, while no activity was detected in wild-type SHP2 and SHP2 p.Gly503Val. Activities of these constitutively activated proteins were suppressed by SHP099; in particular, Glu76 mutants were highly sensitive. In the xenograft mouse model, SHP099 showed anti-tumour activity against a SHP2 p.Glu76Ala mutant cell line. Thus, there was heterogeneity in molecular characteristics among SHP2 mutants. SHP2 p.Glu76Ala and perhaps p.Glu76Gln, but not wild-type SHP2 or SHP2 p.Gly503Val, were considered to be oncogenic drivers targetable with SHP099 in canine HS. Further studies will be needed to elucidate the potential of SHP2 p.Ala72Gly as a therapeutic target of SHP099 in canine HS.

Topics: Animals; Disease Models, Animal; Dog Diseases; Dogs; Heterografts; Histiocytic Sarcoma; Mice; Mutation; Neoplasms; Piperidines; Pyrimidines; Rodent Diseases

Photodynamic therapy with a photosensitizer such as protoporphyrin-IX, a light sensitive metabolite of heme synthesis, is a highly selective treatment for various carcinomas. In previous studies, we found a significant down regulation of the relevant enzyme ferrochelatase in gastrointestinal carcinomas leading to an accumulation of protoporphyrin-IX within the tumor cells. Recent studies showed that a novel anti-cancer drug, Alectinib, an orally available, highly selective, potent second-generation inhibitor of anaplastic lymphoma tyrosinkinase binds to ferrochelatase. Therefore, we were interested to see whether Alectinib treatment might lead to an accumulation of protoporphyrin IX.. Tumor cells of different origin were cultured, treated with LED-light and Alectinib. Results were gained by flow cytometry, immunohistochemistry and western blotting. Apoptosis was determined by flow cytometric analysis of Annexin V-FITC stained cells. In addition, cells were counterstained with propidium iodide to distinguish early apoptotic cells and late apoptotic/necrotic cells.. Here, we report that photodynamic treatment of tumor cell lines of different origin in combination with Alectinib increased protoporphyrin-IX specific fluorescence and concomitantly cell death.. The usage of Alectinib could be another step for enhancing the effectiveness of photodynamic therapy. Further experiments will show whether photodynamic therapy in combination with Alectinib could be a new strategy for the treatment of e.g. peritoneal disseminated carcinomas.

Topics: Aminolevulinic Acid; Carbazoles; Fluorescence; Humans; Light; Neoplasms; Photochemotherapy; Photosensitizing Agents; Piperidines; Protoporphyrins; Tumor Cells, Cultured

Currently, limited tumor drug permeation, poor oxygen perfusion and immunosuppressive microenvironments are the most important bottlenecks that significantly reduce the efficacy of photodynamic therapy (PDT). The main cause of these major bottlenecks is the platelet activation maintained abnormal tumor vessel barriers. Thus, platelet inhibition may present a new way to most effectively enhance the efficacy of PDT. However, to the best of our knowledge, few studies have validated the effectiveness of such a way in enhancing the efficacy of PDT both in vivo and in vitro. In this study, perfluoro-N-(4-methylcyclohexyl) piperidine-loaded albumin (PMP@Alb) nanoparticles were discovered, which possess excellent platelet inhibition ability. After PMP@Alb treatment, remarkably enhanced intra-tumoral drug accumulation, oxygen perfusion and T cell infiltration could be observed owing to the disrupted tumor vessel barriers. Besides, the effect of ICG@Lip mediated PDT was significantly amplified by PMP@Alb nanoparticles. It was demonstrated that PMP@Alb could be used as a useful tool to improve the efficacy of existing PDT by disrupting tumor vessel barriers through effective platelet inhibition.

Topics: Albumins; Animals; Cell Line, Tumor; Humans; Male; Mice, Inbred C57BL; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Piperidines; Tumor Microenvironment

Analysis of the anticancer and antimitotic activity of the plant derived alkaloid securinine along with its effect on the organization of cellular microtubules as well as its binding with purified goat brain tubulin in-vitro.. The cytotoxicity of securinine on different cell lines was conducted using SRB assay. The effect of securinine on the cellular microtubules was analyzed using immunofluorescence microscopy. The binding of securinine on purified goat brain tubulin was evaluated using fluorescent spectroscopy.. Securinine effectively prevented the proliferation of cervical, breast and lung cancer cells with an IC. Considering the strong anticancer and anti-metastatic property and low toxicity in non-malignant cell lines, we suggest that securinine can be used as a chemotherapeutic drug either alone or in combination with other known anticancer molecules.

Topics: A549 Cells; Antineoplastic Agents; Azepines; Dose-Response Relationship, Drug; HEK293 Cells; HeLa Cells; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; MCF-7 Cells; Microtubules; Mitosis; Neoplasms; Piperidines; Tubulin

In this study, we report a case of a 77-year-old woman who was presented with anemia in the winter of 2002. She was diagnosed with cold agglutinin disease (CAD) and treated with corticosteroids. Further, her hemoglobin levels were maintained between 7.0 g/dl and 8.0 g/dl. In May 2019, mature peripheral blood lymphocytes increased with exacerbation of hemolytic anemia. The lymphocytes were positive for CD19 and CD20, but negative for CD5, CD10, and CD23. Additionally, they were positive for cell surface IgM-κ. The B-cell neoplasm could not be further subclassified due to the lack of BCL2-IgH and BCL1-IgH rearrangement and morphology. The IgM-κ-type M-protein was found in serum, and the direct Coombs test was negative for IgG but positive for C3b/C3d. These findings suggested that small B-cell neoplasm-associated M-protein was involved in the development of CAD through complement activation. Based on the presence of TP53 deletion, the patient was treated with ibrutinib monotherapy. Although hemolysis rapidly improved with a dramatic decrease in lymphocytes, she died from a cerebral hemorrhage. It is assumed that ibrutinib improved CAD through suppression of small B-cell neoplasm-related M-protein. CAD can precede lymphoproliferative disorders; however, the risk of ibrutinib-associated hemorrhage should be noted.

Topics: Adenine; Aged; Anemia, Hemolytic, Autoimmune; Female; Humans; Lymphoproliferative Disorders; Neoplasms; Piperidines

P-glycoprotein (P-gp)/MDR-1 plays a major role in the development of multidrug resistance (MDR) by pumping the chemotherapeutic drugs out of the cancer cells and reducing their efficacy. A number of P-gp inhibitors were reported to reverse the MDR when co-administered with chemotherapeutic drugs. Unfortunately, none has approved for clinical use due to toxicity issues. Some of the P-gp inhibitors tested in the clinics are reported to have cross-reactivity with CYP450 drug-metabolizing enzymes, resulting in unpredictable pharmacokinetics and toxicity of co-administered chemotherapeutic drugs. In this study, two piperine analogs (3 and 4) having lower cross-reactivity with CYP3A4 drug-metabolizing enzyme are identified as P-glycoprotein (P-gp) inhibitors through computational design, followed by synthesis and testing in MDR cancer cell lines over-expressing P-gp (KB Ch

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Benzodioxoles; Binding Sites; Cell Line, Tumor; Cell Survival; Cytochrome P-450 CYP3A; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Molecular Docking Simulation; Multidrug Resistance-Associated Proteins; Neoplasms; NF-kappa B; Piperidines; Polyunsaturated Alkamides; Vincristine

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we performed an integrated analysis of malignancy events from the tofacitinib phase 3 UC clinical development program (excluding nonmelanoma skin cancer [NMSC]).. Data (up to May 2019) were pooled from two phase 3 induction studies, a phase 3 maintenance study, and an ongoing, open-label, long-term extension (OLE) study, and analyzed as 3 cohorts: induction (N = 1139), maintenance (N = 592), and overall (induction, maintenance, and ongoing OLE study; N = 1124). Proportions and incidence rates (IRs; unique patients with events per 100 patient-years [PY] of exposure) for malignancies confirmed by adjudication were calculated.. The overall cohort consisted of patients who received at least 1 dose of tofacitinib at 5 or 10 mg twice daily, for up to 6.8 years, with an exposure of 2576.4 PY. Of the 1124 overall cohort tofacitinib-treated patients, 20 developed a malignancy (excluding NMSC; IR, 0.75; 95% confidence interval, 0.46-1.16), of which 17 occurred in patients treated with tofacitinib 10 mg twice daily; importantly, more than 80% of patients predominantly received this dose. Furthermore, there was no apparent clustering of malignancy types, and IRs were stable over time.. In the tofacitinib UC clinical development program, malignancy events were infrequent, and rates were comparable with those in the tofacitinib rheumatoid arthritis and psoriatic arthritis clinical development programs, and for biologic UC treatments. ClinicalTrials.gov: NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

Topics: Clinical Trials, Phase III as Topic; Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Neoplasms; Treatment Outcome

An interesting enzyme of the endocannabinoid system is monoacylglycerol lipase (MAGL). This enzyme, which metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG), has attracted great interest due to its involvement in several physiological and pathological processes, such as cancer progression. Experimental evidences highlighted some drawbacks associated with the use of irreversible MAGL inhibitors in vivo, therefore the research field concerning reversible inhibitors is rapidly growing. In the present manuscript, the class of benzoylpiperidine-based MAGL inhibitors was further expanded and optimized. Enzymatic assays identified some compounds in the low nanomolar range and steered molecular dynamics simulations predicted the dissociation itinerary of one of the best compounds from the enzyme, confirming the observed structure-activity relationship. Biological evaluation, including assays in intact U937 cells and competitive activity-based protein profiling experiments in mouse brain membranes, confirmed the selectivity of the selected compounds for MAGL versus other components of the endocannabinoid system. An antiproliferative ability in a panel of cancer cell lines highlighted their potential as potential anticancer agents. Future studies on the potential use of these compounds in the clinical setting are also supported by the inhibition of cell growth observed both in cancer organoids derived from high grade serous ovarian cancer patients and in pancreatic ductal adenocarcinoma primary cells, which showed genetic and histological features very similar to the primary tumors.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Enzyme Inhibitors; Humans; Mice; Molecular Dynamics Simulation; Monoacylglycerol Lipases; Neoplasms; Piperidines

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Colitis; Humans; Immune Checkpoint Inhibitors; Ipilimumab; Male; Neoplasms; Nivolumab; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Treatment Outcome

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to estimate the overall incidence of safety events in patients with UC in a real-life population cohort for comparison with the tofacitinib UC clinical trial program.. Clinical trial-like criteria were applied to an IBM MarketScan® claims database population-based cohort (n = 22,967) of patients with UC (October 2010 to September 2015) to identify a UC trial-like cohort treated with tumor necrosis factor inhibitors (TNFi; n = 6366) to compare with the tofacitinib UC clinical trial cohort (n = 1157).. Incidence rates (events per 100 patient-years; [95% confidence interval]) in the UC trial-like cohort were as follows: serious infections, 3.33 (2.73-4.02); opportunistic infections (OIs; excluding herpes zoster [HZ]), 1.45 (1.06-1.93); HZ, 1.77 (1.34-2.29); malignancies (excluding nonmelanoma skin cancer [NMSC]), 0.63 (0.43-0.90); NMSC, 1.69 (1.35-2.10); major adverse cardiovascular events (MACE), 0.51 (0.31-0.79); pulmonary embolism (PE), 0.54 (0.30-0.89); deep vein thrombosis (DVT), 1.41 (1.00-1.93); and gastrointestinal perforations, 0.31 (0.16-0.54). Compared with the UC trial-like cohort, tofacitinib-treated patients had numerically lower incidence rates for serious infections (1.75 [1.27-2.36]), OIs (excluding HZ; 0.16 [0.04-0.42]), NMSC (0.78 [0.47-1.22]), PE (0.16 [0.04-0.41]), and DVT (0.04 [0.00-0.23]), and a higher rate for HZ (3.57 [2.84-4.43]); rates for malignancies (excluding NMSC), MACE, and gastrointestinal perforations were similar.. When acknowledging limitations of comparing claims data with controlled clinical trial data, incidence rates for HZ among TNFi-treated patients in the UC trial-like cohort were lower than in the tofacitinib UC clinical trial cohort; rates for serious infections, OIs, NMSC, PE, and DVT were numerically higher.. NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Topics: Colitis, Ulcerative; Humans; Neoplasms; Opportunistic Infections; Piperidines; Product Surveillance, Postmarketing; Pyrimidines; Randomized Controlled Trials as Topic

Cancer therapy is often hampered by the disease's development of resistance to anticancer drugs. We previously showed that the autonomously upregulated product of fibroblast growth factor 13 gene (FGF13; also known as FGF homologous factor 2 (FHF2)) is responsible for the cisplatin resistance of HeLa cisR cells and that it is likely responsible for the poor prognosis of cervical cancer patients treated with cisplatin. Here we show that cloperastine and two other histamine H1 receptor antagonists selectively kill HeLa cisR cells at concentrations that little affect parental HeLa S cells. The sensitivity of HeLa cisR cells to cloperastine was abolished by knocking down FGF13 expression. Cisplatin-resistant A549 cisR cells were similarly susceptible to cloperastine. H2, H3, and H4 receptor antagonists showed less or no cytotoxicity toward HeLa cisR or A549 cisR cells. These results indicate that histamine H1 receptor antagonists selectively kill cisplatin-resistant human cancer cells and suggest that this effect is exerted through a molecular mechanism involving autocrine histamine activity and high-level expression of FGF13. We think this represents a potential opportunity to utilize H1 receptor antagonists in combination with anticancer agents to treat cancers in which emergent drug-resistance is preventing effective treatment.

Topics: Apoptosis; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Fibroblast Growth Factors; Gene Expression; Gene Expression Regulation, Neoplastic; HeLa Cells; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Neoplasms; Piperidines; Receptors, Histamine H1

To describe the incidence, severity and progression of proteinuria over the first 6 months of masitinib treatment in tumour-bearing dogs without pre-existing proteinuria. To describe the effect of treatment on urine protein:creatinine and renal parameters in patients with pre-existing proteinuria.. Records were reviewed from patients receiving masitinib for neoplasms between June 1, 2010, and May 5, 2019. Patients without pre-treatment and at least one urine protein:creatinine after ≥7 days treatment were excluded. Signalment, tumours and concurrent diseases, treatments, haematology, biochemistry and urinalysis results before, during and after treatment for up to 202 days were collected. Patient visits were grouped into six timepoints for analysis.. Twenty-eight dogs were included. Eighteen percent of dogs non-proteinuric at baseline (four of 22) developed proteinuria during treatment, all within 1 month of treatment initiation. One dog developed hypoalbuminaemia, none developed oedema or ascites, azotaemia or were euthanased/died due to proteinuria. Masitinib was immediately discontinued in both dogs in which urine protein:creatinine greater than 2.0 was detected and in both, proteinuria improved. Six dogs with pre-treatment proteinuria were treated with masitinib, significant worsening of proteinuria did not occur. Neither azotaemia nor severe hypoalbuminaemia occurred.. Proteinuria, when it occurs, tends to develop within 1 month of masitinib commencement and may progress rapidly. Weekly proteinuria monitoring should be considered for the first month and a urine protein:creatinine greater than 0.5 should prompt reassessment within 1 week. Masitinib treatment can be considered in patients with pre-treatment proteinuria and does not inevitably cause worsening of proteinuria.

Topics: Animals; Benzamides; Creatinine; Dog Diseases; Dogs; Neoplasms; Piperidines; Proteinuria; Pyridines; Thiazoles

Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (

Topics: Animals; Azetidines; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Dogs; Drug Combinations; Drug Synergism; Female; Humans; Madin Darby Canine Kidney Cells; Mice, Nude; Molecular Structure; Mutation; Neoplasms; Phenylurea Compounds; Piperidines; Protein Binding; Protein Kinase Inhibitors; Quinazolinones; raf Kinases; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity that can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically-based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model-predicted plasma exposures in patients with different health conditions within average 2-fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively, in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively, in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non-small cell lung cancer, moderate HIP, and severe HIP at 1-, 1.5-, and 1.8-fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Carbazoles; Fasting; Female; Humans; Liver Diseases; Male; Middle Aged; Models, Biological; Neoplasms; Nitriles; Panobinostat; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Renal Insufficiency

Anaplastic lymphoma kinase (. We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare. This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with

Topics: Adolescent; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Crizotinib; Female; Gene Rearrangement; Humans; Male; Middle Aged; Neoplasms; Piperidines; Retrospective Studies; Treatment Outcome; Young Adult

Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.

Topics: Adenine; Animals; Autophagy; Beclin-1; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; Enzyme Activation; Mice; Neoplasms; Nuclear Proteins; Phosphoprotein Phosphatases; Phosphorylation; Phosphotyrosine; Piperidines; Protein Binding; Proto-Oncogene Proteins c-akt; Signal Transduction; src-Family Kinases; Tacrolimus Binding Proteins

In this study, the pharmacological properties of six spirocyclic piperidines 1-6 showing very high σ. In vitro receptor binding studies, retinal ganglion assay and in vivo capsaicin assay were used to determine the affinity, selectivity and activity. Influence on human tumour cell growth (cell lines A427, LCLC-103H, 5637 and DAN-G) was determined in different assays. The effect on the ergosterol and cholesterol biosynthesis was determined by GLC/MS analysis.. Receptor binding studies demonstrated high selectivity for the σ. Due to the high selectivity, off-target effects are not expected. The antiallodynic activity underlines the clinical potential of the spirocyclic piperidines for the treatment of neuropathic pain. Due to the antiproliferative activity, the spirocyclic σ

Topics: Animals; Antineoplastic Agents; Calcium; Cell Line, Tumor; Furans; Humans; Ligands; Mice; Mice, Inbred C57BL; Neoplasms; Piperidines; Pyrans; Receptors, sigma; Sigma-1 Receptor; Spiro Compounds; Structure-Activity Relationship

Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for patients with CD19 B-cell malignancies. Combination strategies that improve CAR T-cell potency, limit tumor environment-mediated immune dysfunction, and directly reduce tumor burden may increase the potential for durable clinical benefit of CAR T-cell therapy. Lisocabtagene maraleucel (liso-cel) is a product therapy candidate being tested in patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia. This study assessed the in vitro and in vivo functionality of CAR T cells transduced to express the anti-CD19 CAR of liso-cel in combination with ibrutinib or acalabrutinib. In prolonged stimulation assays, the presence of ibrutinib or acalabrutinib improved the CAR T-cell effector function. RNA-Seq analysis and surface marker profiling of these CAR T cells treated with ibrutinib but not acalabrutinib revealed gene expression changes consistent with skewing toward a memory-like, type 1 T-helper, Bruton tyrosine kinase phenotype. Ibrutinib or acalabrutinib improved CD19 tumor clearance and prolonged survival of tumor-bearing mice when used in combination with CAR T cells. A combination of the defined cell product therapy candidate, liso-cel, with ibrutinib or acalabrutinib is an attractive approach that may potentiate the promising clinical responses already achieved in CD19 B-cell malignancies with each of these single agents.

Topics: Adenine; Animals; Antigens, CD19; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers; Combined Modality Therapy; Cytokines; Cytotoxicity, Immunologic; Disease Models, Animal; Humans; Immunotherapy, Adoptive; Lymphocyte Activation; Mice; Neoplasms; Piperidines; Pyrazines; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome; Xenograft Model Antitumor Assays

Topics: Adenine; B-Lymphocytes; Cell Line; Humans; Mutation; Neoplasms; Piperidines; Protein Kinase Inhibitors

Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.

Topics: Antineoplastic Agents; Binding Sites; Cyclin-Dependent Kinases; Dyrk Kinases; HEK293 Cells; Humans; Indazoles; Indoles; Isoenzymes; Molecular Docking Simulation; Neoplasms; Phthalazines; Piperazines; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polypharmacology; Protein Binding; Protein Interaction Domains and Motifs; Protein Serine-Threonine Kinases; Protein Structure, Secondary; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Substrate Specificity

The small molecule IACS-010759 has been reported to potently inhibit the proliferation of glycolysis-deficient hypoxic tumor cells by interfering with the functions of mitochondrial NADH-ubiquinone oxidoreductase (complex I) without exhibiting cytotoxicity at tolerated doses in normal cells. Considering the significant cytotoxicity of conventional quinone-site inhibitors of complex I, such as piericidin and acetogenin families, we hypothesized that the mechanism of action of IACS-010759 on complex I differs from that of other known quinone-site inhibitors. To test this possibility, here we investigated IACS-010759's mechanism in bovine heart submitochondrial particles. We found that IACS-010759, like known quinone-site inhibitors, suppresses chemical modification by the tosyl reagent AL1 of Asp

Topics: Animals; Cattle; Cell Hypoxia; Electron Transport Complex I; Glycolysis; Humans; Mitochondria, Heart; Neoplasm Proteins; Neoplasms; Oxadiazoles; Piperidines

Topics: Adenine; B-Lymphocytes; Consensus; Humans; Immunosuppressive Agents; Mycoses; Neoplasms; Piperidines

Due to the highly complex biological formation procedure, tumor is still difficult to be treated efficiently and always associated with proliferation, migration and inflammation during treatment. Herein, a novel strategy of boosted photocatalytic activity induced NAMPT-regulating therapy is used for tumors inhibition based on FK866 loaded bismuth-humic acids heterojunction (Bi-HA/FK866). With the reduction function of HA, Bi (Ⅲ) can be reduced to elemental Bi, which can be excited by NIR laser to form electron-hole pair due to the narrow bandgap. Moreover, the coated HA and Bi could form a heterojunction structure, which could decrease the electron-hole recombination, and further boost the photocatalytic activity, leading to highly efficient ROS generation and GSH depletion. The resulted ROS could induce DNA damage of the tumor cells, thus enhancing the sensitivity to the inhibitor of NAMPT (FK866) to downregulate NAD/ERK/NF-κB signal pathways, and eventually simultaneously prevent cancer progression. Moreover, the decreased NAD could downregulate NADPH and further suppress the innate antioxidant defense system by inhibiting reduction of GSSG. The boosted photocatalytic activity induced NAMPT-regulating therapy offers a promising way to address the important issue of penetration depth limitation induced cancer relapse and migration, providing more possibilities toward successful clinical application.

