tretinoin and Skin-Neoplasms

Trichoepithelioma is a rare benign adnexal neoplasm that can occur in various forms including solitary, multiple, familial or nonfamilial. Multiple facial trichoepithelioma can be associated with significant psychosocial burden. Conventional treatment modalities such as surgical excision and ablative laser have variable results and can be associated with unacceptable complications and tumour regrowth. Pharmacological interventions such as topical and systemic agents are potentially effective but clinical data are limited and treatments are poorly standardised. We review the available evidence to determine the role of pharmacological therapies in the management of multiple trichoepithelioma. Demographic and clinical data were retrospectively collected from the available English literature. Majority of cases treated with pharmacological therapies (93.75%) had a positive treatment outcome, achieving partial lesion response. Adverse effects associated with pharmacological therapies were generally well tolerated and did not interrupt treatment. There are limitations as to how our results can be interpreted owing to the paucity of good quality evidence, spectrum of disease severity, and diversity of study designs utilised in the included articles. Nonetheless, the results of our study indicate that while most pharmacological interventions for multiple trichoepithelioma produce a partial response, they can be employed as effective suppressive therapies, either alone or in conjunction with conventional treatments. The current evidence for pharmacological therapies remains largely anecdotal justifying the need for further clinical studies in this area.

Topics: Adalimumab; Administration, Topical; Anilides; Antineoplastic Agents; Aspirin; Humans; Imiquimod; Lasers, Gas; Neoplasms, Adnexal and Skin Appendage; Pyridines; Sirolimus; Skin Neoplasms; Tretinoin

The retinoids are a group of compounds including vitamin A and its active metabolite all-trans-retinoic acid (ATRA). Retinoids regulate a variety of physiological functions in multiple organ systems, are essential for normal immune competence, and are involved in the regulation of cell growth and differentiation. Vitamin A derivatives have held promise in cancer treatment and ATRA is used in differentiation therapy of acute promyelocytic leukemia (APL). ATRA and other retinoids have also been successfully applied in a variety of dermatological conditions such as skin cancer, psoriasis, acne, and ichthyosis. Moreover, modulation of retinoic acid receptors and retinoid X (or rexinoid) receptors function may affect dermal cells. The studies using complex genetic models with various combinations of retinoic acid receptors (RARs) and retinoid X (or rexinoid) receptors (RXRs) indicate that retinoic acid and its derivatives have therapeutic potential for a variety of serious dermatological disorders including some malignant conditions. Here, we provide a synopsis of the main advances in understanding the role of ATRA and its receptors in dermatology.

Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Retinoid X Receptors; Signal Transduction; Skin; Skin Neoplasms; Tretinoin

Topics: Acanthoma; Administration, Topical; Adolescent; Biopsy, Needle; Combined Modality Therapy; Cryotherapy; Dermatologic Surgical Procedures; Diagnosis, Differential; Eczema; Female; Humans; Immunohistochemistry; Keratosis; Nipples; Pruritus; Rare Diseases; Skin Neoplasms; Treatment Outcome; Tretinoin

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

Kaposi's sarcoma remains the most common cancer in Sub-Saharan Africa and the second most common cancer in HIV-infected patients worldwide. Since the introduction of highly active antiretroviral therapy (HAART), there has been a decline in its incidence.However, Kaposi's sarcoma continues to be diagnosed in HIV-infected patients.. To assess the added advantage of chemotherapy plus HAART compared to HAART alone; and the advantages of different chemotherapy regimens in HAART and HAART naive HIV infected adults with severe or progressive Kaposi's sarcoma.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and , GATEWAY, the WHO Clinical Trials Registry Platform and the US National Institutes of Health's ClinicalTrials.gov for ongoing trials and the Aegis archive of HIV/AIDS for conference abstracts. An updated search was conducted in July 2014.. Randomised trials and observational studies evaluating the effects of any chemotherapeutic regimen in combination with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons between different chemotherapy regimens.. Two review authors assessed the studies independently and extracted outcome data.We used the risk ratio (RR) with a 95% confidence interval (CI) as the measure of effect.We did not conduct meta-analysis as none of the included trials assessed identical chemotherapy regimens.. We included six randomised trials and three observational studies involving 792 HIV-infected adults with severe Kaposi's sarcoma.Seven studies included patients with a mix of mild to moderate (T0) and severe (T1) Kaposi's sarcoma. However, this review was restricted to the subset of participants with severe Kaposi's sarcoma disease.Studies comparing HAART plus chemotherapy to HAART alone showed the following: one trial comparing HAART plus doxorubicin,bleomycin and vincristine (ABV) to HAART alone showed a significant reduction in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100 participants); there was no statistically significant reduction in mortality and no difference in adverse events. A cohort study comparing liposomal anthracyclines plus HAART to HAART alone showed a non-statistically significant reduction in Kaposi's sarcoma immune reconstitution inflammatory syndrome in patients that received HAART plus liposomal anthracyclines (RR 0.49; 95% CI 0.16 to 1.55, 129 participants).Studies comparing HAART plus chemotherapy to HAART plus a different chemotherapy regimen showed the following: one trial involving 49 participants and comparing paclitaxel versus pegylated liposomal doxorubicin in patients on HAART showed no difference in disease progression. Another trial involving 46 patients and comparing pegylated liposomal doxorubicin versus liposomal daunorubicin showed no participants with progressive Kaposi's sarcoma disease in either group.Studies comparing different chemotherapy regimens in patients from the pre-HAART era showed the following: in the single RCT comparing liposomal daunorubicin to ABV, there was no significant difference with the use of liposomal daunorubicin compared to ABV in disease progression (RR 0.78; 95% CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178 participants and comparing oral etoposide versus ABV demonstrated no difference in mortality in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a higher median survival time in the ABV group; there was also a non-statistically significant reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to 179.29, 24 participants).An additional non-randomised study showed a non-statistically significant overall mortality benefit from liposomal doxorubicin as compared to conservative management consisting of either bleomycin plus vinblastine, vincr. The findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposi's sarcoma. For patients on HAART, when choosing from different chemotherapy regimens, there was no observed difference between liposomal doxorubicin, liposomal daunorubicin and paclitaxel.

Topics: Alitretinoin; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Bleomycin; Doxorubicin; Drug Therapy, Combination; Etoposide; HIV Infections; Humans; Liposomes; Observational Studies as Topic; Randomized Controlled Trials as Topic; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin; Vincristine

Despite the use of retinoids in the clinic for many years, their mode of action in the prevention of skin cancer is still unclear. Recent microarray analyses of the chemopreventive effect of all-trans retinoic acid (ATRA), one of the primary naturally occurring biologically active retinoids, in the two-stage mouse skin chemical carcinogenesis model have provided novel insight into their action. Comparison of the gene expression profiles of control skin to skin subjected to the two-stage protocol for 3 wk, with or without ATRA, has shown that approximately half of the genes regulated by 12-o-tetradecanoylphorbol-13-acetate (TPA) are oppositely regulated when ATRA is coadministered with TPA. It was further shown the Raf/Mek/Erk branch of mitogen-activated protein (MAP) kinase pathway contains a disproportionate number of oppositely regulated genes, thereby implicating it as one of the key pathways involved in tumor promotion by TPA, that is blocked by ATRA. This result has pointed the way toward the detailed study of Raf/Mek/Erk pathway signaling in skin cancer development and its potential as a target pathway for chemoprevention by ATRA and other chemopreventive drugs.

Topics: Animals; Antineoplastic Agents; Chemoprevention; Gene Expression Profiling; Humans; Oligonucleotide Array Sequence Analysis; Skin Neoplasms; Tretinoin