Topics: Acrylamides; Bismuth; Cell Proliferation; Cytokines; Humans; Humic Substances; Inflammation; Neoplasms; Piperidines

Ibrutinib treatment has been shown to increase survival in patients with B cell malignancies. Real-life data suggest a large part of discontinuations are due to toxicities, impairing ibrutinib efficacy. We aimed to assess the impact of a pharmaceutical care program on the efficacy and safety of ibrutinib. This single-center, cohort, observational study enrolled patients with B cell malignancies. Patients were either assigned to the program or to receive usual care, based on physician decision. The program was conducted by clinical pharmacists specializing in oncology and included patient education for management of toxicities, adherence monitoring, interventions to reduce drug-drug interactions, and follow-up of transition from hospital to community. Between February 2014 and May 2017, we enrolled 155 patients, including 42 (27%) who were allocated to the program group and 113 (73%) to the usual care group. The effect of the program was beneficial in terms of time to treatment failure (p = 0.0005). The 30-month progression-free and overall survivals were significantly superior in the program group (respectively p = 0.002 and p = 0.004). Grade 3 or higher adverse events occurred more frequently for patients in the usual care group (15%) than program group (8%). A pharmaceutical care program provides a personalized environment for outpatient monitoring and control of the key risks associated with oral anticancer agents. This study shows evidence that management of ibrutinib treatment by clinical pharmacists results in significant improvement in survival and better tolerance than usual care.

Topics: Adenine; Aged; Aged, 80 and over; Cohort Studies; Efficiency, Organizational; Female; Humans; Male; Middle Aged; Neoplasms; Pharmaceutical Services; Pharmacists; Piperidines; Pyrazoles; Pyrimidines; Quality Improvement; Survival Analysis; Time Factors; Time-to-Treatment; Treatment Failure

It has been proposed that a mitochondrial switch involving a high mitochondrial superoxide production is associated with cancer metastasis. We here report an EPR analysis of ROS production using cyclic hydroxylamines in superinvasive SiHa-F3 compared with less invasive SiHa wild-type human cervix cancer cells. Using the CMH probe, no significant difference was observed in the overall level of ROS between SiHa and SiHa-F3 cells. However, using mitochondria-targeted cyclic hydroxylamine probe mitoTEMPO-H, we detected a significantly higher mitochondrial ROS content in SiHa-F3 compared with the wild-type SiHa cells. To investigate the nature of mitochondrial ROS, we overexpressed superoxide dismutase 2, a SOD isoform exclusively localized in mitochondria, in SiHa-F3 superinvasive cells. A significantly lower signal was detected in SiHa-F3 cells overexpressing SOD2 compared with SiHa-F3. Despite some limitations discussed in the paper, our EPR results suggest that mitochondrial ROS (at least partly superoxide) are produced to a larger extent in superinvasive cancer cells compared with less invasive wild-type cancer cells.

Topics: Cell Line, Tumor; Electron Spin Resonance Spectroscopy; Female; Humans; Hydroxylamines; Mitochondria; Neoplasm Invasiveness; Neoplasms; Organophosphorus Compounds; Piperidines; Reactive Oxygen Species; Superoxide Dismutase; Superoxides

Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth and metastasis. We have utilized mice over-expressing (Hpa-tg) heparanase to reveal the role of host heparanase in tumor initiation, growth and metastasis. While in wild type mice tumor development in response to DMBA carcinogenesis was restricted to the mammary gland, Hpa-tg mice developed tumors also in their lungs and liver, associating with reduced survival of the tumor-bearing mice. Consistently, xenograft tumors (lymphoma, melanoma, lung carcinoma, pancreatic carcinoma) transplanted in Hpa-tg mice exhibited accelerated tumor growth and shorter survival of the tumor-bearing mice compared with wild type mice. Hpa-tg mice were also more prone to the development of metastases following intravenous or subcutaneous injection of tumor cells. In some models, the growth advantage was associated with infiltration of heparanase-high host cells into the tumors. However, in other models, heparanase-high host cells were not detected in the primary tumor, implying that the growth advantage in Hpa-tg mice is due to systemic factors. Indeed, we found that plasma from Hpa-tg mice enhanced tumor cell migration and invasion attributed to increased levels of pro-tumorigenic factors (i.e., RANKL, SPARC, MIP-2) in the plasma of Hpa-Tg vs. wild type mice. Furthermore, tumor aggressiveness and short survival time were demonstrated in wild type mice transplanted with bone marrow derived from Hpa-tg but not wild type mice. These results were attributed, among other factors, to upregulation of pro-tumorigenic (i.e., IL35

Topics: Animals; Anthracenes; Cell Line, Tumor; Cell Movement; Gene Expression Regulation, Neoplastic; Glucuronidase; Humans; Mice; Mice, Transgenic; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Piperidines; Tumor Microenvironment; Up-Regulation

The C-C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (T

Topics: Animals; Antineoplastic Agents; Azetidines; Cell Line, Tumor; Dogs; Humans; Macaca fascicularis; Neoplasms; Piperidines; Receptors, CCR4; T-Lymphocytes, Regulatory

Ibrutinib is a Burton tyrosine kinase inhibitor (BTKi) approved for the treatment of several hematologic malignancies. Analyze skin adverse events (SAE). All the patients treated with Ibrutinib featuring cutaneous adverse events were selected. Twenty five patients were retrieved with a median interval between Ibrutinib start and SAE time of onset of 120 days. Most common SAE observed involved hairs and nails. Eczematous reaction and leucocytoclastic vasculitis were also detected. One patient had a long-history Ibrutinib treatment and experienced numerous cutaneous adverse events. Infective disease such as superficial mycosis and impetigo were rarely present in our series. Despite the development of cutaneous SAE, all the patients continued their concomitant drugs without the onset of any further SAE. Our data suggest Ibrutinib-associated rash should be distinguished in early and late events and a careful dermatologic management of patients should be scheduled.

Topics: Adenine; Humans; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Topics: Adenine; B-Lymphocytes; Granuloma, Pyogenic; Humans; Neoplasms; Piperidines; Pyrazoles

The combinational therapy is often considered as a desire in chemotherapy despite some limitations. This study aimed to encapsulate two natural-based drugs, curcumin (CUR), and piperine (PIP) into highly biocompatible albumin nanoparticles for anticancer applications.. A simultaneous exertion of CUR and PIP in a biocompatible drug delivery system with the minimum side effects and no limitations was achievable in this work for cancer treatment.. Curcumin and piperine co-loaded human serum albumin nanoparticles (CUR-PIP-HSA-NPs) were synthesized by the self-assembly method. The effectiveness of the codelivery system was evaluated physically, chemically, and pharmaceutically. Moreover, the anticancer activity of CUR-PIP-HSA-NPs was studied on MCF-7 cells by MTT assay.. CUR-PIP-HSA-NPs showed appropriate stability with an average particle size of 154.7 ± 5.2 nm. Loading of drugs was demonstrated by Fourier transform infrared (FT-IR) and differential scanning calorimetry (DSC) analyses. The drug encapsulation efficiencies (DEEs) of CUR and PIP in NPs were 85.3% ± 1.46% and 81.7%, ± 1.67%, respectively. Furthermore, the drug loading efficiency (DLE) of CUR-PIP-HSA-NPs was 8.71% ± 0.24%. The circular dichroism (CD) examination of the NPs confirmed that the conformational structure of albumin remained unchanged during the synthesis. In addition, the cytotoxicity experiments demonstrated the high potential of CUR-PIP-HSA-NPs against breast cancer (MCF-7) cells in the presence of PIP as both bioenhancer and anticancer drug with the capability of suppressing the effect of multidrug resistance (MDR).. The results suggest that CUR-PIP-HSA-NPs can be employed as a practical drug delivery system in cancer treatment with synergistic effects of both CUR and PIP.

Topics: Alkaloids; Benzodioxoles; Curcumin; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Particle Size; Piperidines; Polyunsaturated Alkamides; Serum Albumin, Human; Spectroscopy, Fourier Transform Infrared

Bromodomain (BRD), a protein module that recognizes acetylated lysine residues on histones and other proteins, has recently emerged as a promising therapeutic target for human diseases such as cancer. While most of the studies have been focused on inhibitors against BRDs of the bromo- and extra-terminal domain (BET) family proteins, non-BET family BRD inhibitors remain largely unexplored. Here, we investigated a potential anticancer activity of the recently developed non-BET family BRD inhibitor NVS-CECR2-1 that targets the cat eye syndrome chromosome region, candidate 2 (CECR2). We show that NVS-CECR2-1 inhibits chromatin binding of CECR2 BRD and displaces CECR2 from chromatin within cells. NVS-CECR2-1 exhibits cytotoxic activity against various human cancer cells, killing SW48 colon cancer cells in particular with a submicromolar half maximum inhibition value mainly by inducing apoptosis. The sensitivity of the cancer cells to NVS-CECR2-1 is reduced by CECR2 depletion, suggesting that NVS-CECR2-1 exerts its activity by targeting CECR2. Interestingly, our data show that NVS-CECR2-1 also kills cancer cells by CECR2-independent mechanism. This study reports for the first time the cancer cell cytotoxic activity for NVS-CECR2-1 and provides a possibility of this BRD inhibitor to be developed as an anticancer therapeutic agent.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Chromatin; Colonic Neoplasms; Humans; Indoles; Inhibitory Concentration 50; Neoplasms; Piperidines; Proteins; Pyrimidines; Transcription Factors

Piperine, a bioactive alkaloid, is known to have anticancer activities. Hence, in this study, the effectiveness of piperine pretreatment as a strategy for radio-sensitizing colorectal adenocarcinoma cell line (HT-29) was analyzed. For this, HT-29 cells were pretreated with piperine (12.5 and 25 µg/mL) and exposed to γ-radiation (1.25 Gy) and analyzed for various effector pathways to elucidate the possible mode of action in comparison to individual treatments. The proliferation efficiency of the cells was analyzed by trypan blue dye exclusion assay and MTT assay. The synergistic effects of the combination treatment were analyzed with compuSyn software. Downstream signaling pathways leading to apoptosis were studied using flowcytometry, immunofluorescence, and immunoblot assays. It was observed that combination treatment arrested HT-29 cells at G2/M phase nearly 2.8 folds higher than radiation treatment alone, inducing the radio-resistant cells to undergo apoptosis through mitochondria-dependent pathway. In addition, activation of caspase-3 and cleavage of poly(ADP-ribose) polymerases-1, the key molecular events in apoptotic signaling, were significantly enhanced. Activation of estrogen receptor beta (ERβ), a nuclear hormone transcription factor promoting tumor suppression represents a novel clinical advance towards management and prevention of cancers. Interestingly, the expression of ERβ was increased in the cells treated with piperine. In conclusion, piperine pretreatment enhances radio-sensitization in HT-29 cells by inducing the cells to undergo apoptosis hence, can be used as a classic candidate for colon cancer sensitization towards radiotherapy. PRACTICAL APPLICATION: Piperine induces enhanced radiosensitization of colon cancer cell line (HT-29) by interfering with the cancer cell line proliferation, DNA damage, and apoptosis.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Caspase 3; Cell Line, Tumor; Cell Proliferation; HT29 Cells; Humans; Mitochondria; Neoplasms; Piperidines; Poly (ADP-Ribose) Polymerase-1; Polyunsaturated Alkamides; Radiation; Signal Transduction

Topics: Adenine; Atrial Fibrillation; Humans; Neoplasms; Piperidines; Pyrazoles; Pyrimidines

Efficiently delivering plasmid DNA (pDNA) to the spleen is particularly significant for DNA immunization. However, increasing the efficiency of gene expression in spleen cells for achieving a therapeutic effect remains a serious challenge. An ideal spleen-targeted system should avoid liver uptake and should efficiently transfect specific functional spleen cells. Here, we report on pDNA nanocarriers with enhanced transfection in spleen cells driven by synergism between an octaarginine (R8) peptide and YSK05; a pH-responsive ionizable lipid. A double-coating design is essential for enhancing spleen selective transfection which is significantly affected by the total amount of lipid and the composition of the outer coat. The optimized R8/YSK system shows a high gene expression in the spleen with a high spleen/liver ratio and a surprising ability to target spleen B cells. Compared to other organs, the high spleen activity cannot be explained based on the amount of pDNA delivered to each organ, indicating that the system is extremely efficient in transfecting spleen cells. The system can be used in cancer immunization where a strong anti-tumor effect was observed in mice immunized with the R8/YSK system encapsulating antigen-encoding pDNA. The R8/YSK system holds great promise for future applications in the field of DNA vaccination.

Topics: Animals; B-Lymphocytes; DNA; Female; Gene Transfer Techniques; Humans; Hydrogen-Ion Concentration; Immunization; Lipids; Liver; Male; Mice, Inbred C57BL; Mice, Inbred ICR; Nanocapsules; Neoplasms; Oligopeptides; Piperidines; Plasmids; Spleen; Transfection

Magnetic resonance imaging examinations are frequently carried out using contrast agents to improve the image quality. Practically all clinically used contrast agents are based on paramagnetic metals and lack in selectivity and specificity. A group of stable organic radicals, nitroxides, has raised interest as new metal-free contrast agents for MRI. Their structures can easily be modified to incorporate different functionalities. In the present study, a stable nitroxide TEEPO (2,2,6,6-tetraethylpiperidin-1-oxyl) was linked to a glucose moiety (Glc) to construct a water-soluble, potentially tumor-targeting compound with contrast-enhancing ability. The ability was assessed with

Topics: Animals; Contrast Media; Cyclic N-Oxides; Electron Spin Resonance Spectroscopy; HeLa Cells; Humans; Magnetic Resonance Imaging; Neoplasms; Piperidines; Rats; Spin Labels

Topics: Azetidines; Giant Cell Arteritis; Humans; Neoplasms; Piperidines; Polymyalgia Rheumatica; Prospective Studies

Topics: Azetidines; Giant Cell Arteritis; Humans; Neoplasms; Piperidines; Polymyalgia Rheumatica; Prospective Studies

Tumor-associated neutrophils (TANs) regulate many processes associated with tumor progression, and depending on the microenvironment, they can exhibit pro- or antitumor functions. However, the molecular mechanisms regulating their tumorigenicity are not clear. Using transplantable tumor models, we showed here that nicotinamide phosphoribosyltransferase (NAMPT), a molecule involved in CSF3R downstream signaling, is essential for tumorigenic conversion of TANs and their pro-angiogenic switch. As a result tumor vascularization and growth are strongly supported by these cells. Inhibition of NAMPT in TANs leads to their antitumor conversion. Adoptive transfer of such TANs into B16F10-tumor bearing mice attenuates tumor angiogenesis and growth. Of note, we observe that the regulation of NAMPT signaling in TANs, and its effect on the neutrophil tumorigenicity, are analogous in mice and human. NAMPT is up-regulated in TANs from melanoma and head-and-neck tumor patients, and its expression positively correlates with tumor stage. Mechanistically, we found that targeting of NAMPT suppresses neutrophil tumorigenicity by inhibiting SIRT1 signaling, thereby blocking transcription of pro-angiogenic genes. Based on these results, we propose that NAMPT regulatory axis is important for neutrophils to activate angiogenic switch during early stages of tumorigenesis. Thus, identification of NAMPT as the critical molecule priming protumor functions of neutrophils provides not only mechanistic insight into the regulation of neutrophil tumorigenicity, but also identifies a potential pathway that may be targeted therapeutically in neutrophils. This, in turn, may be utilized as a novel mode of cancer immunotherapy.

Topics: Acrylamides; Adoptive Transfer; Adult; Animals; Cell Line, Tumor; Cells, Cultured; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Neoplasms; Neovascularization, Pathologic; Neutrophils; Nicotinamide Phosphoribosyltransferase; Piperidines; Signal Transduction; Tumor Burden

Pharmacologic targeting of components of ERK signaling in ERK-dependent tumors is often limited by adaptive resistance, frequently mediated by feedback-activation of RTK signaling and rebound of ERK activity. Here, we show that combinatorial pharmacologic targeting of ERK signaling and the SHP2 phosphatase prevents adaptive resistance in defined subsets of ERK-dependent tumors. In each tumor that was sensitive to combined treatment, p(Y542)SHP2 induction was observed in response to ERK signaling inhibition. The strategy was broadly effective in TNBC models and tumors with RAS mutations at G12, whereas tumors with RAS(G13D) or RAS(Q61X) mutations were resistant. In addition, we identified a subset of BRAF(V600E) tumors that were resistant to the combined treatment, in which FGFR was found to drive feedback-induced RAS activation, independently of SHP2. Thus, we identify molecular determinants of response to combined ERK signaling and SHP2 inhibition in ERK-dependent tumors.

Topics: Animals; Cell Line, Tumor; Colonic Neoplasms; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Female; HEK293 Cells; HeLa Cells; HT29 Cells; Humans; MAP Kinase Signaling System; Mice; Mice, Nude; Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyrimidines; Signal Transduction; Xenograft Model Antitumor Assays

The routes by which antibody-based therapeutics reach malignant cells are poorly defined. Tofacitinib, an FDA-approved JAK inhibitor, reduced tumor-associated inflammatory cells and allowed increased delivery of antibody-based agents to malignant cells. Alone, tofacitinib exhibited no antitumor activity, but combinations with immunotoxins or an antibody-drug conjugate resulted in increased antitumor responses. Quantification using flow cytometry revealed that antibody-based agents accumulated in malignant cells at higher percentages following tofacitinib treatment. Profiling of tofacitinib-treated tumor-bearing mice indicated that cytokine transcripts and various proteins involved in chemotaxis were reduced compared with vehicle-treated mice. Histological analysis revealed significant changes to the composition of the tumor microenvironment, with reductions in monocytes, macrophages, and neutrophils. Tumor-associated inflammatory cells contributed to non-target uptake of antibody-based therapeutics, with mice treated with tofacitinib showing decreased accumulation of therapeutics in intratumoral inflammatory cells and increased delivery to malignant cells. The present findings serve as a rationale for conducting trials where short-term treatments with tofacitinib could be administered in combination with antibody-based therapies.

Topics: Animals; Antibodies; Arginase; Breast Neoplasms; Cell Line, Tumor; Cytokines; Disease Models, Animal; Female; Immunoconjugates; Immunotherapy; Immunotoxins; Macrophages; Mice; Mice, Nude; Monocytes; Neoplasms; Neutrophils; Piperidines; Pyrimidines; Pyrroles; RNA, Messenger; Tumor Microenvironment; Xenograft Model Antitumor Assays

Topics: Adenine; Aged; Atrial Fibrillation; Comorbidity; Electrocardiography; Female; Heart Failure; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Patient Outcome Assessment; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies; Risk Factors

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Humans; Neoplasms; Piperidines; Pyrazoles; Pyrimidines

Tyrosine kinases play crucial roles in cellular development and tumorigenesis. Tyrosine kinase inhibitors (TKIs) are effective and widely used drug molecules in targeted cancer therapies. Altered expressions of protooncogenes and tumor suppressor genes after DMBA (7,12-dimethylbenz[a]anthracene) treatment have been described as early markers of tumor induction; however their tissue-specific effects remain still unclear. Our study was aimed at examining the short-term possible antineoplastic and chemopreventive effects of a TKI compound (imatinib mesylate) on a DMBA-induced mouse tumor model. In addition, we also investigated the tissue-specific expressions of

Topics: Animals; Anthracenes; Anticarcinogenic Agents; Gene Expression Regulation, Neoplastic; Humans; Imatinib Mesylate; Mice; Neoplasms; Organ Specificity; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); Tumor Suppressor Protein p53

We report tofacitinib efficacy and safety in Asia-Pacific patients who participated in the rheumatoid arthritis (RA) clinical development program.. This post-hoc analysis included pooled data from patients with RA in the Asia-Pacific region treated with tofacitinib with/without conventional synthetic disease-modifying antirheumatic drugs in Phase (P)1, 2, 3, and long-term extension (LTE) studies (one LTE ongoing; January 2016 data-cut). Efficacy was assessed over 24 months in patients who received tofacitinib 5 (N = 397) or 10 (N = 382) mg twice daily or placebo (N = 243) in three P2 and five P3 studies. Endpoints included American College of Rheumatology (ACR)20/50/70 responses, Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4[ESR]) and Clinical Disease Activity Index (CDAI) remission rates, and change from baseline in Health Assessment Questionnaire-Disability Index (∆HAQ-DI). Safety data pooled over 92 months from one P1, four P2, six P3, and two LTE studies for all tofacitinib doses (N = 1464) included incidence rates (IRs) (patients with events/100 patient-years) for adverse events (AEs) of special interest.. At month 3, patients receiving tofacitinib 5/10 mg twice daily improved vs placebo in ACR20 (69.2%/77.9% vs 27.5%), ACR50 (36.9%/44.4% vs 9.5%), and ACR70 (15.1%/22.4% vs 2.7%) responses, remission rates for DAS28-4(ESR) (8.5%/18.5% vs 2.6%) and CDAI (6.1%/12.3% vs 0.5%), and ∆HAQ-DI (-0.5/-0.6 vs -0.1); improvements were sustained through 24 months. IRs (95% CI) were 9.4 (8.5, 10.3) for serious AEs, 9.1 (8.3, 10.1) for discontinuations due to AEs, 3.7 (3.2, 4.3) for serious infections, 5.9 (5.2, 6.7) for herpes zoster, and 0.8 (0.6, 1.1) for malignancies (excluding non-melanoma skin cancer).. In Asia-Pacific patients, tofacitinib improved signs/symptoms over 24 months. Safety over 92 months was generally consistent with global tofacitinib studies; however, infection IRs were higher in Asia-Pacific patients.

Topics: Adult; Arthritis, Rheumatoid; Asia; Clinical Trials as Topic; Evidence-Based Medicine; Female; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Neoplasms; Opportunistic Infections; Piperidines; Pyrimidines; Pyrroles; Recovery of Function; Remission Induction; Risk Factors; Time Factors; Treatment Outcome

Sigma-1 receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the sigma-1 receptor. In this study, we aimed to develop probes with higher affinity for the sigma-1 receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the sigma-1 receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The sigma-1 receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol (5) (K

Topics: Animals; Aza Compounds; Cell Line, Tumor; Humans; Iodine Radioisotopes; Isotope Labeling; Male; Mice; Mice, Nude; Neoplasms; Piperidines; Protein Binding; Radiopharmaceuticals; Receptors, sigma; Sigma-1 Receptor; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Transplantation, Heterologous

Topics: Adenine; Adult; Aged; Aged, 80 and over; B-Lymphocytes; Female; Humans; Incidence; Male; Middle Aged; Neoplasms; Opportunistic Infections; Piperidines; Pyrazoles; Pyrimidines; Young Adult

Ibrutinib (IBR), an irreversible Bruton's tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)-stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted immunotherapy. Amphiphilic egg phosphatidylglycerol (EPG) structure and strong IBR-EPG interactions render these nanocomplexes high IBR loading capacity, prolonged blood circulation, and optimal particle sizes (∼30 nm), which can effectively deliver IBR to the tumor, followed by subsequent internalization of IBR by TAMs through SA-mediated active targeting. In vitro and in vivo tests showed that the prepared SA/IBR/EPG nanocomplexes could preferentially accumulate in TAMs and exert potent antitumor activity. Immunofluorescence staining analysis further confirmed that SA/IBR/EPG remarkably inhibited angiogenesis and tumorigenic cytokines released by TAM and eventually suppressed tumor progression, without eliciting any unwanted effect. Thus, SA-decorated IBR nanocomplexes present a promising strategy for cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Ibrutinib (IBR), an irreversible Bruton's tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)-stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted delivery of IBR to TAMs. The developed SA/IBR/EPG nanocomplexes exhibited high efficiency in targeting TAMs and inhibiting BTK activation, consequently inhibiting Th2 tumorigenic cytokine release, reducing angiogenesis, and suppressing tumor growth. These results implied that the SA/IBR/EPG nanocomplex could be a promising strategy for TAM-targeting immunotherapy with minimal systemic side effects.

Topics: Adenine; Animals; Drug Delivery Systems; Immunotherapy; Macrophages; Male; Mice; N-Acetylneuraminic Acid; Nanoparticles; Neoplasms; Phosphatidylglycerols; Piperidines; Proton Magnetic Resonance Spectroscopy; Pyrazoles; Pyrimidines; Rats, Wistar; RAW 264.7 Cells; Stearic Acids

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azetidines; Drug Development; Humans; Neoplasms; Piperidines

Topics: Abiraterone Acetate; Adenine; Antineoplastic Agents; Clinical Protocols; Dasatinib; Drug Costs; France; gamma-Glutamyl Hydrolase; Humans; Insurance, Pharmaceutical Services; Medical Oncology; Neoplasms; Nivolumab; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Recombinant Proteins; United States; Zoledronic Acid

Topics: Adenine; Aged; B-Lymphocytes; Hemorrhage; Humans; Neoplasms; Piperidines; Pyrazoles; Pyrimidines

SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell proliferation, differentiation, and survival. Recently, we reported an allosteric mechanism of inhibition that stabilizes the auto-inhibited conformation of SHP2. SHP099 (1) was identified and characterized as a moderately potent, orally bioavailable, allosteric small molecule inhibitor, which binds to a tunnel-like pocket formed by the confluence of three domains of SHP2. In this report, we describe further screening strategies that enabled the identification of a second, distinct small molecule allosteric site. SHP244 (2) was identified as a weak inhibitor of SHP2 with modest thermal stabilization of the enzyme. X-ray crystallography revealed that 2 binds and stabilizes the inactive, closed conformation of SHP2, at a distinct, previously unexplored binding site-a cleft formed at the interface of the N-terminal SH2 and PTP domains. Derivatization of 2 using structure-based design resulted in an increase in SHP2 thermal stabilization, biochemical inhibition, and subsequent MAPK pathway modulation. Downregulation of DUSP6 mRNA, a downstream MAPK pathway marker, was observed in KYSE-520 cancer cells. Remarkably, simultaneous occupation of both allosteric sites by 1 and 2 was possible, as characterized by cooperative biochemical inhibition experiments and X-ray crystallography. Combining an allosteric site 1 inhibitor with an allosteric site 2 inhibitor led to enhanced pharmacological pathway inhibition in cells. This work illustrates a rare example of dual allosteric targeted protein inhibition, demonstrates screening methodology and tactics to identify allosteric inhibitors, and enables further interrogation of SHP2 in cancer and related pathologies.

Topics: Allosteric Regulation; Allosteric Site; Binding Sites; Cell Line, Tumor; Crystallography, X-Ray; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Neoplasms; Piperidines; Protein Conformation; Protein Stability; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyrimidines

Alterations in ERBB family members have been associated with many tumor malignancies. EGFR and ERBB2 have been extensively explored in clinical oncology and several drugs currently target them therapeutically. However, the significance of ERBB4 as a potential therapeutic target remains mostly unexplored, even though ERBB4 is overexpressed or mutated in many solid tumors. Using a unique functional protein microarray platform, we found that ibrutinib inhibits ERBB4 activity in the same nM range as its canonical target, BTK. Cell-based assays revealed that ibrutinib treatment inhibited cell growth and decreased phosphorylation of ERBB4 and downstream targets MEK and ERK in cancer cell lines with high levels of endogenous ERBB4. In vivo, ibrutinib-responsive mouse xenograft tumors showed decreased tumor volumes with ibrutinib treatment. Interestingly, global gene expression comparisons between responsive and non-responsive cells identified a signature featuring the WNT pathway that predicts growth responsiveness to ibrutinib. Non-responsive ERBB4-expressing cell lines featured elevated activity of the WNT pathway, through the overexpression of WNT5A. Moreover, inhibition of WNT5A expression led to an ibrutinib response in non-responsive cell lines. Our data show that inhibiting ERBB4 reduces cell growth in cells that have low WNT5A expression and reveal a link between the ERBB4 and WNT pathways.

Topics: A549 Cells; Adenine; Animals; Cell Proliferation; Cells, Cultured; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasms; Piperidines; Pyrazoles; Pyrimidines; Receptor, ErbB-4; Signal Transduction; Tumor Burden; Wnt-5a Protein; Xenograft Model Antitumor Assays

Cancer is a widespread and life-threatening disease and its early-stage diagnosis is vital. One of the most effective, non-invasive tools in medical diagnostics is magnetic resonance imaging (MRI) with the aid of contrast agents. Contrast agents that are currently in clinical use contain metals, causing some restrictions in their use. Also, these contrast agents are mainly non-specific without any tissue targeting capabilities. Subsequently, the interest has notably increased in the research of organic, metal-free contrast agents. This study presents a new, stable organic radical, TEEPO-Met, where a radical moiety 2,2,6,6-tetraethylpiperidinoxide (TEEPO) is attached to an amino acid, methionine (Met), as a potentially tumour-targeting moiety. We describe the synthesis, stability assessment with electron paramagnetic resonance (EPR) spectroscopy and relaxation enhancement abilities by an in vitro nuclear magnetic resonance (NMR) and phantom MRI studies of TEEPO-Met. The new compound proved to be stable notably longer than the average imaging time in conditions mimicking a biological matrix. Also, it significantly reduced the relaxation times of water, making it a promising candidate as a novel tumour targeting contrast agent for MRI.

Topics: Animals; Contrast Media; Cyclic N-Oxides; Electron Spin Resonance Spectroscopy; Heterocyclic Compounds; Humans; Magnetic Resonance Imaging; Methionine; Molecular Structure; Neoplasms; Phantoms, Imaging; Piperidines

Recent years have seen a number of regulatory approvals for immune oncology or immunotherapies based on their ability to enhance antitumor immune responses. Nevertheless, the majority of patients remain refractory to these treatments; hence, new therapies that augment current immunotherapies are required. Innate immune receptors that recognize nucleic acids are potent activators of subsequent T-cell responses and, as a result, can evoke potent antitumor immune responses. Herein, we present a novel compound N-{3-[(1,4'-bipiperidin)-1'-yl]propyl}-6-[4-(4-methylpiperazin-1-yl)phenyl]picolinamide (SINCRO; STING-mediated interferon-inducing and cytotoxic reagent, original) as an anticancer drug that activates the cytosolic DNA-sensing STING (stimulator of interferon genes) signaling pathway leading to the induction of type I interferon (IFN) genes. Indeed, IFN-β gene induction by SINCRO is abolished in STING-deficient cells. In addition to its IFN-inducing activity, SINCRO shows STING-independent cytotoxic activity against cancer cells. SINCRO does not evoke DNA double-strand break or caspase-3 cleavage. Thus, SINCRO induces cell death in a method different from conventional apoptosis-inducing pathways. Finally, we provide evidence that giving SINCRO significantly attenuates in vivo tumor growth by both type I IFN-dependent and independent mechanisms. Thus, SINCRO is an attractive anticancer compound with dual function in that it evokes type I IFN response to promote antitumor immunity as well as inducing tumor cell death. SINCRO may provide a new platform for the development of drugs for effective cancer therapy.

Topics: 3T3 Cells; Amides; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; DNA Breaks, Double-Stranded; HEK293 Cells; HeLa Cells; Humans; Immunity, Innate; Interferon-beta; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; Picolinic Acids; Piperidines; Signal Transduction

To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking mitogen-activated protein kinase kinase (MEK) inhibitors.. A total of 313 fluid foci in 50 eyes of 25 patients receiving MEK inhibitors for treatment of their metastatic cancer, who had evidence of serous retinal detachments confirmed by optical coherence tomography (OCT).. Single-center, retrospective cohort study.. Clinical examination and OCT were used to evaluate MEK inhibitor-associated subretinal fluid. The morphology, distribution, and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation, and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate interobserver findings and compare choroidal thickness and visual acuity at each time point.. Comparison of OCT characteristics of retinal abnormalities at baseline to fluid accumulation.. The majority of patients had fluid foci that were bilateral (92%) and multifocal (77%) and at least 1 focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into 4 morphologies, as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy, and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than 2 Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation, and fluid resolution). A strong positive interobserver correlation was obtained for choroidal thickness measurements (r = 0.97, P < 0.0001) and grading of foci morphology (r = 0.97, P < 0.0001).. The subretinal fluid foci associated with MEK inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK inhibitors did not cause irreversible loss of vision or serious eye damage.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Azetidines; Benzimidazoles; Central Serous Chorioretinopathy; Female; Fluorescein Angiography; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Retinal Detachment; Retrospective Studies; Subretinal Fluid; Tomography, Optical Coherence; Visual Acuity; Young Adult

Polymeric nanoreactors (NRs) have distinct advantages to improve chemical reaction efficiency, but the in vivo applications are limited by lack of tissue-specificity. Herein, novel glucose oxidase (GOD)-loaded therapeutic vesicular NRs (theraNR) are constructed based on a diblock copolymer containing poly(ethylene glycol) (PEG) and copolymerized phenylboronic ester or piperidine-functionalized methacrylate (P(PBEM-co-PEM)). Upon systemic injection, theraNR are inactive in normal tissues. At a tumor site, theraNR are specifically activated by the tumor acidity via improved permeability of the membranes. Hydrogen peroxide (H

Topics: Antineoplastic Agents; Antioxidants; Boronic Acids; Cell Death; Cell Membrane Permeability; Drug Carriers; Esters; Glucose Oxidase; Glutathione; Humans; Hydrogen Peroxide; Hydrogen-Ion Concentration; Indolequinones; Methacrylates; Microscopy, Electron, Transmission; Nanostructures; Neoplasms; Piperidines; Polyethylene Glycols; Proof of Concept Study

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.

Topics: Animals; Apoenzymes; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Female; Humans; Mice; Models, Molecular; Neoplasms; Piperidines; Proto-Oncogene Proteins c-mdm2; Pyrazoles; Pyrimidines; Substrate Specificity; Transcription, Genetic; Tumor Suppressor Protein p53; Ubiquitin-Specific Peptidase 7; Ubiquitination; Xenograft Model Antitumor Assays

Recent animal studies demonstrated immunosuppressive effects of opioid withdrawal resulting in a higher risk of infection. The aim of this study was to determine the impact of remifentanil discontinuation on Post-Anesthesia Care Unit (PACU)-acquired infection after a schedule of sedoanalgesia of at least 6 days.. All patients over 18 years of age with a unit admission of more than 4 days were consecutively selected. The study population was the one affected by surgical pathology of any origin where sedation was based on any hypnotic and the opioid remifentanil was used as analgesic for at least 96 hours in continuous perfusion. Patients who died during admission to the unit and those with combined analgesia (peripheral or neuroaxial blocks) were excluded. Bivariate analysis was performed to determine risk factors for infection acquired in the unit. A comparative study between periods of 6 days before and after the cessation of remifentanil was performed. Paired samples test and McNemar test was used for quantitative and categorical variables, respectively.. There were 1,789 patients admitted to the PACU during the study and the population eligible was constituted for 102 patients. The incidence rate of PACU-acquired infection was 38 per 1,000 PACU days. Ventilator-associated pneumonia was the most frequently diagnosed PACU-acquired infection. Pseudomona aeruginosa was the most frequently isolated microorganism. Hospital mortality was 36.27%. No statistically significant differences were seen in the incidence of HAI in cancer patients in relation to discontinuation of remifentanil (p=0.068).. The baseline state of immunosuppression of cancer patients does not imply a higher incidence of HAI in relation to the interruption of remifentanil. It would be of interest to carry out a multicenter PACU study that included immunological patterns.

Topics: Aged; Analgesics, Opioid; Cross Infection; Female; Humans; Immunosuppressive Agents; Male; Midazolam; Middle Aged; Neoplasms; Pain, Postoperative; Piperidines; Propofol; Remifentanil; Withholding Treatment

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To characterise the relative safety profile of tofacitinib to biologic disease-modifying antirheumatic drugs (bDMARDs), the accrued patient-years (pt-yrs) of exposure needed in an RA clinical trial programme to detect a potential increase in risk of specific adverse events (AEs) was determined. This case study/framework was constructed on the pt-yrs' accrual within pooled phase (P)1, P2 and P3, as well as long-term extension, studies of tofacitinib in RA (March 2015 data-cut) and published AE incidence rates for bDMARDs. Sample size calculations were based on a Poisson distribution to estimate pt-yrs' exposure required for 90 % probability that the lower bound of the 95 % confidence interval for tofacitinib/bDMARD would be >1, assuming that tofacitinib rates were 1.2×/1.5×/2.0× greater than comparator rates. AE rates for bDMARDs were derived from sources intended to optimise similarity with the tofacitinib database in terms of baseline characteristics, study duration and follow-up. Based on the tofacitinib exposure accrued (19,406 pt-yrs), data were sufficient (90 % probability) to detect potential differences over external bDMARD comparator rates in serious infections (≥1.2×), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE) and lymphoma (each ≥1.5×), as well as opportunistic infections and gastrointestinal perforations (≥2×), should they exist. This risk characterisation approach can support the comparative safety of new RA medications. To date, tofacitinib safety appears similar to approved published data from bDMARDs with respect to serious infections, malignancies (excluding NMSC), NMSC, MACE, lymphoma, opportunistic infections and gastrointestinal perforations.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Neoplasms; Opportunistic Infections; Piperidines; Pyrimidines; Pyrroles; Risk Assessment

Topics: Alanine; Alkaloids; Benzodioxoles; Humans; Inhibitor of Apoptosis Proteins; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Piperidines; Polyunsaturated Alkamides; Protein Binding; Survivin; User-Computer Interface

Thioredoxin reductase (TrxR) and thioredoxin (Trx) are two major components of the thioredoxin system, which plays essential roles in regulating cellular redox signaling. Mammalian TrxRs are essential seleno-flavoenzymes with a conserved penultimate selenocysteine (Sec) residue at the C-terminus, and have attracted considerable interests as promising targets for anticancer drugs. Securinine (SCR), a major active alkaloid lactone from the Chinese herbal medicine Securinega suffruticosa, has been established clinical success in treatment of neurological disorders. Recently, increasing evidence demonstrates that SCR has potential cytotoxicity to various types of tumor cells, which enables this old central nervous system drug as a potential cancer therapeutic agent. However, the mechanism underlying the anticancer activity of SCR is not well defined. We reported here that SCR inhibits both the purified TrxR and the enzyme in intact cells. SCR elicits accumulation of reactive oxygen species (ROS), elevation of oxidized glutathione and Trx, disturbs redox homeostasis, and eventually leads to oxidative stress-mediated HeLa cell apoptosis. Importantly, pharmacological inhibition or knockdown of TrxR sensitizes the cells to SCR treatment, underpinning the physiological significance of targeting TrxR by SCR. Our discovery discloses a novel mechanism underlying the anticancer activity of SCR and provides basic data for further development of SCR as a cancer chemotherapeutic drug.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Azepines; Cell Line, Tumor; Enzyme Inhibitors; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Neoplasms; Oxidation-Reduction; Oxidative Stress; Piperidines; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Humans; Neoplasms; NF-kappa B; Piper nigrum; Piperidines; Signal Transduction

Extended-release (XR) formulations enable less frequent dosing vs. conventional (e.g., immediate release (IR)) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model-informed, exposure-response (E-R) approach to translate controlled trial data from one formulation to another without a phase III trial, using a tofacitinib case study. Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). E-R analyses were conducted using validated clinical endpoints from phase II dose-response and nonclinical dose fractionation studies of the IR formulation. Consistent with the delay in clinical response dynamics relative to PK, average concentration was established as the relevant PK parameter for tofacitinib efficacy and supported pharmacodynamic similarity. These evaluations, alongside demonstrated equivalence in total systemic exposure between IR and XR formulations, provided the basis for the regulatory approval of tofacitinib XR once daily by the US Food and Drug Administration.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Area Under Curve; Delayed-Action Preparations; Drug Administration Schedule; Drug Approval; Humans; Janus Kinases; Male; Metabolic Clearance Rate; Models, Animal; Models, Biological; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rats, Sprague-Dawley; Therapeutic Equivalency; Treatment Outcome; United States; United States Food and Drug Administration

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We report an integrated safety summary of tofacitinib from two phase I, nine phase II, six phase III and two long-term extension studies in adult patients with active RA.. Data were pooled for all tofacitinib-treated patients (data cut-off: 31 March 2015). Incidence rates (IRs; patients with event/100 patient-years) and 95% CIs are reported for adverse events (AEs) of interest.. 6194 patients received tofacitinib for a total 19 406 patient-years' exposure; median exposure was 3.4 patient-years. IR (95% CI) for serious AEs was 9.4 (9.0 to 9.9); IR for serious infections was 2.7 (2.5 to 3.0). IR for (all) herpes zoster was 3.9 (3.6 to 4.2); IR for disseminated or multidermatomal herpes zoster was 0.3 (0.2 to 0.4). IR for opportunistic infections (excluding tuberculosis) was 0.3 (0.2 to 0.4) and was 0.2 (0.1 to 0.3) for tuberculosis. IR for malignancies (excluding non-melanoma skin cancer (NMSC)) was 0.9 (0.8 to 1.0); NMSC IR was 0.6 (0.5 to 0.7). IR for gastrointestinal perforations was 0.1 (0.1 to 0.2). Analysis of IR for serious infections, herpes zoster and malignancies by 6-month intervals did not reveal any notable increase in IR with longer-duration tofacitinib exposure.. This analysis of tofacitinib exposure up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. AEs were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports.. NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT00413699, NCT00661661; Results.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Clinical Trials as Topic; Female; Herpes Zoster; Humans; Immunocompromised Host; Incidence; Infections; Male; Middle Aged; Neoplasms; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Time Factors; Tuberculosis; Young Adult

Paclitaxel is one of the most widely used antineoplastic drugs in the clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP-binding cassette subfamily B member 1 (ABCB1/P-glycoprotein) and subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here, we demonstrated that the Bruton tyrosine kinase inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and ABCC10 in cells overexpressing these transporters. Furthermore, we demonstrated that the ABCB1 or ABCC10 protein expression was not altered after treatment with ibrutinib for up to 72 hours using Western blot analysis. However, the ATPase activity of ABCB1 was significantly stimulated by treatment with ibrutinib. Molecular docking analysis suggested the binding conformation of ibrutinib within the large cavity of the transmembrane region of ABCB1. Importantly, ibrutinib could effectively enhance paclitaxel-induced inhibition on the growth of ABCB1- and ABCC10-overexpressing tumors in nude athymic mice. These results demonstrate that the combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance that could be of great clinical interest.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression; Humans; Male; Mice; Models, Molecular; Molecular Conformation; Multidrug Resistance-Associated Proteins; Neoplasms; Paclitaxel; Piperidines; Protein Binding; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Tumor Burden; Xenograft Model Antitumor Assays

The present study is aimed to elucidate the structural features of substituted 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide required for poly (ADP-ribose) polymerase inhibition and to obtain predictive 2D QSAR models to guide the rational synthesis of novel poly (ADP-ribose) polymerase inhibitors. The statistical analysis has shown that excellent results are obtained by using partial least regression based on simulated annealing method. The best model was selected based on the highest correlation coefficient r (2) = 0.8590, and cross-validated squared correlation coefficient q (2) = 0.7875 with external predictive ability of [Formula: see text] was developed by stepwise PLS method with the descriptors like T_N_F_1, SdsCHcount, and Rotatable Bond Count. The generated models provide insight into the influence of various interactive fields on the activity and, thus, can help in designing and forecasting the inhibition activity of novel (ADP-ribose) polymerase molecules.