In many countries, Kaposi's sarcoma (KS) is the commonest malignancy among individuals infected with the human immunodeficiency virus-1 (HIV) and is a cause of substantial morbidity and mortality.. The aim of this review was to assess the effectiveness of current therapeutic regimens for the treatment of HIV associated KS, with a focus on options that may be available in resource poor settings.. We searched Cochrane HIV/AIDS Group trials register, Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2002), MEDLINE, EMBASE, AIDSLINE, CINAHL, CANCER LIT, AIDSDRUGS, AIDSTRIALS, African index medicus, physicians data query protocols, United Kingdom Co-ordinating committee on Cancer Research Register of Cancer trials, proceedings and abstracts from AIDS and cancer conferences. The search was conducted between 1st October 2001 and completed 14th December 2002. We also contacted experts in the field of cancer.. Randomised trials of therapy for KS in HIV infected adults.. All reviewers assessed trial quality and extracted data. We contacted study authors for additional information.. Five trials involving 915 people were included. Two trials involving 499 people compared pegylated liposomal doxorubicin (PLD) to a standard regimen among patients with advanced KS were analysed together. There was no difference in mortality between the two regimens RR1.26 (95% confidence interval (CI) 0.83 to 1.91). The response to PLD was superior to that of the control regimen RR 2.16, (95% CI 1.68 to 2.78). Two other trials involving 402 people demonstrated that topical alitretinoin was effective treatment compared to placebo among patients with cutaneous Kaposi's sarcoma. The results were analysed separately due to heterogeneity; (1) the relative risk (RR) was 5.34 (95%CI 2.16 to 13.21) and (2) RR 1.96, 95% CI 1.27 to 3.01). The final trial compared different radiotherapy regimens for treatment of cutaneous KS. The initial complete response of lesions to 20Gy given in 10 fractions or 40Gy in 20 fractions was similar and slightly superior to that of lesions treated with 8Gy as a single fraction, RR 1.58, (95% CI 1.01 to 2.48) and RR 1.65, (95% CI 1.06 to 2.57) respectively.. Alitretinoin gel is effective in treating cutaneous KS, PLD is effective treatment for advanced KS and radiotherapy appears effective in treating cutaneous lesions. Apart from the trial of radiotherapy no trials applicable to developing settings were identified.

Topics: Alitretinoin; Antineoplastic Agents; Doxorubicin; HIV Infections; Humans; Liposomes; Randomized Controlled Trials as Topic; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin

There has been a significant increase in the number of cases of skin cancer diagnosed in the US in the past few years. Thus, it seems appropriate to review the available compounds that might be used in the chemoprevention of these lesions. This review focuses on the retinoids and details their results in clinical trials for treatment and prevention of skin cancer. Side effects of the various retinoid derivatives are also discussed. It is concluded that isotretinoin (13-cis-retinoic acid) is the most effective retinoid for the prevention of non-melanoma skin cancers in high-risk patients in clinical trials. Current basic research is focused on developing receptor-selective retinoids which would have a higher therapeutic index for the treatment and chemoprevention of skin cancer.

Topics: Benchmarking; Humans; Isotretinoin; Retinoids; Skin Neoplasms; Tretinoin

Extramedullary disease (EMD) is a rare clinical event in acute promyelocytic leukemia (APL). Although the skin is involved in half of the reported EMD cases, the occurrence of cutaneous promyelocytic sarcoma (PS) has been described very rarely. We report here three cases of PS which have the peculiarity of appearing at sites of punctures for arterial and venous blood and marrow samples (sternal manubrium, antecubital fossa, wrist over the radial artery pulse, catheter insertion scar). At presentation, all patients had hyperleukocytosis and a morphologic diagnosis of microgranular acute promyelocytic leukemia variant confirmed at the genetic level by demonstration of the specific chromosomal translocation t(15;17). A BCR3 type PML/RARa transcript was documented in the two patients for whom diagnostic RT-PCR was available. Patients had morphologic bone marrow remission at the time the PS appeared. A predilection for the development of cutaneous PS at sites of previous vascular damage has been noted, but the pathogenesis remains largely unknown. A potential role for all-trans retinoic acid has been advocated, although one of the three patients in our series had received no ATRA. A review of the literature revealed six similar cases and hyperleukocytosis at diagnosis was a consistent finding in all of them. A careful physical examination of these particular sites in the follow-up of patients at risk, as well as cutaneous biopsy and laboratory examination of suspected lesions are strongly recommended.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biopsy, Needle; Catheterization, Central Venous; Endothelium, Vascular; Female; Granulocytes; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Leukocytosis; Male; Middle Aged; Punctures; Sarcoma; Skin Neoplasms; Tretinoin