Topics: Benzimidazoles; Humans; Inhibitory Concentration 50; Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Quantitative Structure-Activity Relationship

A series of new securinine analogues was prepared by Heck reaction from readily accessible securinine and commercially available iodoarenes. The in vitro cytotoxicity of the prepared compounds was assayed against a panel of four cancer cell lines: A375, A549, HCT-116 and HL-60 showing promising growth inhibition with excellent IC50 values in the nanomolar range. The plasmatic stability of the most potent analogue was also investigated demonstrating that they might serve as valuable leads for the development of anticancer drugs.

Topics: Antineoplastic Agents; Apoptosis; Azepines; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Neoplasms; Piperidines

Topics: Adenine; Antineoplastic Agents; Drug Evaluation; Humans; Neoplasms; Patient Selection; Piperazines; Piperidines; Pragmatic Clinical Trials as Topic; Pyrazoles; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Research Design

Although MAPK pathway inhibitors are becoming a promising anticancer strategy, they are insufficient to fully eliminate cancer cells and their long-term efficacy is strikingly limited in patients with BRAF-mutant melanomas. It is well established that BRAF inhibitors (BRAFi) hamper glucose uptake before the apparition of cell death. Here, we show that BRAFi induce an extensive restructuring of mitochondria including an increase in mitochondrial activity and biogenesis associated with mitochondrial network remodeling. Furthermore, we report a close interaction between ER and mitochondria in melanoma exposed to BRAFi. This physical connection facilitates mitochondrial Ca2+ uptake after its release from the ER. Interestingly, Mfn2 silencing disrupts the ER-mitochondria interface, intensifies ER stress and exacerbates ER stress-induced apoptosis in cells exposed to BRAFi in vitro and in vivo. This mitochondrial control of ER stress-mediated cell death is similar in both BRAF- and NRAS-mutant melanoma cells exposed to MEK inhibitors. This evidence reinforces the relevance in combining MAPK pathway inhibitors with mitochondriotropic drugs to improve targeted therapies.

Topics: Animals; Antineoplastic Agents; Apoptosis; Azetidines; Calcium; Cell Death; Cell Line, Tumor; Drug Resistance, Neoplasm; Endoplasmic Reticulum; Female; Gene Silencing; GTP Phosphohydrolases; Humans; Indoles; MAP Kinase Signaling System; Melanoma; Mice; Mice, SCID; Mitochondria; Mitochondrial Proteins; Neoplasms; Oxidative Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; RNA Interference; Sulfonamides; Treatment Outcome; Vemurafenib

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

Topics: Allosteric Regulation; Animals; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Inhibitory Concentration 50; MAP Kinase Signaling System; Mice; Mice, Nude; Models, Molecular; Neoplasms; Oncogene Protein p21(ras); Piperidines; Protein Kinase Inhibitors; Protein Stability; Protein Structure, Tertiary; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyrimidines; Receptor Protein-Tyrosine Kinases; Reproducibility of Results; Xenograft Model Antitumor Assays

Inhibition of angiogenesis is considered as one of the desirable pathways for the treatment of tumor growth and metastasis. Herein we demonstrated that a series of pyridinyl-thiazolyl carboxamide derivatives were designed, synthesized and examined against angiogenesis through a colony formation and migration assays of human umbilical vein endothelial cells (HUVECs) in vitro. A structure-activity relationship (SAR) study was carried out and optimization toward this series of compounds resulted in the discovery of N-(3-methoxyphenyl)-4-methyl-2-(2-propyl-4-pyridinyl)thiazole-5-carboxamide (3k). The results indicated that compound 3k showed similar or better effects compared to Vandetanib in suppressing HUVECs colony formation and migration as well as VEGF-induced angiogenesis in the aortic ring spreading model and chick embryo chorioallantoic membrane (CAM) model. More importantly, compound 3k also strongly blocked tumor growth with the dosage of 30 mg/kg/day, and subsequent mechanism exploration suggested that this series of compounds took effect mainly through angiogenesis signaling pathways. Together, these results suggested compound 3k may serve as a lead for a novel class of angiogenesis inhibitors for cancer treatments.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chick Embryo; Colony-Forming Units Assay; Drug Design; Drug Discovery; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Phosphorylation; Piperidines; Quinazolines; Rats, Sprague-Dawley; Signal Transduction; Stress Fibers; Thiazoles; Wound Healing

Piperine, a naturally occurring alkaloid, is well known as anti-oxidant, anti-mutagenic, anti-tumor and anti-proliferative agent. Piperine exerts such pharmacological activities by binding or interacting with various cellular targets. Recently, the first report for Piperine interaction with duplex DNA has been published last year but its interaction with G-quadruplex structures has not been studied yet. Herein, we report for the first time the interaction of Piperine with various DNA G-quadruplex structures. Comprehensive biophysical techniques were employed to determine the basis of interaction for the complex formed between Piperine and G-quadruplex DNA sequences. Piperine showed specificity for G-quadruplex DNA over double stranded DNA, with highest affinity for G-quadruplex structure formed at c-myc promoter region. Further, in-vitro studies show that Piperine causes apoptosis-mediated cell death that further emphasizes the potential of this natural product, Piperine, as a promising candidate for targeting G-quadruplex structure and thus, acts as a potent anti-cancer agent.

Topics: A549 Cells; Alkaloids; Antineoplastic Agents; Apoptosis; Benzodioxoles; Binding Sites; Circular Dichroism; Electrophoretic Mobility Shift Assay; G-Quadruplexes; Humans; Molecular Docking Simulation; Neoplasms; Nuclear Magnetic Resonance, Biomolecular; Nucleic Acid Conformation; Nucleic Acid Denaturation; Piperidines; Polyunsaturated Alkamides; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc; Spectrometry, Fluorescence; Temperature

Solid cancers induce the formation of new blood vessels to promote growth and metastasis. Unlike the normal vascular networks, the tumor induced vasculatures exhibit abnormal shape and function. Past efforts have been focused on characterizing the altered growth factor signaling pathway in tumor capillary endothelial cells; however, the mechanical microenvironment of tumor also plays a significant role in regulating the formation of vascular patterns. Here, we used synthetic hydrogel based cell culture platforms to probe how activation of human umbilical endothelial cells (HUVECs) by tumor secreted factors alters the responses to matrix modulus and in turn the capillary network formation and drug sensitivity. Our study revealed that while in absence of activation, HUVECs prefer a substrate of appropriate stiffness for optimal capillary network formation; stimulation by tumor cells disrupts the mechano-responsive behavior of HUVECs. Additionally, the effect of vandetanib on reducing the capillary network was also investigated. The response of HUVECs to the anti-angiogenic agent was substrate modulus dependent displaying increased sensitivity on the compliant gels. Stimulation by tumor cells reduced the responsiveness to vandetanib, particularly when plated on stiffer gels.

Topics: Cell Line, Tumor; Coculture Techniques; Human Umbilical Vein Endothelial Cells; Humans; Hydrogels; Intercellular Signaling Peptides and Proteins; Mechanotransduction, Cellular; Neoplasms; Neovascularization, Pathologic; Piperidines; Polyethylene Glycols; Quinazolines

Poly(ADP-ribose) polymerases (PARPs) are involved in DNA repair following damage by endogenous or exogenous processes. It has become clear over the past decade that inhibition of PARP in the context of defects in other DNA repair mechanisms provide a tumor specific way to kill cancer cells. We describe the rationale for this approach and the design and discovery of niraparib, a potent PARP-1/2 inhibitor with good cell based activity, selectivity for cancer over normal cells, and oral bioavailability. Niraparib was characterized in a number of preclinical models before moving to phase I clinical trials, where it showed excellent human pharmacokinetics suitable for once a day oral dosing, achieved its pharmacodynamic target for PARP inhibition, and had promising activity in cancer patients. It is currently being tested in phase 3 clinical trials as maintenance therapy in ovarian cancer and as a treatment for breast cancer.

Topics: Animals; BRCA1 Protein; BRCA2 Protein; Drug Discovery; Enzyme Inhibitors; Homologous Recombination; Humans; Indazoles; Models, Molecular; Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases

Nicotinamide phosphoribosyltransferase (NAMPT) has been extensively studied due to its essential role in NAD(+) biosynthesis in cancer cells and the prospect of developing novel therapeutics. To understand how NAMPT regulates cellular metabolism, we have shown that the treatment with FK866, a specific NAMPT inhibitor, leads to attenuation of glycolysis by blocking the glyceraldehyde 3-phosphate dehydrogenase step (Tan, B., Young, D. A., Lu, Z. H., Wang, T., Meier, T. I., Shepard, R. L., Roth, K., Zhai, Y., Huss, K., Kuo, M. S., Gillig, J., Parthasarathy, S., Burkholder, T. P., Smith, M. C., Geeganage, S., and Zhao, G. (2013) Pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme essential for NAD(+) biosynthesis, in human cancer cells: metabolic basis and potential clinical implications. J. Biol. Chem. 288, 3500-3511). Due to technical limitations, we failed to separate isotopomers of phosphorylated sugars. In this study, we developed an enabling LC-MS methodology. Using this, we confirmed the previous findings and also showed that NAMPT inhibition led to accumulation of fructose 1-phosphate and sedoheptulose 1-phosphate but not glucose 6-phosphate, fructose 6-phosphate, and sedoheptulose 7-phosphate as previously thought. To investigate the metabolic basis of the metabolite formation, we carried out biochemical and cellular studies and established the following. First, glucose-labeling studies indicated that fructose 1-phosphate was derived from dihydroxyacetone phosphate and glyceraldehyde, and sedoheptulose 1-phosphate was derived from dihydroxyacetone phosphate and erythrose via an aldolase reaction. Second, biochemical studies showed that aldolase indeed catalyzed these reactions. Third, glyceraldehyde- and erythrose-labeling studies showed increased incorporation of corresponding labels into fructose 1-phosphate and sedoheptulose 1-phosphate in FK866-treated cells. Fourth, NAMPT inhibition led to increased glyceraldehyde and erythrose levels in the cell. Finally, glucose-labeling studies showed accumulated fructose 1,6-bisphosphate in FK866-treated cells mainly derived from dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. Taken together, this study shows that NAMPT inhibition leads to attenuation of glycolysis, resulting in further perturbation of carbohydrate metabolism in cancer cells. The potential clinical implications of these findings are also discussed.

Topics: Acrylamides; Carbohydrate Metabolism; Cytokines; Enzyme Inhibitors; Humans; Mass Spectrometry; NAD; Neoplasm Proteins; Neoplasms; Nicotinamide Phosphoribosyltransferase; Piperidines; Sugar Phosphates

Adnectins are a family of binding proteins derived from the 10th type III domain of human fibronectin (10Fn3), which is part of the immunoglobulin superfamily and normally binds integrin. The 10Fn3 has the potential for broad therapeutic applications given its structural stability, ability to be manipulated, and its abundance in the human body. The most commonly studied adnectin is CT-322, which is an inhibitor of vascular endothelial growth factor receptor-2. A bispecific adnectin, El-Tandem, has also been developed and binds to epidermal growth factor receptor and insulin-like growth factor-1 receptor simultaneously. Pre-clinical studies have shown promising results in relation to reducing tumor growth, decreasing microvessel density, and promoting normalization of tumor architecture. The phase I trial with CT-322 demonstrates relatively low toxicities. However, the phase II study done with CT-322 in recurrent glioblastoma does not reveal as promising results.

Topics: Adenine; Angiogenesis Inhibitors; Antineoplastic Agents; Bortezomib; Clinical Trials as Topic; Drug Evaluation, Preclinical; Fibronectins; Humans; Lenalidomide; Molecular Targeted Therapy; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pyrazoles; Pyrimidines; Thalidomide; Vascular Endothelial Growth Factor Receptor-2

To characterize cobimetinib pharmacokinetics and evaluate impact of clinically relevant covariates on cobimetinib pharmacokinetics.. Plasma samples (N = 4886) were collected from 487 patients with various solid tumors (mainly melanoma) in three clinical studies (MEK4592g, NO25395, GO28141). Cobimetinib was administered orally, once daily on either a 21-day-on/7-day-off, 14-day-on/14-day-off or 28-day-on schedule in a 28-day dosing cycle as single agent or in combination with vemurafenib. Cobimetinib doses ranged from 2.1 to 125 mg. NONMEM was used for pharmacokinetic analysis.. A linear two-compartment model with first-order absorption, lag time and first-order elimination described cobimetinib pharmacokinetics. The typical estimates (inter-individual variability) of apparent clearance (CL/F), central volume of distribution (V2/F) and terminal half-life were 322 L/day (58 %), 511 L (49 %) and 2.2 days, respectively. Inter-occasion variability on relative bioavailability was estimated at 46 %. CL/F decreased with age. V2/F increased with body weight (BWT). However, the impact of age and BWT on cobimetinib steady-state exposure (peak and trough concentrations and AUC following the recommended daily dose of 60 mg 21-day-on/7-day-off) was limited (<25 % changes across the distribution of age and BWT). No significant difference in cobimetinib pharmacokinetics or steady-state exposure was observed between patient subgroups based on sex, renal function, ECOG score, hepatic function tests, race, region, cancer type, and co-administration of moderate and weak CYP3A inducers or inhibitors and vemurafenib.. A population pharmacokinetic model was developed for cobimetinib in cancer patients. Covariates had minimal impact on steady-state exposure, suggesting no need for dose adjustments and supporting the recommended dose for all patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Body Weight; Cytochrome P-450 CYP3A; Drug Administration Schedule; Female; Glucuronosyltransferase; Half-Life; Humans; Inactivation, Metabolic; Indoles; Kidney; Liver; Male; MAP Kinase Signaling System; Middle Aged; Models, Biological; Neoplasm Proteins; Neoplasms; Piperidines; Protein Kinase Inhibitors; Sulfonamides; Vemurafenib; Young Adult

Topics: Adenine; Aniline Compounds; Antineoplastic Agents; Bevacizumab; Brentuximab Vedotin; Cost-Benefit Analysis; Drug Industry; Humans; Immunoconjugates; Neoplasms; Nitriles; Piperidines; Pyrazoles; Pyrimidines; Quinolines; State Medicine; Trastuzumab; United Kingdom

Angiogenesis is one of crucial processes associated with tumor growth and development, and consequently a prime target for cancer therapy. Although tumor endothelial cells (TECs) play a key role in pathological angiogenesis, investigating phenotypical changes in neovessels when a gene expression in TEC is suppressed is a difficult task. Small interfering RNA (siRNA) represents a potential agent due to its ability to silence a gene of interest. We previously developed a system for in vivo siRNA delivery to cancer cells that involves a liposomal-delivery system, a MEND that contains a unique pH-sensitive cationic lipid, YSK05 (YSK-MEND). In the present study, we report on the development of a system that permits the delivery of siRNA to TECs by combining the YSK-MEND and a ligand that is specific to TECs. Cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) is a well-known ligand to αVβ3 integrin, which is selectively expressed at high levels in TECs. We incorporated cRGD into the YSK-MEND (RGD-MEND) to achieve an efficient gene silencing in TECs. Quantitative RT-PCR and the 5' rapid amplification of cDNA ends PCR indicated that the intravenous injection of RGD-MEND at a dose of 4.0mg/kg induced a significant RNAi-mediated gene reduction in TEC but not in endothelial cells of other organs. Finally, we evaluated the therapeutic potency of the RGD-MEND encapsulating siRNA against vascular endothelial growth factor receptor 2. A substantial delay in tumor growth was observed after three sequential RGD-MEND injections on alternate days. In conclusion, the RGD-MEND represents a new approach for the characterization of TECs and for us in anti-angiogenic therapy.

Topics: Animals; Drug Delivery Systems; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Lipids; Liposomes; Male; Mice; Mice, Inbred BALB C; Neoplasms; Neovascularization, Pathologic; Peptides, Cyclic; Piperidines; RNA Interference; RNA, Small Interfering; Vascular Endothelial Growth Factor Receptor-2

(R,R')-4'-Methoxy-1-naphthylfenoterol (MNF) promotes growth inhibition and apoptosis of human HepG2 hepatocarcinoma cells via cannabinoid receptor (CBR) activation. The synthetic CB1R inverse agonist, AM251, has been shown to block the anti-mitogenic effect of MNF in these cells; however, AM251 is also an agonist of the recently deorphanized, lipid-sensing receptor, GPR55, whose upregulation contributes to carcinogenesis. Here, we investigated the role of MNF in GPR55 signaling in human HepG2 and PANC-1 cancer cell lines in culture by focusing first on internalization of the fluorescent ligand Tocrifluor 1117 (T1117). Initial results indicated that cell pretreatment with GPR55 agonists, including the atypical cannabinoid O-1602 and l-α-lysophosphatidylinositol, dose-dependently reduced the rate of cellular T1117 uptake, a process that was sensitive to MNF inhibition. GPR55 internalization and signaling mediated by O-1602 was blocked by MNF in GPR55-expressing HEK293 cells. Pretreatment of HepG2 and PANC-1 cells with MNF significantly abrogated the induction of ERK1/2 phosphorylation in response to AM251 and O-1602. Moreover, MNF exerted a coordinated negative regulation of AM251 and O-1602 inducible processes, including changes in cellular morphology and cell migration using scratch wound healing assay. This study shows for the first time that MNF impairs GPR55-mediated signaling and, therefore, may have therapeutic potential in the management of cancer.

Topics: Cell Movement; Drug Inverse Agonism; Endocytosis; Fenoterol; HEK293 Cells; Hep G2 Cells; Humans; Ligands; Molecular Targeted Therapy; Neoplasms; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Receptors, G-Protein-Coupled

Cyclic dinucleotides are of importance in the field of microbiology and immunology. They function as second messengers and are thought to participate in the signal transduction of cytosolic DNA immune responses. One such dinucleotide, cyclic di-GMP (c-di-GMP), stimulates the immune system. It is thought that c-di-GMP is recognized by ATP dependent RNA helicase (DDX41) in the cytosol, forms a complex with the Stimulator of interferon genes protein (STING), triggers a signal via the tank binding kinase 1-interferon regulatory factor 3 (TBK1-IRF3) pathway and induces the production of type I interferons. Therefore c-di-GMP can be thought of as a new class of adjuvant. However, because c-di-GMP contains two phosphate groups, this prevents its use as an adjuvant because it cannot pass through the cell membrane, even though the target molecule of c-di-GMP is located in the cytoplasm. Our group has been developing a series of liposomal drug delivery systems and recently investigated YSK05 which is a synthetic, pH sensitive lipid that has a high fusogenicity. We utilized this lipid as a carrier to transport c-di-GMP into the cytosol to then use c-di-GMP as an adjuvant. Based on screening experiments, YSK05/POPE/cholesterol=40/25/35 was found to induce IFN-β in Raw264.7 cells. The induction of IFN-β from c-di-GMP liposomes was inhibited by adding BX795, a TBK1 inhibitor, indicating that the production of IFN-β caused the activation of the STING-TBK1 pathway. C-di-GMP liposomes also showed significantly higher levels of expression of CD80, CD86 and MHC class I. The c-di-GMP/YSK05 liposome facilitated antigen specific cytotoxic T cell activity and the inhibition of tumor growth in a mouse model. These findings indicate that c-di-GMP/YSK05 liposomes could be used, not only to transfer c-di-GMP to the cytosol and induce an innate immune system but also as a platform for investigating the mechanism of immune sensing with cyclic dinucleotides in vitro and in vivo.

Topics: Adjuvants, Immunologic; Animals; Cancer Vaccines; Cell Line; Cell Line, Tumor; Cyclic GMP; Female; Immunotherapy; Interferon-beta; Lipids; Liposomes; Mice, Inbred C57BL; Neoplasms; Ovalbumin; Piperidines; T-Lymphocytes, Cytotoxic; Tumor Burden

Diacylglycerol kinase (DGK)α converts diacylglycerol to phosphatidic acid. This lipid kinase sustains survival, migration and invasion of tumor cells, with no effect over untransformed cells, suggesting its potential as a cancer-specific target. Nonetheless the mechanisms that underlie DGKα specific contribution to cancer survival have not been elucidated. Using three-dimensional (3D) colon and breast cancer cell cultures, we demonstrate that DGKα upregulation is part of the transcriptional program that results in Src activation in these culture conditions. Pharmacological or genetic DGKα silencing impaired tumor growth in vivo confirming its function in malignant transformation. DGKα-mediated Src regulation contributed to limit the effect of Src inhibitors, and its transcriptional upregulation in response to PI3K/Akt inhibitors resulted in reduced toxicity. Src oncogenic properties and contribution to pharmacological resistance have been linked to its overactivation in cancer. DGKα participation in this central node helps to explain why its pharmacological inhibition or siRNA-mediated targeting specifically alters tumor viability with no effect on untransformed cells. Our results identify DGKα-mediated stabilization of Src activation as an important mechanism in tumor growth, and suggest that targeting this enzyme, alone or in combination with other inhibitors in wide clinical use, could constitute a treatment strategy for aggressive forms of cancer.

Topics: Animals; Caco-2 Cells; Cell Growth Processes; Diacylglycerol Kinase; Enzyme Activation; Enzyme Inhibitors; Female; HEK293 Cells; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, SCID; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Proto-Oncogene Proteins c-akt; Quinazolinones; src-Family Kinases; Xenograft Model Antitumor Assays

Punica granatum (family: Lythraceae) is mainly found in Iran, which is considered to be its primary centre of origin. Studies on pomegranate peel have revealed antioxidant, anti-inflammatory, anti- angiogenesis activities, with prevention of premature aging and reducing inflammation. In addition to this it is also useful in treating various diseases like diabetes, maintaining blood pressure and treatment of neoplasms such as prostate and breast cancer.. In this study we identified anti-cancer targets of active compounds like corilagin (tannins), quercetin (flavonoids) and pseudopelletierine (alkaloids) present in pomegranate peel by employing dual reverse screening and binding analysis.. The potent targets of the pomegranate peel were annotated by the PharmMapper and ReverseScreen 3D, then compared with targets identified from different Bioassay databases (NPACT and HIT's). Docking was then further employed using AutoDock pyrx and validated through discovery studio for studying molecular interactions.. A number of potent anti-cancerous targets were attained from the PharmMapper server according to their fit score and from ReverseScreen 3D server according to decreasing 3D scores.. The identified targets now need to be further validated through in vitro and in vivo studies.

Topics: Alkaloids; Antineoplastic Agents; Computer Simulation; Drug Discovery; Flavonoids; Fruit; Glucosides; Humans; Hydrolyzable Tannins; Lythraceae; Molecular Docking Simulation; Molecular Targeted Therapy; Neoplasms; Piperidines; Quercetin; Tannins

Small interfering RNA (siRNA) would be predicted to function as a cancer drug, but an efficient siRNA delivery system is required for clinical development. To address this issue, we developed a liposomal siRNA carrier, a multifunctional envelope-type nanodevice (MEND). We previously reported that a MEND composed of a pH-sensitive cationic lipid, YSK05, showed significant knockdown in both in vitro and in tumor tissue by intratumoral injection. Here, we report on the development of an in vivo siRNA delivery system that is delivered by systemic injection and an analysis of the pharmacokinetics of an intravenously administered siRNA molecule in tumor tissue. Tumor delivery of siRNA was quantified by means of stem-loop primer quantitative reverse transcriptase PCR (qRT-PCR) method. PEGylation of the YSK-MEND results in the increase in the accumulation of siRNA in tumor tissue from 0.0079% ID/g tumor to 1.9% ID/g tumor. The Administration of the MEND (3 mg siRNA/kg body weight) showed about a 50% reduction in the target gene mRNA and protein. Moreover, we verified the induction of RNA interference by 5' RACE-PCR method. The collective results reported here indicate that an siRNA carrier was developed that can deliver siRNA to a target cell in tumor tissue through an improved siRNA bioavailability.

Topics: Administration, Intravenous; Amino Acid Sequence; Animals; Cell Line, Tumor; Gene Transfer Techniques; Humans; Lipids; Liposomes; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Microscopy, Confocal; Molecular Sequence Data; Neoplasms; Piperidines; Polyethylene Glycols; RNA Interference; RNA, Messenger; RNA, Small Interfering; Toxicity Tests

Topics: BRCA1 Protein; BRCA2 Protein; Female; Humans; Indazoles; Male; Mutation; Neoplasm Recurrence, Local; Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

NAD(+) is mainly synthesized in human cells via the "salvage" pathways starting from nicotinamide, nicotinic acid, or nicotinamide riboside (NR). The inhibition with FK866 of the enzyme nicotinamide phosphoribosyltransferase (NAMPT), catalyzing the first reaction in the "salvage" pathway from nicotinamide, showed potent antitumor activity in several preclinical models of solid and hematologic cancers. In the clinical studies performed with FK866, however, no tumor remission was observed. Here we demonstrate that low micromolar concentrations of extracellular NAD(+) or NAD(+) precursors, nicotinamide mononucleotide (NMN) and NR, can reverse the FK866-induced cell death, this representing a plausible explanation for the failure of NAMPT inhibition as an anti-cancer therapy. NMN is a substrate of both ectoenzymes CD38 and CD73, with generation of NAM and NR, respectively. In this study, we investigated the roles of CD38 and CD73 in providing ectocellular NAD(+) precursors for NAD(+) biosynthesis and in modulating cell susceptibility to FK866. By specifically silencing or overexpressing CD38 and CD73, we demonstrated that endogenous CD73 enables, whereas CD38 impairs, the conversion of extracellular NMN to NR as a precursor for intracellular NAD(+) biosynthesis in human cells. Moreover, cell viability in FK866-treated cells supplemented with extracellular NMN was strongly reduced in tumor cells, upon pharmacological inhibition or specific down-regulation of CD73. Thus, our study suggests that genetic or pharmacologic interventions interfering with CD73 activity may prove useful to increase cancer cell sensitivity to NAMPT inhibitors.

Topics: 5'-Nucleotidase; Acrylamides; ADP-ribosyl Cyclase 1; Cell Death; Cell Line, Tumor; Cytokines; Down-Regulation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene Silencing; GPI-Linked Proteins; Humans; Membrane Glycoproteins; NAD; Neoplasm Proteins; Neoplasms; Nicotinamide Mononucleotide; Nicotinamide Phosphoribosyltransferase; Piperidines

KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. Conversely, potent inhibition of active, phosphorylated MEK is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in superior efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to improved clinical responses in patients.

Topics: Allosteric Regulation; Azetidines; Cell Survival; Clinical Trials as Topic; Crystallography, X-Ray; Enzyme Activation; Feedback, Physiological; Genes, ras; HCT116 Cells; Humans; Imidazoles; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Models, Molecular; Neoplasms; Niacinamide; Oncogene Protein p21(ras); Phosphorylation; Phosphoserine; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for cellular metabolism, energy production, and DNA repair. NAMPT has been extensively studied because of its critical role in these cellular processes and the prospect of developing therapeutics against the target, yet how it regulates cellular metabolism is not fully understood. In this study we utilized liquid chromatography-mass spectrometry to examine the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and serine biosynthesis in cancer cells and tumor xenografts. We show for the first time that NAMPT inhibition leads to the attenuation of glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step due to the reduced availability of NAD(+) for the enzyme. The attenuation of glycolysis results in the accumulation of glycolytic intermediates before and at the glyceraldehyde 3-phosphate dehydrogenase step, promoting carbon overflow into the pentose phosphate pathway as evidenced by the increased intermediate levels. The attenuation of glycolysis also causes decreased glycolytic intermediates after the glyceraldehyde 3-phosphate dehydrogenase step, thereby reducing carbon flow into serine biosynthesis and the TCA cycle. Labeling studies establish that the carbon overflow into the pentose phosphate pathway is mainly through its non-oxidative branch. Together, these studies establish the blockade of glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step as the central metabolic basis of NAMPT inhibition responsible for ATP depletion, metabolic perturbation, and subsequent tumor growth inhibition. These studies also suggest that altered metabolite levels in tumors can be used as robust pharmacodynamic markers for evaluating NAMPT inhibitors in the clinic.

Topics: Acrylamides; Adenosine Triphosphate; Animals; Carbon Isotopes; Cell Death; Cell Line, Tumor; Citric Acid Cycle; Enzyme Inhibitors; Female; Glycolysis; Humans; Isotope Labeling; Mice; Mice, SCID; NAD; Neoplasms; Nicotinamide Phosphoribosyltransferase; Pentose Phosphate Pathway; Piperidines; Serine; Xenograft Model Antitumor Assays

It has been previously suggested that overexpression of mitochondrial superoxide dismutase (SOD) attenuates cancer development; however, the exact mechanism remains unclear. In this work, we have studied the direct effect of the mitochondria-targeted superoxide scavenger, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), on B16-F0 mouse melanoma cells and tumor growth in a nude mouse model of human melanoma. We show that scavenging of mitochondrial superoxide inhibited cell growth, reduced viability, and induced apoptosis in melanoma cells, but did not affect nonmalignant skin fibroblasts. Diminished mitochondrial superoxide inhibited redox-dependent Akt, restored activity of mitochondrial pyruvate dehydrogenase, and reduced HIF1-α and lactate dehydrogenase expression in cancer cells. Suppression of glycolysis in mitoTEMPO-treated melanoma cells resulted in a significant drop of cellular adenosine-5'-triphosphate and induced cell death. In vivo mitoTEMPO treatment effectively suppressed growth of established tumor in the mouse model of human melanoma. Therefore, our data lead to the hypothesis that scavenging of mitochondrial superoxide selectively inhibits redox-sensitive survival and metabolic pathways, resulting in cancer cell death. In contrast to existing anticancer therapies, inhibition of mitochondrial superoxide may represent a novel specific anticancer treatment with reduced cytotoxic side effects.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Humans; Mice; Mitochondria; Neoplasms; Organophosphorus Compounds; Piperidines; Signal Transduction; Superoxides

Cancer cells appear to depend heavily on antiapoptotic proteins for survival and so targeted inhibition of these proteins has therapeutic potential. One innovative strategy is to inhibit the cyclin-dependent kinases (CDKs) responsible for the regulation of RNA polymerase II (RNAPII). In our study, we investigated the detailed cellular mechanism of a novel small-molecule CDK inhibitor (CDKI-71) in cancer cell lines, primary leukemia cells, normal B - & T- cells, and embryonic lung fibroblasts and compared the cellular and molecular responses to the clinical CDK inhibitor, flavopiridol. Like flavopiridol, CDKI-71 displayed potent cytotoxicity and caspase-dependent apoptosis induction that were closely associated with the inhibition of RNAPII phosphorylation at serine-2. This was caused by effective targeting of cyclinT-CDK9 and resulted in the downstream inhibition of Mcl-1. No correlation between apoptosis and inhibition of cell-cycle CDKs 1 and 2 was observed. CDKI-71 showed a 10-fold increase in potency in tumor cell lines when compared to MRC-5 human fibroblast cells. Significantly, CDKI-71 also demonstrated potent anti-chronic lymphocytic leukemia activity with minimal toxicity in normal B- and T-cells. In contrast, flavopiridol showed little selectivity between cancer and normal cells. Here, we provide the first cell-based evidence that flavopiridol induces DNA double-strand breaks: a fact which may explain why flavopiridol has such a narrow therapeutic window in preclinical and clinical settings. Taken together, our data provide a rationale for the development of selective CDK inhibitors as therapeutic agents and CDKI-71 represents a promising lead in this context.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 9; Drug Evaluation, Preclinical; Enzyme Inhibitors; Flavonoids; Humans; Neoplasms; Piperidines; Sulfonamides

NK1 is a tachykinin receptor highly relevant to tumorigenesis and metastasis development in breast cancer and other carcinomas. Despite the substantial efforts done to develop potent NK1 receptor antagonists, none of these antagonists had shown good antitumor activity in clinical trials. Now, we have tested the effect of inhibition of the neuropeptide Substance P (SP), a NK1 ligand, as a potential therapeutic approach in cancer. We found that the inhibition of SP with antibodies strongly inhibit cell growth and induce apoptosis in breast, colon, and prostate cancer cell lines. These effects were accompained by a decrease in the mitogen-activated kinase singaling pathway. Interestingly, in some cell lines SP abrogation decreased the steady state of Her2 and EGFR, suggesting that SP-mediated signaling is important for the basal activity of these ErbB receptors. In consequence, we observed a blockade of the cell cycle progression and the inhibition of several cell cycle-related proteins including mTOR. SP inhibition also induced cell death in cell lines resistant to Lapatinib and Trastuzumab that have increased levels of active Her2, suggesting that this therapeutic approach could be also effective for those cancers resistant to current anti-ErbB therapies. Thus, we propose a new therapeutic strategy for those cancers that express NK1 receptor and/or other tachykinin receptors, based in the immuno-blockade of the neuropeptide SP.

Topics: Antibodies; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lapatinib; Ligands; Male; Neoplasms; Neurokinin-1 Receptor Antagonists; Piperidines; Prostatic Neoplasms; Quinazolines; Receptor, ErbB-2; Receptors, Neurokinin-1; Signal Transduction; Substance P; Trastuzumab

Topics: Androstenes; Androstenols; Antibodies, Monoclonal; Antineoplastic Agents; Axitinib; Biomarkers, Tumor; Brentuximab Vedotin; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Drug Approval; Female; Humans; Imidazoles; Immunoconjugates; Indazoles; Indoles; Ipilimumab; Lung Neoplasms; Male; Melanoma; Molecular Targeted Therapy; Neoplasms; Piperidines; Prostatic Neoplasms; Pyrazoles; Pyridines; Quinazolines; Rare Diseases; Sulfonamides; Survival Analysis; United States; United States Food and Drug Administration; Vemurafenib

Previously, we reported that the 3,4-epoxypiperidine structure, whose design was based on the active site of DNA alkylating antitumor antibiotics, azinomycins A and B, possesses prominent DNA cleavage activity. In this report, novel caged DNA alkylating agents, which were designed to be activated by UV irradiation, were synthesized by the introduction of four photo-labile protecting groups to a 3,4-epoxypiperidine derivative. The DNA cleavage activity and cytotoxicity of the caged DNA alkylating agents were examined under UV irradiation. Four caged DNA alkylating agents showed various degrees of bioactivity depending on the photosensitivity of the protecting groups.

Topics: Antineoplastic Agents, Alkylating; Cell Survival; DNA; Epoxy Compounds; Hep G2 Cells; Humans; Neoplasms; Piperidines; Plasmids; Ultraviolet Rays

Inactivation of p53 protein by endogenous and exogenous carcinogens is involved in the pathogenesis of different human malignancies. In cancer associated with SV-40 DNA tumor virus, p53 is considered to be non-functional mainly due to its interaction with the large T-antigen. Using the 293T cell line (HEK293 cells transformed with large T antigen) as a model, we provide evidence that p53 is one of the critical downstream targets involved in FK866-mediated killing of 293T cells. A reduced rate of apoptosis and an increased number of cells in S-phase was accompanied after knockdown of p53 in these cells. Inhibition of NAMPT by FK866, or inhibition of SIRT by nicotinamide decreased proliferation and triggered death of 293T cells involving the p53 acetylation pathway. Additionally, knockdown of p53 attenuated the effect of FK866 on cell proliferation, apoptosis, and cell cycle arrest. The data presented here shed light on two important facts: (1) that p53 in 293T cells is active in the presence of FK866, an inhibitor of NAMPT pathway; (2) the apoptosis induced by FK866 in 293T cells is associated with increased acetylation of p53 at Lys382, which is required for the functional activity of p53.

Topics: Acetylation; Acrylamides; Apoptosis; Cell Cycle; Cytokines; Enzyme Inhibitors; Gene Knockdown Techniques; HEK293 Cells; Humans; Lysine; Metabolic Networks and Pathways; Neoplasms; Nicotinamide Phosphoribosyltransferase; Piperidines; Simian virus 40; Sirtuin 1; Tumor Suppressor Protein p53

Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.

Topics: Animals; Binding Sites; Cell Line, Tumor; Crystallography, X-Ray; Cytochrome P-450 CYP3A; Drug Design; Female; Half-Life; Humans; Indoles; Lung; Mice; Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein Structure, Tertiary; Rats; Receptor Protein-Tyrosine Kinases; Structure-Activity Relationship; Transplantation, Heterologous

Topics: Animals; Antineoplastic Agents; Benzamides; Breast Neoplasms; Cats; Disease Models, Animal; Dogs; Female; Humans; Imatinib Mesylate; Indoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mast-Cell Sarcoma; Neoplasms; Piperazines; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Pyrroles; Thiazoles; Transcriptome

Modification of liposomal siRNA carriers with polyethylene glycol, i.e., PEGylation, is a generally accepted strategy for achieving in vivo stability and delivery to tumor tissue. However, PEGylation significantly inhibits both cellular uptake and the endosomal escape process of the carriers. In a previous study, we reported on the development of a multifunctional envelope-type nano device (MEND) for siRNA delivery and peptide-based functional devices for overcoming the limitations and succeeded in the efficient delivery of siRNA to tumors. In this study, we synthesized a pH-sensitive cationic lipid, YSK05, to overcome the limitations. The YSK05-MEND had a higher ability for endosomal escape than other MENDs containing conventional cationic lipids. The PEGylated YSK05-MEND induced efficient gene silencing and overcame the limitations followed by optimization of the lipid composition. Furthermore, the intratumoral administration of the YSK05-MEND resulted in a more efficient gene silencing compared with MENDs containing conventional cationic lipids. Collectively, these data confirm that YSK05 facilitates the endosomal escape of the MEND and thereby enhances the efficacy of siRNA delivery into cytosol and gene silencing.

Topics: Animals; Cell Cycle Proteins; Cell Line, Tumor; Endocytosis; Erythrocytes; Gene Silencing; HeLa Cells; Humans; Hydrogen-Ion Concentration; Lipids; Liposomes; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Nanostructures; Neoplasms; Peptides; Piperidines; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; RNA, Small Interfering

The extensive involvement of the HER kinases in epithelial cancer suggests that kinase inhibitors targeting this receptor family have the potential for broad spectrum antitumor activity. BMS-690514 potently inhibits all three HER kinases, and the VEGF receptor kinases. This report summarizes data from biochemical and cellular pharmacology studies, as well as antitumor activity of BMS-690514.. The potency and selectivity of BMS-690514 was evaluated by using an extensive array of enzymatic and binding assays, as well as cellular assays that measure proliferation and receptor signaling. Antitumor activity was evaluated by using multiple xenograft models that depend on HER kinase signaling. The antiangiogenic properties of BMS-690514 were assessed in a matrigel plug assay, and effect on tumor blood flow was measured by dynamic contrast-enhanced MRI.. BMS-690514 is a potent and selective inhibitor of epidermal growth factor receptor (EGFR), HER2, and HER4, as well as the VEGF receptor kinases. It inhibits proliferation of tumor cells with potency that correlates with inhibition of receptor signaling, and induces apoptosis in lung tumor cells that have an activating mutation in EGFR. Antitumor activity was observed with BMS-690514 at multiple doses that are well tolerated in mice. There was evidence of suppression of tumor angiogenesis and endothelial function by BMS-690514, which may contribute to its efficacy.. By combining inhibition of two receptor kinase families, BMS-690524 is a novel targeted agent that disrupts signaling in the tumor and its vasculature.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Cell Line; Cell Proliferation; Endothelial Cells; ErbB Receptors; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Piperidines; Pyrroles; Receptor, ErbB-2; Receptors, Vascular Endothelial Growth Factor; Regional Blood Flow; Signal Transduction; Triazines; Xenograft Model Antitumor Assays

Vandetanib is a multi-targeted receptor tyrosine kinase inhibitor that is in clinical development for the treatment of solid tumours. This preclinical study examined the inhibition of two key signalling pathways (VEGFR-2, EGFR) at drug concentrations similar to those achieved in the clinic, and their contribution to direct and indirect antitumour effects of vandetanib. For in vitro studies, receptor phosphorylation was assessed by Western blotting and ELISA, cell proliferation was assessed using a cell viability endpoint, and effects on cell cycle determined using flow cytometry. For in vivo studies, Western blotting, ELISA and immunohistochemistry (IHC) were used to assess receptor phosphorylation. Cell culture experiments demonstrated that anti-proliferative effects of vandetanib resulted from inhibition of either EGFR or VEGFR-2 signalling in endothelial cells, but were associated with inhibition of EGFR signalling in tumour cells. Vandetanib inhibited both EGFR and VEGFR-2 signalling in normal lung tissue and in tumour xenografts. In a lung cancer model expressing an activating EGFR mutation, the activity of vandetanib was similar to that of a highly selective EGFR inhibitor (gefitinib), and markedly greater than that of a highly selective VEGFR inhibitor (vatalanib). These data suggest that at the plasma exposures achieved in the clinic, vandetanib will significantly inhibit both VEGFR-2 and EGFR signalling, and that both inhibition of angiogenesis and direct inhibition of tumour cell growth can contribute to treatment response.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Endothelial Cells; ErbB Receptors; Female; Humans; Mice; Mice, SCID; Neoplasms; Phenotype; Piperidines; Quinazolines; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

Vandetanib (ZD6474) and its chlorine analogue chloro-Vandetanib are potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with low nanomolar IC(50) values. [(11)C]Vandetanib and [(11)C]chloro-Vandetanib, new potential PET agents for imaging of VEGFR in cancer, were first designed, synthesized and labeled at nitrogen and oxygen positions from their corresponding N- and O-des-methylated precursors, in 40-50% decay corrected radiochemical yield and 370-555GBq/μmol specific activity at end of bombardment (EOB).

Topics: Carbon Radioisotopes; Chlorine; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Methylation; Molecular Structure; Neoplasms; Piperidines; Positron-Emission Tomography; Quinazolines; Radiopharmaceuticals; Receptors, Vascular Endothelial Growth Factor

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.