Amelanotic lentigo maligna melanoma (ALMM) is an infrequent presentation of lentigo maligna melanoma, less than thirty cases having been reported to date. Hypopigmented or erythematous macules on the face of older women, resembling Bowen's disease or eczema, are the most common clinical presentation. We report a case of ALMM in a 73-year-old woman. Therapeutic trials with cryotherapy, 5-fluorouracil, and azelaic acid were unsuccessful, and the lesions were eventually cured by surgical excision. ALMM requires early clinical suspicion and histopathologic confirmation of diagnosis in every patient presenting with a slowly enlarging erythematous or hypopigmented macule, especially when located on the face of an older woman with a light complexion.

Topics: Aged; Antineoplastic Agents; Combined Modality Therapy; Cryotherapy; Dicarboxylic Acids; Female; Fluorouracil; Humans; Hutchinson's Melanotic Freckle; Melanoma, Amelanotic; Skin Neoplasms; Tretinoin

Overexposure to ultraviolet and visible radiation causes sunburn. Aspirin and other nonsteroidal anti-inflammatory drugs, cool baths and topical steroids offer only mild relief. Long-term sun exposure causes chronic inflammatory skin changes. Photodamage, rather than the normal aging process, may account for 90 percent of age-associated cosmetic skin problems. Physicians should stress to their patients that all ultraviolet exposure (including sun beds and tanning salons) causes skin damage. Regular sunscreen use during childhood and adolescence may result in an 80 percent reduction in the lifetime incidence of ultraviolet-induced skin damage, including nonmelanoma skin cancers.

Topics: Carcinoma, Squamous Cell; Hemoglobins; Humans; Light; Melanins; Skin; Skin Aging; Skin Neoplasms; Skin Pigmentation; Sunburn; Sunscreening Agents; Tretinoin; Ultraviolet Rays

Topics: Animals; Epithelium; Humans; Receptors, Retinoic Acid; Skin Neoplasms; Tretinoin; Vitamin A; Vitamin A Deficiency

Dermal dendrocytes represent a population of resident cells of the dermis identified recently by virtue of the immunohistochemical expression of the coagulation factor XIIIa (fXIIIa). These dendritic cells of bone-marrow origin bear particular histoenzymatic and immunohistochemical features, some of which are shared with antigen-presenting cells; however, they are clearly distinct from epidermal Langerhans cells. Dermal dendrocytes could act as macrophages, antigen-presenting cells or participate in the homeostasis of macromolecules of the dermis. These cells give rise to some cutaneous tumours and seem involved in inflammatory dermatoses where they act by means of cytokine production; they could even represent targets of HIV infection. Future functional studies will hopefully lead to a better understanding of their precise role in normal and diseased skin, which remains presently partly speculative.

Topics: Acquired Immunodeficiency Syndrome; Cytokines; Dermatitis; Granuloma; Histiocytoma, Benign Fibrous; HLA-DR Antigens; Humans; Sarcoma, Kaposi; Skin; Skin Neoplasms; Skin Physiological Phenomena; Transglutaminases; Tretinoin; Ultraviolet Rays; Vasculitis, Leukocytoclastic, Cutaneous

Retinoic acid and interferon-alpha have limited single-agent activity in advanced cancer. Cell culture data indicate that in combination these agents have enhanced activity (modulating growth and differentiation) in a number of malignant cell types. Recent clinical work in advanced squamous cell carcinoma reports major activity with this regimen. This paper reviews the preclinical and clinical data testing retinoic acid in combination with interferons and presents recent work integrating these agents with radiotherapy in locally advanced cervical cancer.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Humans; Interferon-alpha; Middle Aged; Skin Neoplasms; Tretinoin; Uterine Cervical Neoplasms

Extensive well-controlled clinical studies performed over the past 5 years have demonstrated a consistent, dose-dependent, statistically significant improvement in the appearance of photodamaged skin after 3-6 months of daily treatment with topical 0.001-0.1% tretinoin cream. Clinical changes included decreases in surface roughness, irregular pigmentation, fine and coarse wrinkling, and sallowness. Actinic keratoses have also been reported to decrease in size and number. Blinded analysis of biopsies from more than 500 subjects showed that there was compaction of the stratum corneum, an increase in the number of granular layers, thickening of the epidermis and a decrease in epidermal melanin. There were no detectable histological changes in any dermal parameters. The specific cellular mechanisms by which retinoic acid (RA) exerts its beneficial effect on photodamaged skin are currently the subject of intensive investigation. It is well established that RA enters the nucleus where it binds to an RA receptor (RAR), and that the RA-RAR complex then binds to specific RA response elements in the DNA, modulating the expression of target genes. It is thus likely that RA improves at least some aspects of photoageing by modifying cellular differentiation programmes, as retinoids have been shown to do during embryogenesis, in malignantly transformed cells and in skin affected by certain dermatoses.

Topics: Dose-Response Relationship, Drug; Humans; Keratosis; Skin; Skin Aging; Skin Neoplasms; Skin Pigmentation; Sunlight; Tretinoin

Primary care physicians should be familiar with the effects and appropriate uses of retinoids. Topical tretinoin (Retin-A) can reverse photoaging of the skin, although some transient, undesirable side effects usually occur. In patients with acne vulgaris, topical tretinoin and systemic isotretinoin (Accutane) are the only agents that act upon the apparent underlying causes. Recurrence is unlikely after successful results are achieved. Chronic hypervitaminosis A presents insidiously, and physicians must maintain a high index of suspicion. Complete history taking should always include questions about the patient's use of vitamin supplements.

Topics: Acne Vulgaris; Administration, Topical; Animals; Drug Eruptions; Drug Therapy, Combination; Humans; Hypervitaminosis A; Isotretinoin; Medical History Taking; Physical Examination; Skin Aging; Skin Neoplasms; Tretinoin

Topics: Acne Vulgaris; Administration, Topical; Humans; Keratosis; Pigmentation Disorders; Skin; Skin Neoplasms; Tretinoin

The process of involution of aging skin is essentially caused by functional changes progressing as a consequence of the chronic influence of exogenous noxae. Reasonably, prophylaxis should avoid actinic damages, and skin care should be adapted to the changes due to age, which means providing a substitute for cutaneous lipids and stabilizing the hydration of the horny layer. Placebo-controlled studies proved that topical treatment with 0.05% tretinoin can result in the regression of degenerative and precancerous changes of the senile skin caused by chronic exposure to UVB. However, long-term results remain to be seen.

Topics: Aged; DNA Damage; DNA Repair; Humans; Neoplasms, Radiation-Induced; Skin Aging; Skin Neoplasms; Tretinoin

We have shown that retinoic acid, applied either to the skin or administered in diet, inhibits skin tumor promotion by TPA. Retinoic acid does not inhibit the initiation step of mouse skin carcinogenesis. Our results indicate that retinoic acid inhibits both stage I and stage II of tumor promotion, and the inhibition of tumor promotion depends upon the duration of retinoic acid treatment. The inhibition of skin carcinogenesis by retinoic acid is not universal; retinoids exhibit specificity towards carcinogens and tumor promoters. In conclusion, the results presented indicate that the inhibition of TPA-induced ODC gene expression may be one of the mechanisms contributing to the antitumor promoting property of the retinoids. However, other mechanisms concerning the effect of retinoic acid on chromatin structure (Porter et al., 1986), glycoprotein synthesis (Levin et al., 1983), peptide growth factors (Sporn et al., 1986), induction of transglutaminase (Lichti and Yuspa, 1985) and the host-immune system (Dennert, 1985) may also explain the molecular basis of retinoid action.