Topics: Administration, Oral; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carbazoles; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Mice; Mice, Nude; Mice, SCID; Models, Molecular; Mutation; Neoplasms; Piperidines; Protein Conformation; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Recombinant Fusion Proteins; Time Factors; Transfection; Tumor Burden; Xenograft Model Antitumor Assays

Anemia is considered as one of the most frequent hematological demonstration of malignant diseases, which lead to momentous impairment in every tissues and organs of cancer patients and put them under serious stress. This major problem may arise because of the underlining diseases (i.e., cancer diseases) or radiotherapy or chemotherapy treatment received. This present study tries to find the association between anemia onset and severity with different chemotherapeutics regimens used in the treatment of several solid cancers and to find the association of anemia onset and severity with different doses of these chemotherapeutics drugs.. This retrospective observational study was conducted in Penang General Hospital on 534 anemic solid cancer patients who were admitted between 2003 and 2009. The main statistical tests used were Chi-square test and Logistic regression test for categorical data. While for continues data the main statistical tests were Linear regression and correlation test. The significance of the result will be when the P<0.05, while the confidence interval for this study was 95%.. FEC, 5-FU+5-FU, Docetaxel and Cisplatin+ 5-FU regimen has strong association and correlation with anemia onset and severity. However the associations and correlations with anemia severity were stronger than those with the onset. Different doses of 5-FU, cyclophosphamide, docetaxel and cisplatin play a critical role in anemia onset and severity.. Monitoring and determination of hemoglobin levels for cancer patients treated with FEC, 5-FU+5-FU, Docetaxel, Cisplatin+ 5-FU specifically with high doses must be emphasized and a focus of particular attention.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Docetaxel; Erythrocyte Count; Female; Fluorouracil; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Piperidines; Pyridines; Retrospective Studies; Taxoids; Young Adult

Rohitukine, a chromane alkaloid, is a precursor of flavopiridol, a promising anti-cancer compound. Currently in Phase III clinical trials, flavopiridol is a potent inhibitor of several cyclin-dependent kinases (CDKs). Rohitukine was first reported from Amoora rohituka (0.083% dry weight) followed by that in Dysoxylum binectariferum (0.9% dry weight), both belonging to the family Meliaceae. Here, we report incredibly high yields of rohitukine (7% dry weight) in trees of D. binectariferum from the Western Ghats, India. Crude extracts of the tree were found to be highly effective against ovarian and breast cancer lines tested.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Female; Flavonoids; Humans; India; Limonins; Meliaceae; Neoplasms; Ovarian Neoplasms; Phytotherapy; Piperidines; Plant Bark; Plant Extracts; Plant Stems; Protein Kinase Inhibitors; Trees

Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10(-4)M, 10(-5)M, and 10(-6) M BQ-3020) significantly increased the production of beta-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300microg/kg and 3mg/kg) had no effects. Local naloxone methiodide (500microg/kg) or selective mu-opioid receptor antagonist (CTOP, 500microg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating beta-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment.

Topics: Animals; beta-Endorphin; Cell Line, Tumor; Disease Models, Animal; Down-Regulation; Endothelin-1; Endothelins; Humans; Mice; Mice, Nude; Narcotic Antagonists; Neoplasm Transplantation; Neoplasms; Nociceptors; Oligopeptides; Opioid Peptides; Pain; Peptide Fragments; Piperidines; Receptor, Endothelin B; Receptors, Opioid; Sensory Receptor Cells; Up-Regulation

The serine/threonine kinase AKT plays a pivotal role in signal transduction events involved in malignant transformation and chemoresistance and is an attractive target for the development of cancer therapeutics. Fragment-based lead discovery, combined with structure-based drug design, has recently identified AT7867 as a novel and potent inhibitor of both AKT and the downstream kinase p70 S6 kinase (p70S6K) and also of protein kinase A. This ATP-competitive small molecule potently inhibits both AKT and p70S6K activity at the cellular level, as measured by inhibition of GSK3beta and S6 ribosomal protein phosphorylation, and also causes growth inhibition in a range of human cancer cell lines as a single agent. Induction of apoptosis was detected by multiple methods in tumor cells following AT7867 treatment. Administration of AT7867 (90 mg/kg p.o. or 20 mg/kg i.p.) to athymic mice implanted with the PTEN-deficient U87MG human glioblastoma xenograft model caused inhibition of phosphorylation of downstream substrates of both AKT and p70S6K and induction of apoptosis, confirming the observations made in vitro. These doses of AT7867 also resulted in inhibition of human tumor growth in PTEN-deficient xenograft models. These data suggest that the novel strategy of AKT and p70S6K blockade may have therapeutic value and supports further evaluation of AT7867 as a single-agent anticancer strategy.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Down-Regulation; HCT116 Cells; HT29 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Models, Molecular; Neoplasms; Oncogene Protein v-akt; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Ribosomal Protein S6 Kinases, 70-kDa; Treatment Outcome; Xenograft Model Antitumor Assays

A bottleneck in drug discovery is the identification of the molecular targets of a compound (mode of action, MoA) and of its off-target effects. Previous approaches to elucidate drug MoA include analysis of chemical structures, transcriptional responses following treatment, and text mining. Methods based on transcriptional responses require the least amount of information and can be quickly applied to new compounds. Available methods are inefficient and are not able to support network pharmacology. We developed an automatic and robust approach that exploits similarity in gene expression profiles following drug treatment, across multiple cell lines and dosages, to predict similarities in drug effect and MoA. We constructed a "drug network" of 1,302 nodes (drugs) and 41,047 edges (indicating similarities between pair of drugs). We applied network theory, partitioning drugs into groups of densely interconnected nodes (i.e., communities). These communities are significantly enriched for compounds with similar MoA, or acting on the same pathway, and can be used to identify the compound-targeted biological pathways. New compounds can be integrated into the network to predict their therapeutic and off-target effects. Using this network, we correctly predicted the MoA for nine anticancer compounds, and we were able to discover an unreported effect for a well-known drug. We verified an unexpected similarity between cyclin-dependent kinase 2 inhibitors and Topoisomerase inhibitors. We discovered that Fasudil (a Rho-kinase inhibitor) might be "repositioned" as an enhancer of cellular autophagy, potentially applicable to several neurodegenerative disorders. Our approach was implemented in a tool (Mode of Action by NeTwoRk Analysis, MANTRA, http://mantra.tigem.it).

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Algorithms; Antineoplastic Agents; Autophagy; Blotting, Western; Camptothecin; Cell Line, Tumor; Doxorubicin; Drug Discovery; Drug Screening Assays, Antitumor; Flavonoids; Fuzzy Logic; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Irinotecan; Neoplasms; Oligonucleotide Array Sequence Analysis; Phosphorylation; Piperidines; Pyrazoles; Pyrroles; RNA Polymerase II

Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) are promising cancer drugs currently in clinical trials in oncology, including APO866, CHS-828 and the CHS-828 prodrug EB1627/GMX1777, but cancer cell resistance to these drugs has not been studied in detail.. Here, we introduce an analogue of CHS-828 called TP201565 with increased potency in cellular assays. Further, we describe and characterize a panel of cell lines with acquired stable resistance towards several NAMPT inhibitors of 18 to 20,000 fold compared to their parental cell lines.. We find that 4 out of 5 of the resistant sublines display mutations of NAMPT located in the vicinity of the active site or in the dimer interface of NAMPT. Furthermore, we show that these mutations are responsible for the resistance observed. All the resistant cell lines formed xenograft tumours in vivo. Also, we confirm CHS-828 and TP201565 as competitive inhibitors of NAMPT through docking studies and by NAMPT precipitation from cellular lysate by an analogue of TP201565 linked to sepharose. The NAMPT precipitation could be inhibited by addition of APO866.. We found that CHS-828 and TP201565 are competitive inhibitors of NAMPT and that acquired resistance towards NAMPT inhibitors can be expected primarily to be caused by mutations in NAMPT.

Topics: Acrylamides; Animals; Antineoplastic Agents; Binding Sites; Binding, Competitive; Catalytic Domain; Cell Line, Tumor; Cyanides; Cytokines; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Guanidines; HCT116 Cells; Humans; Inhibitory Concentration 50; Mice; Mice, Nude; Models, Molecular; Mutation; Neoplasms; Nicotinamide Phosphoribosyltransferase; Piperidines; Protein Conformation; Time Factors; Transfection; Xenograft Model Antitumor Assays

ZD6474 (vandetanib, Zactima, Astra Zeneca) is an anilinoquinazoline used to target the receptor tyrosine kinase RET in familial and sporadic thyroid carcinoma (IC(50): 100 nM). The aim of this study was to identify molecular determinants of RET sensitivity to ZD6474. Here, we show that mutation of RET tyrosine 806 to cysteine (Y806C) induced RET kinase resistance to ZD6474 (IC(50): 933 nM). Y806 maps close to the gate-keeper position at the RET kinase nucleotide-binding pocket. Although tyrosine 806 is a RET auto-phosphorylation site, its substitution to phenylalanine (Y806F) did not markedly affect RET susceptibility to ZD6474 (IC(50): 87 nM), suggesting that phosphorylation of Y806 is not required for compound binding. Accordingly, the introduction of a phosphomimetic residue (Y806E) also caused resistance to ZD6474, albeit of a lesser degree (IC(50): 512 nM) than the cysteine mutation. Y806C/E RET mutants were also resistant to ZD6474 with respect to intracellular signalling and activation of an AP1-responsive promoter. We conclude that Y806 is a molecular determinant of RET sensitivity to ZD6474. Y806C is a natural RET mutation identified in a patient affected by multiple endocrine neoplasia type 2B. Based on its rare occurrence, it is unlikely that Y806C will be a frequent cause of refractoriness to ZD6474; however, it may be envisaged that mutations at this site can mediate secondary resistance formation in patients treated with the compound.

Topics: Amino Acid Sequence; Drug Resistance, Neoplasm; HeLa Cells; Humans; Kidney; Molecular Sequence Data; Mutagenesis, Site-Directed; Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein Structure, Tertiary; Proto-Oncogene Proteins c-ret; Quinazolines; Structure-Activity Relationship; Tyrosine

(R,S)-N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolinamine (PAQ) is a tyrosine kinase inhibitor with high affinity for the vascular endothelial growth factor receptor 2 (VEGFR-2), which plays an important role in tumour angiogenesis. The aim of this work was to develop and evaluate in mice the (11)C-labelled analogue as an in vivo tracer for VEGFR-2 expression in solid tumours.. [(11)C]PAQ was synthesized by an N-methylation of desmethyl-PAQ using [(11)C]methyl iodide. The tracer's pharmacokinetic properties and its distribution in both subcutaneous and intraperitoneal tumour models were evaluated with positron emission tomography (PET). [(18)F]FDG was used as a reference tracer for tumour growth. PET results were corroborated by ex vivo and in vitro phosphor imaging and immunohistochemical analyses.. In vitro assays and PET in healthy animals revealed low tracer metabolism, limited excretion over 60 min and a saturable and irreversible binding. Radiotracer uptake in subcutaneous tumour masses was low, while focal areas of high uptake (up to 8% ID/g) were observed in regions connecting the tumour to the host. Uptake was similarly high but more distributed in tumours growing within the peritoneum. The pattern of radiotracer uptake was generally different from that of the metabolic tracer [(18)F]FDG and correlated well with variations in VEGFR-2 expression determined ex vivo by immunohistochemical analysis.. These results suggest that [(11)C]PAQ has potential as a noninvasive PET tracer for in vivo imaging of VEGFR-2 expression in angiogenic "hot spots".

Topics: Animals; Biological Transport; Carbon Radioisotopes; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Immunohistochemistry; Male; Mice; Microsomes; Neoplasms; Piperidines; Positron-Emission Tomography; Quinazolines; Radioactive Tracers; Radiochemistry; Rats; Tissue Distribution; Vascular Endothelial Growth Factor Receptor-2

We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.

Topics: Administration, Oral; Amides; Animals; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Drug Discovery; Drug Stability; Enzyme Inhibitors; Female; Genes, BRCA1; Genes, BRCA2; Humans; Indazoles; Inhibitory Concentration 50; Mutation; Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Rats

Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Enzyme Inhibitors; Humans; Kinesins; Neoplasms; Piperidines; Pyrroles; Taxoids

The resistance to selective EGFR inhibitors involves the activation of alternative signaling pathways, and Akt activation and VEGF induction have been described in EGFR inhibitor-resistant tumors. Combined inhibition of EGFR and other signaling proteins has become a successful therapeutic approach, stimulating the search for further determinants of resistance as basis for novel therapeutic strategies.. We established human cancer cell lines with various degrees of EGFR expression and sensitivity to EGFR inhibitors and analyzed signal transducers under the control of EGFR-dependent and EGFR-independent pathways.. Multitargeted inhibitor vandetanib (ZD6474) inhibited the growth and the phosphorylation of Akt and its effector p70S6 kinase in both wild-type and EGFR inhibitor-resistant human colon, prostate, and breast cancer cells. We found that the resistant cell lines exhibit, as common feature, VEGFR-1/Flt-1 overexpression, increased secretion of VEGF and placental growth factor, and augmented migration capabilities and that vandetanib is able to antagonize them. Accordingly, a new kinase assay revealed that in addition to VEGF receptor (VEGFR)-2, RET, and EGFR, vandetanib efficiently inhibits also VEGFR-1. The contribution of VEGFR-1 to the resistant phenotype was further supported by the demonstration that VEGFR-1 silencing in resistant cells restored sensitivity to anti-EGFR drugs and impaired migration capabilities, whereas exogenous VEGFR-1 overexpression in wild-type cells conferred resistance to these agents.. This study shows that VEGFR-1 contributes to anti-EGFR drug resistance in different human cancer cells. Moreover, vandetanib inhibits VEGFR-1 activation, cell proliferation, and migration, suggesting its potential utility in patients resistant to EGFR inhibitors.

Topics: Antineoplastic Agents; Blotting, Western; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Immunoprecipitation; Neoplasms; Piperidines; Quinazolines; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Transfection; Vascular Endothelial Growth Factor Receptor-1

Quantitative structure-activity relationship of the 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide as a potent inhibitor of poly(ADP-ribose) polymerase for cancer treatment was studied. A suitable set of molecular descriptors was calculated and the genetic algorithm was employed to select those descriptors that resulted in the best fitted models. Excellent results were obtained employing multiple linear regressions and critically discussed using a variety of statistical parameters. Furthermore, the model was validated using leave-one-out and leave-group-out cross-validation, external test set and chance correlation. A genetic algorithm-multiple linear regression model with seven selected descriptors was obtained. This model, with high statistical significance (R(2) = 0.935, Q(2)_(LOO)= 0.894, Q(2)_(LGO)= 0.875, F = 53.481), could be used to predict poly(ADP-ribose) polymerase inhibitor activity of the molecules.

Topics: Algorithms; Antineoplastic Agents; Benzimidazoles; Databases, Genetic; Least-Squares Analysis; Models, Chemical; Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Predictive Value of Tests; Quantitative Structure-Activity Relationship; Regression Analysis; Software

Although flavopiridol, a semisynthetic flavone, was initially thought to be a specific inhibitor of cyclin-dependent kinases, it has now been shown that flavopiridol mediates antitumor responses through mechanism(s) yet to be defined. We have shown previously that flavopiridol abrogates tumor necrosis factor (TNF)-induced nuclear factor-kappaB (NF-kappaB) activation. In this report, we examined whether this flavone affects other cellular responses activated by TNF. TNF is a potent inducer of activator protein-1 (AP-1), and flavopiridol abrogated this activation in a dose- and time-dependent manner. Flavopiridol also suppressed AP-1 activation induced by various carcinogens and inflammatory stimuli. When examined for its effect on other signaling pathways, flavopiridol inhibited TNF-induced activation of various mitogen-activated protein kinases, including c-Jun NH(2)-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and p44/p42 MAPK. It is noteworthy that this flavone also suppressed TNF-induced activation of Akt, a cell survival kinase, and expression of various antiapoptotic proteins, such as IAP-1, IAP-2, XIAP, Bcl-2, Bcl-xL, and TRAF-1. Flavopiridol also inhibited the TNF-induced induction of intercellular adhesion molecule-1, c-Myc, and c-Fos, all known to mediate tumorigenesis. Moreover, TNF-induced apoptosis was enhanced by flavopiridol through activation of the bid-cytochrome-caspase-9-caspase-3 pathway. Overall, our results clearly suggest that flavopiridol interferes with the TNF cell-signaling pathway, leading to suppression of antiapoptotic mechanisms and enhancement of apoptosis.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Caspases; Cell Line; Cell Nucleus; Cell Proliferation; Cytochromes c; Enzyme Activation; Flavonoids; Gene Expression Regulation; Genes, Reporter; Humans; Intercellular Adhesion Molecule-1; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Myeloid Cells; Neoplasms; p38 Mitogen-Activated Protein Kinases; Piperidines; Protein Transport; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-myc; Transcription Factor AP-1; Tumor Necrosis Factors

Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Design; Drug Screening Assays, Antitumor; ErbB Receptors; Humans; Inhibitory Concentration 50; Insecta; Models, Chemical; Neoplasm Transplantation; Neoplasms; Piperidines; Pyrroles; Receptor, ErbB-2; Triazines

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Biomedical Research; Breast Neoplasms; Cetuximab; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Female; Gemcitabine; Humans; Imidazoles; Indazoles; Male; Molecular Structure; Neoplasms; Organoplatinum Compounds; Pancreatic Neoplasms; Piperidines; Prednisolone; Prostatic Neoplasms; Quinazolines; Treatment Outcome

Radiation enhances both epithelial growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) expression, which are a part of key pathways for tumor progression. Some tumors may not respond well to EGFR inhibitors alone or may develop resistance to EGFR inhibitors. Therefore, drug therapy targeted to VEGF receptors and EGFRs, when combined with radiotherapy (RT), may improve tumor control and provide wider applicability. This article focuses on ZD6474, an inhibitor of EGFR and VEGF receptor signaling in combination with RT. We discuss preclinical and clinical studies with RT and inhibitors of VEGF or EGFR signaling first. We then address issues associated with ZD6474 pharmacokinetic dosing, and scheduling when combined with RT. We also discuss ZD6474 in the context of anti-EGFR therapy resistance. Dual inhibition of EGFR and VEGF receptor signaling pathways shows promise in enhancing RT efficacy.

Topics: Angiogenesis Inhibitors; Animals; Combined Modality Therapy; ErbB Receptors; Humans; Neoplasms; Neovascularization, Pathologic; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Up-Regulation; Vascular Endothelial Growth Factor Receptor-2

All the nine 1,3-dialkylated-pyrimidin-2,4-diones investigated are active against all the 59 human tumor cell lines. Compounds 2, 3, 4, and 6 show significant anti-cancer activities at some specific cell lines while compounds 7 and 9 exhibit anti-cancer activities against more number of cell lines. The structure-activity relationship studies indicate that the presence of piperidine/pyrrolidine at the end of C-6 chain, benzoyl group at C-5, and benzyl groups at N-1, N-3 of the pyrimidine ring increases the anti-cancer activities of these molecules.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Neoplasms; Piperidines; Propanolamines; Pyrimidines; Pyrimidinones; Pyrrolidines; Structure-Activity Relationship

Selective cyclin-dependent kinase (cdk) 2 inhibition is readily compensated. However, reduced cdk2 activity may have antiproliferative effects in concert with other family members. Here, inducible RNA interference was used to codeplete cdk2 and cdk1 from NCI-H1299 non-small cell lung cancer and U2OS osteosarcoma cells, and effects were compared with those mediated by depletion of either cdk alone. Depletion of cdk2 slowed G1 progression of NCI-H1299 cells and depletion of cdk1 slowed G2-M progression in both cell lines, with associated endoreduplication in U2OS cells. However, compared with the incomplete cell cycle blocks produced by individual depletion, combined depletion had substantial consequences, with G2-M arrest predominating in NCI-H1299 cells and apoptosis the primary outcome in U2OS cells. In U2OS cells, combined depletion affected RNA polymerase II expression and phosphorylation, causing decreased expression of the antiapoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis (XIAP), effects usually mediated by inhibition of the transcriptional cdk9. These events do not occur after individual depletion of cdk2 and cdk1, suggesting that reduction of cdk2, cdk1, and RNA polymerase II activities all contribute to apoptosis in U2OS cells. The limited cell death induced by combined depletion in NCI-H1299 cells was significantly increased by codepletion of cdk9 or XIAP or by simultaneous treatment with the cdk9 inhibitor flavopiridol. These results show the potency of concomitant compromise of cell cycle and transcriptional cdk activities and may guide the selection of clinical drug candidates.

Topics: Apoptosis; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; CDC2 Protein Kinase; Cell Division; Cell Line, Tumor; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 9; Flavonoids; G1 Phase; G2 Phase; Humans; Lung Neoplasms; Neoplasms; Osteosarcoma; Piperidines; RNA Polymerase II; RNA, Small Interfering

We examined the efficacy of flavopiridol, a cyclin-dependent kinase inhibitor that is undergoing clinical trials, on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers.. Metastasized cancer cells were isolated from the pleural fluids (n = 20) or ascites (n = 15) of patients, most of whom were refractory to chemotherapy. These primary cancer cells were used within 2 weeks of isolation without selecting for proliferative capacities. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay was used to characterize the response of these cancer cells to commonly used chemotherapeutic agents, and their response to flavopiridol was compared with rapidly dividing cultured cell lines.. The primary cancer cells displayed phenotypes that were different from established cell lines; they had very low replication rates, dividing every 1 to 2 weeks, and underwent replicative senescence within five passages. These primary tumor cells retained their resistance to chemotherapeutic drugs exhibited by the respective patients but did not show cross-resistance to other agents. However, these cancer cells showed sensitivity to flavopiridol with an average LD50 of 50 nmol/L (range, 21.5-69 nmol/L), similar to the LD50 in established cell lines. Because senescent cells also showed similar sensitivity to flavopiridol, it suggests that the mechanism of action is not dependent on the activity of cyclin-dependent kinases that regulate the progression of the cell cycle.. Using cancer cells isolated from the ascites or pleural fluids, this study shows the potential of flavopiridol against cancer cells that have developed resistance to conventional chemotherapeutic agents.