Topics: Animals; Humans; Ornithine Decarboxylase; Skin Neoplasms; Tetradecanoylphorbol Acetate; Transcription, Genetic; Tretinoin

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Animals; Female; Humans; Infant, Newborn; Isotretinoin; Kinetics; Precancerous Conditions; Pregnancy; Skin Neoplasms; Tretinoin

There is considerable evidence that retinoids, including retinoic acid, prevent or normalize many malignant transformations. Contrary reports are few in number and are often problematic in design or interpretation. The mechanism of action of retinoids in differentiation and in neoplasia is not understood. The effects, however, are multifarious, and may be exerted directly on normal tumor cells, or indirectly via cytotoxic mechanisms and the immune system. After extensive testing and after almost 25 years of use on human skin, retinoic acid has not been found to be a carcinogen. When applied topically to non-irradiated mouse skin for up to 18 months it does not produce tumors (130). It was also negative in the Ames test. Moreover, the role of retinoic acid in normal differentiation of skin and mucous membranes appears to make it a physiologic necessity. Since UV radiation apparently destroys epidermal vitamin A (127, 128), its metabolite, retinoic acid, may need to be replenished continuously. The extreme vulnerability of the hairless mouse to UV radiation makes it a valuable animal for many photobiologic studies, including studies of carcinogenesis. However, this same extraordinary vulnerability means that we must be cautious in making casual extrapolations to humans. This problem is compounded when active topical agents are added, especially when application is made to the entire dorsum of the mouse, in contrast to limited areas of human skin. In most cases, animal studies have to be interpreted very carefully. The final judgment must rest on the human experience.

Topics: Animals; Cricetinae; Humans; Mice; Mice, Hairless; Neoplasms; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Rabbits; Rats; Skin Neoplasms; Tretinoin; Ultraviolet Rays

Topics: Adult; Benzoates; Bowen's Disease; Carcinoma, Basal Cell; Child; Etretinate; Female; Humans; Isotretinoin; Male; Precancerous Conditions; Psoriasis; Retinoids; Skin Diseases; Skin Neoplasms; Tretinoin; Xeroderma Pigmentosum

All-trans-retinoic acid (tretinoin) is a biologically active metabolite of vitamin A. Topical tretinoin has been shown to have antineoplastic activity in a variety of experimentally induced and naturally occurring tumors. In some animal studies it has inhibited the development of ultraviolet-induced carcinomas. However, in other studies it accelerated such ultraviolet tumorigenesis. Other work has shown that the drug can eradicate chemically induced papillomas and carcinomas. These various effects may stem from tretinoin's influences on deoxyribonucleic acid synthesis, polyamine enzyme systems, sister-chromatid exchanges, oncogene expression, or lysosome lability. In clinical trials, tretinoin removed premalignant actinic keratoses from the face. Combined with 5-fluorouracil, it is also quite effective in the treatment of such lesions on the forearms and hands, areas where neither agent alone has much effect. It should be emphasized that tretinoin has not been shown to be carcinogenic in either animals or humans. After more than a decade of topical use of tretinoin on human skin, there is no evidence that the drug either initiates or promotes carcinogenesis in humans.

Topics: Animals; DNA; Humans; Skin; Skin Neoplasms; Tretinoin

Since topical retinoic acid was first used for acne in 1959, many additional uses have been described for lesions on the skin, oral mucosa, and ocular surface epithelia. The topical application of retinoic acid has been shown to be effective in the treatment of several disorders of keratinization, keloids and hypertrophic scars, and various infections and inflammatory, pigmentation, and malignant and premalignant disorders. This article briefly reviews the use of topical retinoic acid for selected cutaneous conditions.

Topics: Administration, Topical; Humans; Mouth Diseases; Pigmentation Disorders; Precancerous Conditions; Skin Diseases; Skin Neoplasms; Tretinoin

The potential of vitamin A, or retinol, in the treatment of a variety of skin diseases has long been recognized, but because of serious toxic effects this substance generally could not be used. The recent development and marketing of two relatively non-toxic synthetic analogues, which are known as retinoids, has made it possible to treat some of the diseases that are resistant to standard forms of therapy. Isotretinoin is very effective in cystic and conglobate acne, while etretinate is especially useful in the more severe forms of psoriasis. Good results have also been obtained in other disorders of keratinization. Vitamin A and its derivatives apparently have an antineoplastic effect as well and may come to be used in both the prevention and the treatment of epithelial cancer. In many of these diseases the retinoids act by enhancing the normal differentiation and proliferation of epidermal tissues, but the exact mechanisms are not well understood. Their influence on the intracellular polyamines that control the synthesis of nucleic acids and proteins may be an important factor. Although the retinoids have few serious systemic effects, they are teratogenic, and because they persist in the body their use in women of childbearing potential is limited.

Topics: Acne Vulgaris; Bone Diseases; Chemical and Drug Induced Liver Injury; Etretinate; Female; Humans; Isomerism; Isotretinoin; Keratosis; Kinetics; Psoriasis; Skin Diseases; Skin Neoplasms; Tretinoin; Triglycerides; Vitamin A

The retinoids are synthetic derivatives of vitamin A. Isotretinoin (13-cis-retinoic acid) is now being widely used in the United States for severe acne and etretinate is available in Europe and other countries for psoriasis. These drugs are also effective for a number of other skin diseases. This is an attempt to review basic knowledge of retinoids with which the practicing dermatologist should be familiar, to review the current status of studies, and to speculate on the present and future roles of these drugs in dermatology.

Topics: Acne Vulgaris; Etretinate; Humans; Inflammation; Isotretinoin; Keratins; Psoriasis; Retinoids; Sebum; Skin Diseases; Skin Neoplasms; Sweat Gland Diseases; Tretinoin; Vitamin A

Isotretinoin is a new orally active retinoic acid derivative for the treatment of severe refractory nodulocystic acne. The pharmacological profile of isotretinoin suggests that it acts primarily by reducing sebaceous gland size and sebum production, and as a result alters skin surface lipid composition. Bacterial skin microflora is reduced, probably as a result of altered sebaceous factors. Isotretinoin 1 to 2 mg/kg/day for 3 to 4 months produces 60 to 95% clearance of inflammatory lesions in patients with severe, recalcitrant nodulocystic acne, with evidence of continued healing and prolonged remissions in many patients after treatment withdrawal. Doses as low as 0.1 mg/kg/day have also proven successful in the clearance of lesions; however, with such low doses the duration of remission after discontinuation of therapy is usually shorter. Encouraging results have also been seen in small numbers of patients with rosacea, Gram-negative folliculitis, Darier's disease, ichthyosis and pityriasis rubra pilaris, the response in keratinising disorders resembling that with the related drug etretinate. While long term follow-up studies in these patients have not been reported, prolonged remission after withdrawal of isotretinoin in disorders of keratinisation is unlikely, as with other drugs used in these conditions. Isotretinoin is only partially effective in psoriasis, in contrast to etretinate which is very effective in psoriasis but ineffective in severe acne. Some encouraging results have also been reported with isotretinoin in patients with squamous and basal cell carcinomas, but isotretinoin has proven unsuccessful in non-squamous cell epithelial and non-epithelial cancer. Side effects affecting the mucocutaneous system occur in nearly all patients receiving isotretinoin, but rarely lead to drug withdrawal. Raised serum triglyceride levels are also commonly reported. The possibility of long term spinal or skeletal bone toxicity may restrict the use of isotretinoin in severe disorders of keratinisation requiring prolonged administration. Isotretinoin is strictly contraindicated in women of childbearing potential due to its severe teratogenic properties, unless an effective form of contraception is used. Thus, isotretinoin offers an effective advance on the treatment options available in a difficult therapeutic area - those patients with severe, nodulocystic acne not responding to 'traditional' therapy.

Topics: Acne Vulgaris; Animals; Anti-Inflammatory Agents; Carcinogens; Cell Differentiation; Cell Division; Humans; Immunity; Isotretinoin; Kinetics; Mutagens; Psoriasis; Rosacea; Sebaceous Glands; Skin; Skin Absorption; Skin Diseases; Skin Neoplasms; Teratogens; Tissue Distribution; Tretinoin