Topics: Antineoplastic Agents; Ascites; Blotting, Western; Carboplatin; Cell Line, Tumor; Cell Proliferation; Cisplatin; Cyclin-Dependent Kinases; Dose-Response Relationship, Drug; Doxorubicin; Flavonoids; Humans; Neoplasms; Paclitaxel; Piperidines; Pleural Effusion, Malignant; Proto-Oncogene Proteins c-bcl-2; Time Factors; Tumor Cells, Cultured

ZD6474 (N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy] quinazolin-4-amine) is a tyrosine kinase inhibitor with anti-angiogenic and anti-tumor activity that is currently undergoing human trials for cancer treatment. Pharmacokinetic studies in animal models are an important component in clinical development of this agent to relate pre-clinical models to patient treatment. A liquid chromatography tandem mass spectrometry method was developed for the determination of ZD6474 levels in mouse plasma and tissues. Plasma (0.05 mL) and tissue homogenates (0.1 mL of 10 mg/mL) were extracted under alkaline conditions with ethyl acetate:pentane (1:1, v/v) after addition of the internal standard (trazodone, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridine-3(2H)-one). Separation was achieved on a C18, 50 mm x 2 mm column with quantitation by internal standard reference and multiple reaction monitoring of the ion transitions m/z 475-->112 (ZD6474) and m/z 372-->176 (trazodone). The calibration curve was linear from a range spanning 20-20,000 ng/mL in plasma and 10-320 ng/mg in tissue homogenates. Mean recoveries from plasma and tissue homogenates were 88 and 90%, respectively. The accuracy in plasma was 88% at the lower limit of quantitation (20 ng/mL with a 50 microL plasma sample) with high precision (R.S.D.%<10%). Assay performance in liver and other tissue homogenates is also reported. The assay was applied to a pharmacokinetic study in mice to determine dosing schedules that would approximate therapeutic ZD6474 levels determined in humans.

Topics: Acetates; Animals; Antineoplastic Agents; Calibration; Chemistry, Pharmaceutical; Chromatography; Chromatography, Liquid; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Female; Humans; Ions; Liver; Mass Spectrometry; Mice; Mice, Inbred BALB C; Models, Chemical; Neoplasms; Pentanes; Piperidines; Protein-Tyrosine Kinases; Quinazolines; Reproducibility of Results; Sensitivity and Specificity; Time Factors; Tissue Distribution; Trazodone

Lonafarnib (SCH66336) is a farnesyl transferase inhibitor (FTI) that inhibits the post-translational lipid modification of H-Ras and other farnesylated proteins. K- and N-Ras are also substrates of farnesyl transferase; however, upon treatment with FTIs, they are alternatively prenylated by geranylgeranyl transferase-1. Despite the failure to abrogate prenylation of K- and N-Ras, growth of many tumors in preclinical models is inhibited by FTIs. This suggests that the anti-proliferative action of FTIs is dependent on blocking the farnesylation of other proteins. Rheb (Ras homologue enriched in brain) is a farnesylated small GTPase that positively regulates mTOR (mammalian target of rapamycin) signaling. We found that Rheb and Rheb2 mRNA were elevated in various tumor cell lines relative to normal cells. Peptides derived from the carboxyl termini of human Rheb and Rheb2 are in vitro substrates for farnesyl transferase but not geranylgeranyl transferase-1. Rheb prenylation in cell culture was completely inhibited by SCH66336, indicating a lack of alternative prenylation. SCH66336 treatment also inhibited the phosphorylation of S6 ribosomal protein, a downstream target of Rheb and mTOR signaling. SCH66336 did not inhibit S6 phosphorylation in cells expressing Rheb-CSVL, a mutant construct of Rheb designed to be geranylgeranylated. Importantly, expression of Rheb-CSVL also abrogated SCH66336 enhancement of tamoxifen- and docetaxel-induced apoptosis in MCF-7 breast cancer cells and ES-2 ovarian cancer cells, respectively. Further, inhibition of Rheb signaling by rapamycin treatment, small interfering RNA, or dominant negative Rheb enhanced tamoxifen- and docetaxel-induced apoptosis, similar to FTI treatment. These studies demonstrated that Rheb is modified by farnesylation, is not a substrate for alternative prenylation, and plays a role in SCH66336 enhancement of the anti-tumor response to other chemotherapeutics.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Bridged-Ring Compounds; Caspases; Cell Line, Tumor; Farnesyltranstransferase; Humans; Monomeric GTP-Binding Proteins; Neoplasms; Neuropeptides; Phosphorylation; Piperidines; Protein Kinases; Protein Prenylation; Pyridines; Ras Homolog Enriched in Brain Protein; Recombinant Fusion Proteins; RNA, Messenger; Signal Transduction; Tamoxifen; Taxoids; TOR Serine-Threonine Kinases

Flavopiridol has been shown to inhibit the proliferation of a variety of human tumor cells and is currently undergoing clinical evaluation in cancer treatment. Although the antiproliferative effect of flavopiridol has been attributed to the inhibition of cyclin-dependent kinases 2 and 4, recent reports indicate that the mechanism responsible for the cell death induced by this agent is more complex. To provide insight into the molecular processes mediating flavopiridol-induced cytotoxicity and to investigate the availability of markers indicative of its activity, we have applied cDNA microarray technology. Gene expression profiles were determined for four human tumor cell lines (prostate carcinomas PC3 and DU145 and gliomas SF359 and U251) following exposure to selected concentrations of flavopiridol. Treatment of these cell lines with a concentration of flavopiridol sufficient to reduce survival to 10% resulted in the identification of a set of 209 genes, the expression of which were altered in each of the cell lines. This common set of 209 gene expression changes suggested that flavopiridol-induced cell death can be defined in terms of a specific transcriptome. The flavopiridol death transcriptome consisted primarily of down-regulated genes; however, there were also a significant number of genes with increased expression. Whereas causal relationships were not established, these data suggest molecular events/processes that may be associated with flavopiridol-induced tumor cell death. Moreover, the identification of a set of gene expression changes in four human tumor cell lines suggests that such a transcriptome may be applicable to investigations of flavopiridol pharmacodynamics.

Topics: Antineoplastic Agents; Cell Death; Cell Line, Tumor; Flavonoids; Gene Expression Profiling; Humans; Neoplasms; Oligonucleotide Array Sequence Analysis; Piperidines; RNA, Messenger; RNA, Neoplasm; Transcription, Genetic

ZD6474 is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2/KDR) tyrosine kinase, with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. ZD6474 inhibits angiogenesis and growth of a wide range of tumor models in vivo. Gefitinib ("Iressa") is a selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer cell proliferation. Here, the ability of gefitinib and ZD6474 to inhibit tumor cell proliferation was examined directly in eight cancer cell lines in vitro, and a strong correlation was noted between the IC(50) values of gefitinib and ZD6474 (r = 0.79). No correlation was observed between the sensitivity to ZD6474 and the level of EGFR or VEGFR expression. The NSCLC cell line PC-9 was seen to be hypersensitive to gefitinib and ZD6474, and a small (15-bp) in-frame deletion of an ATP-binding site (exon 19) in the EGFR was detected (delE746-A750-type deletion). To clarify the involvement of the deletional mutation of EGFR in the cellular sensitivity to ZD6474, we examined the effect of this agent on HEK293 stable transfectants expressing deletional EGFR that designed as the same deletion site observed in PC-9 cells (293-pDelta15). These cells exhibited a 60-fold higher sensitivity to ZD6474 compared with transfectants expressing wild-type EGFR. ZD6474 inhibited the phosphorylation of the mutant EGFR by 10-fold compared with cells with wild-type EGFR. In conclusion, the findings suggested that a small in-frame deletion in the EGFR increased the cellular sensitivity to ZD6474.

Topics: Base Sequence; Cell Line, Tumor; Gefitinib; Gene Deletion; Genes, erbB-1; Humans; Molecular Sequence Data; Neoplasms; Piperidines; Quinazolines; Transfection; Vascular Endothelial Growth Factor Receptor-2

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Cyclosporins; Dibenzocycloheptenes; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs, Investigational; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Membrane Transport Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; National Institutes of Health (U.S.); Neoplasms; Piperidines; Pyridines; Quinolines; United States

Topics: Adenosine Triphosphate; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; ErbB Receptors; Humans; Inhibitory Concentration 50; Neoplasms; Piperidines; Quinazolines; Vascular Endothelial Growth Factor Receptor-2

Vascular endothelial growth factor (VEGF) is a major mitogen for endothelial cells and enhances vascular permeability. Enhanced VEGF secretion is found in human cancers and correlates with increased tumor neovascularization. ZD6474 is a p.o. bioavailable, VEGF flk-1/KDR receptor (VEGFR-2) tyrosine kinase inhibitor with antitumor activity in many human cancer xenografts and is currently in Phase I clinical development.. We tested the effects of ZD6474 on EGFR phosphorylation in cell expressing functional epidermal growth factor receptor (EGFR) and the antiproliferative and the proapoptotic activity of ZD6474 alone or in combination taxanes in human cancer cell lines with functional EGFR but lacking VEGFR-2. The antitumor activity of this drug was also tested in nude mice bearing established GEO colon cancer xenografts.. ZD6474 causes a dose-dependent inhibition of EGFR phosphorylation in mouse NIH-EGFR fibroblasts and human MCF-10A ras breast cancer cells, two cell lines that overexpress the human EGFR. ZD6474 treatment resulted in a dose-dependent inhibition of soft agar growth in seven human cell lines (breast, colon, gastric, and ovarian) with functional EGFR but lacking VEGFR-2. A dose-dependent supra-additive effect in growth inhibition and in apoptosis in vitro was observed by the combined treatment with ZD6474 and paclitaxel or docetaxel. ZD6474 treatment of nude mice bearing palpable GEO colon cancer xenografts (which are sensitive to inhibition of EGFR signaling) induced dose-dependent tumor growth inhibition. Immunohistochemical analysis revealed a significant dose-dependent reduction of neoangiogenesis. The antitumor activity of ZD6474 in GEO tumor xenografts was also found to be enhanced when combined with paclitaxel. Tumor regression was observed in all mice after treatment with ZD6474 plus paclitaxel, and it was accompanied by a significant potentiation in inhibition of angiogenesis. Six of 20 mice had no histological evidence of tumors after treatment with ZD6474 plus paclitaxel.. This study suggests that in addition to inhibiting endothelial cell proliferation by blocking VEGF-induced signaling, ZD6474 may also be able to inhibit cancer cell growth by blocking EGFR autocrine signaling. These results provide also a rationale for the clinical evaluation of ZD6474 combined with taxanes in cancer patients.

Topics: Agar; Animals; Antibodies, Monoclonal; Apoptosis; Blotting, Western; Cell Division; Cell Line, Tumor; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; ErbB Receptors; Flow Cytometry; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms; NIH 3T3 Cells; Paclitaxel; Phosphorylation; Piperidines; Protein-Tyrosine Kinases; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Time Factors; Vascular Endothelial Growth Factor Receptor-2

Pain associated with cancer and chronic musculoskeletal disorders can be difficult to control. We used murine models of cancer and inflammatory muscle pain to examine whether the cannabinoid receptor agonist WIN55,212-2 reduces hyperalgesia originating in deep tissues. C3H/He mice were anesthetized and implanted with osteolytic NCTC clone 2472 cells into the humeri or injected with 4% carrageenan into the triceps muscles of both forelimbs. At the time of peak hyperalgesia, WIN55,212-2 (1-30mg/kg) or vehicle was administered intraperitoneally and forelimb grip force was measured 0.5-24h later. WIN55,212-2 produced time- and dose-related antihyperalgesia in both models. A 10mg/kg dose of WIN55,212-2 fully reversed carrageenan-evoked muscle hyperalgesia. However, 30mg/kg of WIN55,212-2 attenuated tumor-evoked hyperalgesia only approximately 50%. After controlling for the difference in magnitude of hyperalgesia between the two models, WIN55,212-2 was still more potent at reducing hyperalgesia in the inflammatory model. In the cancer pain model, the antihyperalgesic effect of WIN55,212-2 was partially blocked by pretreatment with the selective CB1 (SR141716A) but not the CB2 (SR144528) receptor antagonist. In contrast, both antagonists blocked antihyperalgesic effects of WIN55,212-2 on carrageenan-evoked muscle hyperalgesia. Catalepsy and loss of motor coordination, known side effects of cannabinoids, did not account for the antihyperalgesia produced by WIN55,212-2. These data show that cannabinoids attenuate deep tissue hyperalgesia produced by both cancer and inflammatory conditions. Interestingly, cannabinoids differentially modulated carrageenan- and tumor-evoked hyperalgesia in terms of potency and receptor subtypes involved suggesting that differences in underlying mechanisms may exist between these two models of deep tissue pain.

Topics: Animals; Benzoxazines; Calcium Channel Blockers; Camphanes; Cannabinoids; Carrageenan; Catalepsy; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Fibrosarcoma; Haloperidol; Hand Strength; Humerus; Hyperalgesia; Male; Mice; Mice, Inbred C3H; Morpholines; Myositis; Naphthalenes; Neoplasm Transplantation; Neoplasms; Pain; Piperidines; Psychomotor Performance; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Topics: Antineoplastic Agents; Clinical Trials as Topic; Cyclin-Dependent Kinases; Drug Evaluation, Preclinical; Enzyme Inhibitors; Flavonoids; Humans; Neoplasms; Piperidines

Hypohalites (OCl-, OBr-) are formed at inflammation sites as antimicrobial agents. OCl- is also used for the disinfection of water supplies and the association of drinking chlorinated water with cancer risk is pointed out. In this study, OCl- itself induced 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation, while OBr- damaged DNA only when glutathione (GSH) was added. OCl- caused oxidative DNA damage more efficiently than OBr-/GSH. In experiment with 32P-labeled DNA fragments, OCl- strongly caused piperidine-labile sites at guanine residues than piperidine-inert 8-oxodG, whereas OBr-/GSH caused no piperidine-labile sites. Endogenous OCl- may play a role in genotoxicity close to the site of inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Bromates; Carcinogens; Cattle; Cell Line; Deoxyguanosine; Dimethyl Sulfoxide; DNA; DNA Damage; Electron Spin Resonance Spectroscopy; Genes, p53; Genes, ras; Genes, Tumor Suppressor; Glutathione; Humans; Inflammation; Neoplasms; Oxidation-Reduction; Phosphorus Isotopes; Piperidines; Sodium Hypochlorite

Tamoxifen is an antiestrogen used in women who have estrogen receptor (ER)-alpha-positive breast cancer. Unfortunately, resistance to tamoxifen is common in women with metastatic disease and side effects, including increased risk of endometrial cancer, exist. Here we describe the activity of a new selective ER modulator, ERA-923, in preclinical models focused on these limitations.. The ability of ERA-923, 4-OH tamoxifen, or raloxifene to inhibit estrogen-stimulated growth was evaluated in cell-based and xenograft assays with tumor cells that are sensitive or resistant to tamoxifen. Uterine effects of selective ER modulators were compared in rodents.. ERA-923 potently inhibits estrogen binding to ER-alpha (IC(50), 14 nM). In ER-alpha-positive human MCF-7 breast carcinoma cells, ERA-923 inhibits estrogen-stimulated growth (IC(50), 0.2 nM) associated with cytostasis. In vitro, a MCF-7 variant with inherent resistance to tamoxifen (10-fold) or 4-OH tamoxifen (>1000-fold) retains complete sensitivity to ERA-923. Partial sensitivity to ERA-923 exists in MCF-7 variants that have acquired profound tamoxifen resistance. In tumor-bearing animals, ERA-923 (10 mg/kg/day given p.o.) inhibits 17beta-estradiol-stimulated growth in human tumors derived from MCF-7, EnCa-101 endometrial, or BG-1 ovarian carcinoma cells, including a MCF-7-variant that is inherently resistant to tamoxifen. Raloxifene is inactive in the MCF-7 xenograft model. Unlike tamoxifen, droloxifene, or raloxifene, ERA-923 is not uterotropic in immature rats or ovariectomized mice. Consistent with this, tamoxifen, but not ERA-923, stimulates the growth of EnCa-101 tumors.. In preclinical models, ERA-923 has an improved efficacy and safety compared with tamoxifen. Clinical trials with ERA-923 are in progress.

Topics: Animals; Binding, Competitive; Cell Division; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor Modulators; Female; Fulvestrant; Humans; Indoles; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Organ Size; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Sensitivity and Specificity; Tamoxifen; Time Factors; Tumor Cells, Cultured; Uterus; Xenograft Model Antitumor Assays

Coagulation abnormalities, including an increased platelet turnover, are frequently found in patients with cancer. Because platelets secrete angiogenic factors on activation, this study tested the hypothesis that platelets contribute to angiogenesis. Stimulation with vascular endothelial growth factor (VEGF, 25 ng/mL) of human umbilical vein endothelial cells (HUVECs) promoted adhesion of nonactivated platelets 2.5-fold. In contrast, stimulation of HUVECs with basic fibroblast growth factor (bFGF) did not promote platelet adhesion. By blocking tissue factor (TF) activity, platelet adhesion was prevented and antibodies against fibrin(ogen) and the platelet-specific integrin, alpha(IIb)beta(3), inhibited platelet adhesion for 70% to 90%. These results indicate that VEGF-induced platelet adhesion to endothelial cells is dependent on activation of TF. The involvement of fibrin(ogen) and the alpha(IIb)beta(3) integrin, which exposes a high-affinity binding site for fibrin(ogen) on platelet activation, indicates that these adhering platelets are activated. This was supported by the finding that the activity of thrombin, a product of TF-activated coagulation and a potent platelet activator, was required for platelet adhesion. Finally, platelets at physiologic concentrations stimulated proliferation of HUVECs, indicative of proangiogenic activity in vivo. These results support the hypothesis that platelets contribute to tumor-induced angiogenesis. In addition, they may explain the clinical observation of an increased platelet turnover in cancer patients. Platelets may also play an important role in other angiogenesis-dependent diseases in which VEGF is involved, such as diabetes and autoimmune diseases. (Blood. 2000;96:4216-4221)

Topics: Adult; Blood Platelets; Cell Division; Cells, Cultured; Endothelial Growth Factors; Endothelium, Vascular; Fibroblast Growth Factor 2; Flow Cytometry; Humans; Lymphokines; Microscopy, Fluorescence; Neoplasms; Neovascularization, Pathologic; Phenylalanine; Piperidines; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Thrombin; Thrombophilia; Umbilical Veins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The ras gene product regulates transduction of growth-proliferative signals from the membrane to the nucleus. Mutationally-activated Ras is the oncogene most frequently found in human tumors. In order to perform its function in cell signaling, Ras must be farnesylated on the CAAX motif present on the carboxyl terminus of the ras protein. This reaction is catalysed by farnesyl protein transferase. In the present study, SCH 66336, an orally bioavailable nonpeptide tricyclic farnesyltransferase inhibitor, was tested against a large variety of human tumors to define its preclinical activity profile, utilizing the human tumor cloning assay.. A soft agar cloning assay was used to determine the in vitro effects of SCH 66336 against primary human tumor specimens taken directly from patients. A total of 70 evaluable specimens were exposed to SCH 66336 for 14-day continuous exposure at concentrations ranging from 0.1 to 2.5 microM. In vitro responses were defined as an inhibition > or = 50% of human tumor colony forming units at a given concentration.. There was a positive relationship between concentration and response to SCH 66336. With the highest concentration (2.5 microM), response was demonstrated in 50% (three of six) of breast tumors, 40% (6 of 15) of ovarian tumors, and 38% (5 of 13) of non-small-cell lung tumor colony forming units. Among the 69 specimens tested at the concentration of 2.5 microM, SCH 66336 had activity in 27% of tumor specimens that were resistant to doxorubicin, 38% of tumor specimens resistant to cisplatin, 33% of tumor specimens resistant to paclitaxel, and 27% of tumor specimens resistant to etoposide.. The broad spectrum of soft agar growth inhibition by SCH 66336 in the human tumor cloning assay, and its efficacy at physiologically relevant concentrations in animal models, suggest that SCH 66336 may deserve future clinical trials in patients with ovarian, breast and non-small-cell lung cancer.

Topics: Alkyl and Aryl Transferases; Cell Survival; Cisplatin; Clone Cells; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Etoposide; Farnesyltranstransferase; Humans; Neoplasms; Neoplastic Stem Cells; Paclitaxel; Piperidines; Pyridines; Sensitivity and Specificity; Tumor Cells, Cultured; Tumor Stem Cell Assay

Receptors for regulatory peptides, such as somatostatin or vasoactive intestinal peptide (VIP), expressed at high density by neoplastic cells, can be instrumental for tumor diagnosis and therapy. Little is known about the expression of neurotensin receptors in human tumors. In the present study, 464 human neoplasms of various types were investigated for their neurotensin receptor content by in vitro receptor autoradiography on tissue sections using 125I-[Tyr3]-neurotensin as radioligand. Neurotensin receptors were identified and localized in tumor cells of 11/17 Ewing's sarcomas, 21/40 meningiomas, 10/23 astrocytomas, 5/13 medulloblastomas, 7/24 medullary thyroid cancers and 2/8 small cell lung cancers. They were rarely found in non-small cell lung cancers and breast carcinomas; they were absent in prostate, ovarian, renal cell and hepatocellular carcinomas, neuroendocrine gut tumors, pituitary adenomas, schwannomas, neuroblastomas and lymphomas. When present, the receptors bound with nanomolar affinity neurotensin and acetyl-neurotensin-(8-13), with lower affinity neuromedin N, diethylenetriamine penta-acetic acidneurotensin-(8-13) and SR 48692, but not neurotensin-(1-11). They were all of the NT1 type, without high affinity for levocabastine. Further, in 2 receptor-positive Ewing's sarcomas, neurotensin mRNA was detected by in situ hybridization techniques. Since neurotensin is known to stimulate cell proliferation, the presence of neurotensin receptors in human neoplasia may be of biological relevance, possibly as an integrative part of an autocrine feedback mechanism of tumor growth stimulation.

Topics: Animals; Bone Neoplasms; Humans; Neoplasm Proteins; Neoplasms; Neurotensin; Organ Specificity; Peptide Fragments; Piperidines; Pyrazoles; Quinolines; Rats; Receptors, Neurotensin; RNA, Messenger; RNA, Neoplasm; Sarcoma, Ewing

Halofuginone, an inhibitor of collagen alpha1(I) gene expression was used for the treatment of subcutaneously implanted C6 glioma tumors. Halofuginone had no effect on the growth of C6 glioma spheroids in vitro, and these spheroids showed no collagen alpha1(I) expression and no collagen synthesis. However, a significant attenuation of tumor growth was observed in vivo, for spheroids implanted in CD-1 nude mice which were treated by oral or intraperitoneal (4 microg every 48 hours) administration of halofuginone. In these mice, treatment was associated with a dose-dependent reduction in collagen alpha1(I) expression and dose- and time-dependent inhibition of angiogenesis, as measured by MRI. Moreover, halofuginone treatment was associated with improved re-epithelialization of the chronic wounds that are associated with this experimental model. Oral administration of halofuginone was effective also in intervention in tumor growth, and here, too, the treatment was associated with reduced angiogenic activity and vessel regression. These results demonstrate the important role of collagen type I in tumor angiogenesis and tumor growth and implicate its role in chronic wounds. Inhibition of the expression of collagen type I provides an attractive new target for cancer therapy.

Topics: Animals; Antineoplastic Agents; Collagen; Dose-Response Relationship, Drug; In Situ Hybridization; Kinetics; Magnetic Resonance Imaging; Male; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Piperidines; Protein Synthesis Inhibitors; Quinazolines; Quinazolinones; Time Factors; Tumor Cells, Cultured; Wound Healing

The discovery of a series of novel halogenated arylsulfonamides (HAS) as new sigma receptor binding tumor imaging agents is described. Several substituted halogenated sulfonamides have been prepared and characterized. Target compounds were examined for their affinity for sigma1 and sigma2 receptor subtypes using guinea pig brain membranes and rat liver membranes, respectively. A number of substituted halogenated sulfonamides displayed subnanomolar affinities for sigma1 sites and low nanomolar affinities for sigma2 subtype receptors. A limited structure-activity relationship study of this chemical series is discussed. The radioiodination (I-125) of one congener member (4-[125I]iodo-N-[2-(1'-piperidinyl)ethyl]benzenesulfonamide, 4-[125I]IPBS) was accomplished in high yields. The in vitro competition binding studies of 4-[125I]IPBS in guinea pig brain membranes with sigma receptor binding ligands confirmed its sigma pharmacology. The rank order of potency was BD1008 (N-[2-(3, 4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) > 4-IPBS > haloperidol > (+)-pentazocine > DTG (1, 3-di-o-tolylguanidine) > (-)-pentazocine. The inhibition constants (IC50) were 0.70, 1.46, 6.28, 10.4, 87.2, and 152 nM, respectively, and are consistent with labeling of sigma1 receptors. The tumor imaging potential of 4-[125I]IPBS was studied in C57 black mice bearing B16 melanoma xenograft. A high tumor uptake of 4-[125I]IPBS was observed (7.40% ID/g) at 1 h postinjection. The wash out of activity from the tumor was slow at 6 h postinjection (7.22% ID/g). The tumor also had the highest amount of radioactivity (1.54% ID/g) at 24 h postinjection. These results demonstrate that radiohalogenated benzenesulfonamides could be a potentially useful class of compounds in nuclear oncologic scintigraphy.

Topics: Animals; Binding, Competitive; Brain; Guinea Pigs; Iodine Radioisotopes; Isotope Labeling; Ligands; Liver; Melanoma; Membranes; Mice; Neoplasm Transplantation; Neoplasms; Piperidines; Radionuclide Imaging; Radiopharmaceuticals; Rats; Receptors, sigma; Structure-Activity Relationship; Sulfonamides; Tissue Distribution; Transplantation, Heterologous; Tumor Cells, Cultured

The aim of this study was, (1) to characterize the serum protein binding of lerisetron, a new 5-hydroxytryptamine (5-HT3) receptor antagonist under investigation as an antiemetic agent, and (2) to measure the percentage of unbound lerisetron in cancer patients. The binding parameters were determined in human serum albumin (HSA), alpha1-acid glycoprotein (AAG) and in pooled serum from six healthy volunteers. Concentrations of lerisetron ranging from 50 ng/ml to 2 microg/ml were used. The serum protein binding of 14C-lerisetron (2 microg/ml) was determined by ultrafiltration in three groups of individuals. Group I comprised healthy subjects (n = 11), group II comprised cancer patients undergoing radiotherapy (n = 9), and group III comprised cancer patients receiving chemotherapy (n = 18). The unbound concentration of lerisetron was measured in all samples by liquid scintillation counting. Concentrations of both AAG and HSA were also measured in all serum samples. The drug was extensively bound in pooled serum, involving a nonsaturated process. In HSA, lerisetron was also highly bound (4.04+/-0.8% unbound) and the protein binding was essentially unchanged within the studied concentration range of lerisetron. The extent of binding to AAG was high but significantly lower than in serum and in HSA and was also independent of lerisetron concentration. The unbound lerisetron was significantly decreased in group II cancer patients when compared with group I subjects (2.38+/-0.64% vs 3.70+/-0.70%; P < 0.001). No significant changes in lerisetron binding were observed in group III patients. HSA was diminished in both groups of patients and AAG was only significantly increased in group II. Unbound lerisetron was correlated with AAG in group II and with HSA in group III.

Topics: Adult; Antiemetics; Benzimidazoles; Carbon Radioisotopes; Female; Humans; Male; Middle Aged; Neoplasms; Orosomucoid; Piperidines; Protein Binding; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Serum Albumin

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Drugs, Investigational; Estrogen Antagonists; Female; Humans; Lavandula; Male; Neoplasms; Oils, Volatile; Ovarian Neoplasms; Piperidines; Plant Oils; Plants, Medicinal; Prostatic Neoplasms; Raloxifene Hydrochloride; Retinoids; Tamoxifen; Toremifene

Significant activity has been identified using S9788, a triazineaminopiperidine derivative, as a new modulator of multi-drug resistance against a series of drug-resistant human tumour-cell lines in vitro. Maximal non-cytotoxic concentrations (i.e., those resulting in < or = 10% cytotoxicity) of S9788 or verapamil were tested in combination with vinblastine, Adriamycin or vincristine and cytotoxicity was evaluated using a clonogenic assay, or the metabolic dye reduction MTT assay, or by monitoring growth inhibition. Under these conditions, the extent of resistance modulation by verapamil and by S9788 was comparable in the various tumour cell lines tested, although a definite concentration-dependent modulation was noted with both compounds. The highest dose-modification factors were noted in the highly vinblastine-resistant classic multi-drug-resistant subline CEM/VLB100, although resistance reversal was only partial. Resistance modulation by both verapamil and S9788 was noted in 4 drug-selected resistant sublines and 4 "intrinsically" resistant human tumour cell lines, which all exhibited significant P-glycoprotein expression. In contrast, in 2 drug-resistant human tumour sublines (GLC4/ADR and CEM/VM-1) characterized by altered topoisomerase-II activity and proving to be P-glycoprotein-negative, no resistance modulation relative to parental cells was observed. These data are consistent with the proposal that resistance modulation is mediated by interaction between S9788 and P-glycoprotein and support its clinical evaluation in patients with P-glycoprotein-positive tumours.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carrier Proteins; Doxorubicin; Drug Resistance; Drug Screening Assays, Antitumor; Humans; Membrane Glycoproteins; Molecular Structure; Neoplasms; Piperidines; Triazines; Tumor Cells, Cultured; Verapamil; Vinblastine; Vincristine

S9788, a new triazinoaminopiperidine derivative, was 250-fold more active than verapamil in sensitizing DC-3F/AD cells to actinomycin D. This multidrug-resistance modulating activity of S9788 was confirmed on DC-3F/AD, P388/ADR-10, P388/VCR-20, KB/A1, K562/R, S1/tMDR, and COLO320DM cells, with respect to actinomycin D, doxorubicin, vincristine, vinblastine and etoposide. S9788 is 2-255-fold more active than verapamil, depending on the cell line and the cytotoxic agent used, potentiating preferentially the cytotoxicity of the vinca-alkaloid derivatives. S9788 only had a slight effect on vincristine accumulation and retention by parental sensitive cells, as well as on their sensitivity to cytotoxic drugs. S9788 fully restored vincristine accumulation and retention by S1/tMDR cells (S1 cells transfected by the mdr 1 gene) to a level similar to that measured in S1 cells, leading to a blockade in the G2 + M phase of the cell cycle. Therefore, S9788 enhances vincristine activity by restoring its cellular accumulation in resistant cells. After a short incubation period of cells with vincristine (4 h), a condition close to the clinical administration of this cytotoxic agent, a post-incubation for 20 hours more with 5 microM S9788, fully restored the sensitivity of S1/tMDR cells to vincristine. After an exposure of 4 hours at equal concentrations, the accumulation of S9788 was 13-fold that of verapamil in S1/tMDR cells, and 20 hours after the removal of the modulators, S9788 was retained at a concentration 20-fold that of verapamil. S9788 is therefore a powerful new modifier of the P-gp-mediated multidrug-resistance, which by its pharmacological properties (cellular kinetics and activity), might be used in combination with existing chemotherapy against tumors displaying the MDR phenotype.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Drug Resistance; Drug Screening Assays, Antitumor; Humans; In Vitro Techniques; Mice; Neoplasms; Neoplasms, Experimental; Phenotype; Piperidines; Triazines; Tumor Cells, Cultured; Verapamil

Previous data indicated that opioid receptors occur in both neural and nonneural human tumors. However, it has recently been shown that some of the putative opioid binding may be attributable to sigma sites. In this study the occurrence of sigma and opioid receptors in nonneural human tumors was assessed. The neoplasms included renal and colon carcinomas and a sarcoma. [3H]1,3-di-o-tolylguanidine was used to assay sigma receptors by homologous competition binding assays, which when analyzed provided dissociation constant and receptor density values. Opioid binding was measured with [3H]-(-)-ethylketocyclazocine, a ligand which interacts with mu, delta, and kappa subtypes. Fresh surgical specimens were obtained from 9 human neoplasms, selected for their large size, and compared with nonmalignant tissues. All 9 tumors contained sigma sites, and dissociation constant values were within the range of 27-83 nM. Occasionally, two-site fit the data better than one-site binding, suggesting the presence of multiple sigma sites. Opioid binding was not detected. Intratumoral variability was evaluated by sampling several locations on the periphery of the mass and one in the center. Each of the samples was bisected, with a portion reserved for histological examination to correlate morphological features with receptor data. Changes in sigma binding were not associated with the extent of fibrosis, viability, or necrosis. Receptor density values displayed moderate intra- and intertumoral variation (coefficients of variation, 8-39 and 27-49%, respectively). More important, sigma binding in tumors was found to be greater than or equal to 2-fold higher than that of control nonmalignant tissue.

Topics: Binding, Competitive; Carcinoma; Colonic Neoplasms; Guanidines; Humans; In Vitro Techniques; Kidney Neoplasms; Neoplasms; Piperidines; Receptors, Opioid; Receptors, sigma; Sarcoma

Synthetic Antineoplaston A10, 3-phenylacetylamino-2,6-piperidinedione, has been shown to produce promising clinical results, similar to those obtained with antineoplastons derived from urine. Antineoplaston A10 is capable of reducing the excessive excretion of peptides often associated with cancer patients, thereby boosting endogenous levels of antineoplaston. Its therapeutic effect is partially attributable to endogenous antineoplastons, the level of which Antineoplaston A10 can help to raise. A patient must have a certain reserve of endogenous antineoplastons in order to benefit from therapy with Antineoplaston A10. The critical plasma peptide level seems to be above 30 nmoles/ml. Patients who responded favourably to the treatment with Antineoplaston A10 invariably showed an increase of plasma peptide levels and a decrease of urinary excretion of peptides. These results suggest that the body, under normal circumstances, is protected by antineoplastons against cancer. This chemical mechanism of protection is hereby termed chemo-surveillance.

Topics: Antineoplastic Agents; Benzeneacetamides; Humans; Neoplasms; Peptides; Piperidines; Piperidones

The antineoplastic activity of two ether lipid derivatives, the alkyl-lysophospholipid derivative (ALP) ET-18-OCH3 and the ether-linked lipoidal amine CP-46,665 was tested in a human tumor clonogenic assay (HTCA) in vitro. CP-46,665 suppressed the colony formation of various human tumors with a slight dose response relation after 1 hr incubation and with a clear optimum (85% response rate) after continuous exposure in the higher dose range tested (10 micrograms/ml). ET-18-OCH3 did not have substantial activity after 1 hr of incubation. However, when continuous exposure to the compound was used, ET-18-OCH3 seemed to have a modest dose response effect and yielded a response in about 60% of the tumor cell samples tested in the higher dose range (10 micrograms/ml). Thus, both compounds have in vitro antitumor activity in the HTCA within a dose range of 1-10 micrograms/ml, especially during continuous exposure. The tumor specific type activity was found in breast cancer, ovarian cancer, lung cancer and mesothelioma. Both compounds caused decreases in colony formation down to the 0%, 2% and 4% levels. In a comparison of specimens in which both compounds were used, only one of five times showed a discordance in sensitivity or resistance; therefore the compounds appear similar in their in vitro activity. In a second set of experiments we tested the structure-activity relationship among a variety of ALP in the [3H]thymidine incorporation assay after incubation with HL-60 leukemic blasts and other neoplastic cells from human origin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Agents; Cell Survival; Female; Humans; Lysophosphatidylcholines; Neoplasms; Phospholipid Ethers; Piperidines; Structure-Activity Relationship

The alkyl-linked lipoidal amine 4-aminomethyl-1-[2,3-(di-n-decyloxy)-n-propyl]-4-phenylpiperidine (CP-46,665) inhibited the in vitro incorporation of tritiated thymidine into blasts of eight leukemias and cells of nine different solid tumors of human origin. This activity was well correlated with trypan blue dye exclusion, which was tested to assess cell membrane damage. Scanning electron microscopy revealed loss of cell surface features and severe cell membrane destruction after incubation with CP-46,665. These effects on thymidine uptake and single cell viability were accompanied by a clear loss of the reproductive capacities of human tumor and leukemic cells as measured in a human tumor stem cell assay after incubation with CP-46,665. The above-mentioned cytostatic and cytotoxic effects of CP-46,665 were dependent on dosage and incubation time. Destruction of leukemic blasts was often completed with greater than or equal to 5 micrograms/ml after an incubation of greater than or equal to 48 hr or greater than or equal to 10 micrograms/ml after an incubation of greater than or equal to 24 hr. Cells from solid tumors usually required a slightly higher drug concentration and longer incubation period for maximum killing. The alkyl-linked lipoidal amine CP-46,665 often showed considerably greater efficacy than did the alkyl-linked phospholipid rac-1-O-octadecyl-2-O-methylglycero-3-phosphocholine tested in comparison. In contrast to both drugs, 2-lysophosphatidylcholine showed only minor activity within the same dose range.

Topics: Adjuvants, Immunologic; Cell Line; Cell Survival; Humans; Leukemia; Microscopy, Electron, Scanning; Neoplasms; Neoplastic Stem Cells; Piperidines; Thymidine; Trypan Blue

4-Chloronitrosopiperidine was administered to a group of 15 male Sprague-Dawley rats as a 0.005% solution in drinking water for 27 weeks. Of the 15 animals, 12 died with tumors induced by the treatment, half of them by the 41 st week; all 15 were dead at 58 weeks. Seven rats had liver tumors, 5 had esophageal tumors, 2 had tumors of the nonglandular stomach and 2 had tumors of the nasal turbinates. Several rats had tumors of more than one organ.

Topics: Animals; Carcinogens; Male; Neoplasms; Nitrosamines; Piperidines; Rats; Structure-Activity Relationship

The kinetics of nornicotine and anabasine nitrosation, studied in aqueous solution, obeyed equations typical for the nitrosation of aliphatic secondary amines, with third-order stoichiometric rate constants of 1.15 (nornicotine) and 0.86 (anabasine) M-2 sec-1. The similarity of the two rate constants suggested that the nitrosonornicotine occurring in tobacco arises from nicotine rather than nornicotine, because tobacco contains anabasine but apparently does not contain nitrosoanabasine. The high rate constants suggested that in vivo nitrosation of these secondary amines may constitute a hazard to tobacco smokers and chewers, in addition to that presented by preformed nitrosonornicotine.

Topics: Anabasine; Animals; Humans; In Vitro Techniques; Kinetics; Neoplasms; Nicotiana; Nicotine; Nitrosamines; Piperidines; Plants, Toxic; Smoking; Tobacco, Smokeless

In order to determine whether piperazinedione used in low doses in combination with cyclophosphamide plus dimethyl-triazeno-imidazole carboxamide (DTIC) produced variable or severe myelosuppression, a Phase I Study was performed in 10 patients who received 16 courses of the three-drug combination. Although mild myelosuppression was consistently observed at doses of 4 mg piperazinedione, 400 mg cyclophosphamide, plus 400 mg DTIC, variable, severe, and prolonged myelosuppression was seen in three of six patients who received a dose of each of the drugs only 25% higher. The only other abnormality observed was nausea and vomiting. This study indicates that low doses of piperazinedione can produce variable and severe myelosuppression when used in combination with other myelosuppressive agents, and that only small increments in dosage may produce marked increases in the degree of myelosuppression. Future combination chemotherapy regimens employing piperazinedione should undergo cautious Phase I toxicity testing to avoid severe depression of blood counts.

Topics: Bone Marrow; Cyclophosphamide; Dacarbazine; Drug Therapy, Combination; Humans; Neoplasms; Piperazines; Piperidines; Triazenes

Topics: Analgesics; Anesthetics, Local; Humans; Hypnotics and Sedatives; Morphine Derivatives; Neoplasms; Neurosurgery; Pain, Intractable; Palliative Care; Piperidines; Propylamines

Topics: Amines; Animals; Azetines; Azirines; Cell Line; Chemical Phenomena; Chemistry; Electrons; Hydrogen-Ion Concentration; Imidazoles; Imines; Kinetics; Mast Cells; Mice; Mice, Inbred Strains; Neoplasms; Nicotine; Piperidines; Pyrroles; Pyrrolidines; Serotonin; Solubility; Spectrometry, Fluorescence; Structure-Activity Relationship

Topics: Adolescent; Adult; Aged; Analgesics; Benperidol; Benzimidazoles; Child; Chronic Disease; Cough; Drug Synergism; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Pain; Palliative Care; Piperidines; Psychology; Substance-Related Disorders

Topics: Amines; Carcinogens; Dealkylation; Dimethylamines; Dimethylformamide; Environmental Exposure; Ethanolamines; Food Additives; Humans; Hydrogen-Ion Concentration; Methylamines; Morpholines; Naphthalenes; Neoplasms; Nitrites; Nitrosamines; p-Dimethylaminoazobenzene; Piperazines; Piperidines; Propylamines; Pyrrolidines; Temperature; Time Factors; Urea

Topics: Analgesics; Arthritis; Aspirin; Codeine; Dioxoles; Drug Synergism; Humans; Neoplasms; Pain; Palliative Care; Piperidines

Topics: Adult; Aged; Anesthesia, General; Anesthesia, Intravenous; Anilides; Arrhythmias, Cardiac; Arteries; Blood Pressure; Diuresis; Electrocardiography; Female; Humans; Male; Middle Aged; Neoplasms; Palliative Care; Piperidines; Xylenes

Topics: Adult; Aged; Anxiety Disorders; Biliary Tract Diseases; Cardiovascular Diseases; Depression; Dysautonomia, Familial; Female; Gastrointestinal Diseases; Humans; Hypertension; Lung Diseases; Male; Middle Aged; Neoplasms; Piperidines; Tranquilizing Agents

Topics: Animals; Antineoplastic Agents; Blood; Carcinoma, Ehrlich Tumor; DNA; DNA, Neoplasm; Mice; Neoplasms; Neoplasms, Experimental; Piperidines; Prochlorperazine; Rabbits; Research; Reserpine; RNA; RNA, Neoplasm; Sarcoma 180

Topics: Abdomen; Abdominal Neoplasms; Diarrhea; Humans; Neoplasms; Pelvic Neoplasms; Piperidines; Radiation Injuries

Topics: Anesthesia; Anesthesia, Endotracheal; Blood Gas Analysis; Chlorpromazine; Hemodynamics; Hibernation; Humans; Hypothermia, Induced; Hypoxia; Intubation; Muscle Relaxants, Central; Neoplasms; Phenothiazines; Piperidines; Surgical Procedures, Operative

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Neoplasms; Piperidines