Mouse skin has a long history as a useful model for the study of the mechanism of carcinogenesis (6). In particular, the availability of specific diterpene esters has made possible rapid progress in understanding the mechanism of tumor formation (4,6,8,19,36,41), although certain details may be unique to promotion by phorbol esters. Evidence is compatible with an essential role for elevated levels of polyamines in tumor promotion, but other components of phorbol ester action on mouse skin are also essential (27,40,54). These may include the production of dark cells (22), inhibition of maturation (2,19,41), and the elimination of metabolic cooperation (12,57). Factors modifying biochemical processes that are essential to tumor formation produce a parallel effect on tumor formation. Some of these inhibitors act synergistically to inhibit tumor formation (50,55), and knowledge of their action may lead to practical application for the prevention of human cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Alkylating Agents; Animals; Carcinogens; Cell Communication; Cell Differentiation; Cell Division; Cocarcinogenesis; DNA; Indomethacin; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Polyamines; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Topics: Animals; Carcinogens; Cocarcinogenesis; Diterpenes; Epidermal Cells; Fluocinolone Acetonide; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Phorbol Esters; Polyamines; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Tosylphenylalanyl Chloromethyl Ketone; Tretinoin

Topical vitamin A acid (VAA) has various mechanisms of action which may be responsible for its therapeutic success in many different disorders. Although the absorption, metabolism, and excretion of VAA are not completely understood, VAA appears to remain mainly on the skin surface. The question of carcinogenicity is unresolved, and more research is needed to clarify this problem. This article reviews the literature regarding the therapeutic uses of VAA and summarizes various investigators' experiences with VAA.

Topics: Acne Vulgaris; Animals; Callosities; Cocarcinogenesis; Fox-Fordyce Disease; Humans; Ichthyosis; Keloid; Keratoacanthoma; Keratosis; Lichen Planus; Melanoma; Melanosis; Molluscum Contagiosum; Nevus; Psoriasis; Skin Absorption; Skin Diseases; Skin Neoplasms; Tretinoin

Topics: Breast Neoplasms; Etretinate; Humans; Isomerism; Isotretinoin; Skin Diseases; Skin Neoplasms; Tretinoin

Experimental investigations of the antineoplastic effects of retinoids are reviewed in this paper. In vitro studies have shown that the hyperplastic and metaplastic response to chemical carcinogens of mouse prostate cultures is suppressed by the addition of retinoids to the culture medium, that retinoids can partially inhibit the morphologic transformation of 10T 1/2 cells by physical or chemical carcinogens, and that the growth of some non-neoplastic and some neoplastic cell lines can be inhibited by retinoids. In vivo studies have shown that retinoids can suppress papilloma and carcinoma development (the promotion phase) in the two-stage skin carcinogenesis assay, inhibit mammary and bladder carcinogenesis in mice and rats, and inhibit the growth of some transplantabletumor lines. So far it has not been possible to inhibit predictably tumour formation in the intestinal tract or the respiratory tract of rodents. Almost all the synthetic retinoids have a higher therapeutic index than the natural retinoids in the prevention or treatment of cancer.

Topics: Animals; Cell Transformation, Neoplastic; Lung Neoplasms; Neoplasms, Experimental; Skin Neoplasms; Tretinoin; Vitamin A

Topics: Animals; Cricetinae; Liver Neoplasms; Lung Neoplasms; Mice; Neoplasms; Rats; Skin Neoplasms; Tretinoin; Vitamin A

A review of recent investigations in the retinoid field is presented. Retinoic acid exerts a prophylactic and a therapeutic effect on chemically induced benign and malignant epithelial tumors in mice. In clinical studies positive therapeutic results have been obtained in patients with preneoplastic and neoplastic epithelial lesions. However, treatment with retinoic acid is limited by serious side effects (hypervitaminosis A syndrome). Therefore, the synthesis of analogs of retinoic acid (retinoids) possessing a more favorable therapeutic ratio has been initiated. Among a large series of synthesized compounds, certain aromatic analogs proved to have a particularly favorable therapeutic ratio. The structure-activity relationship of the most active retinoids is discussed including some biological data concerning prophylaxis and therapy of epithelial tumors. The total synthesis of retinoids according to various building schemes is discussed in detail. Methods for the synthesis of the cyclic end group, of the polyene chain component, and of the full retinoid skeleton are described. Metabolic studies of retinoic acid and of the most active retinoid, as well as the synthesis of some isolated metabolites are outlined. Suggestions concerning the mechanism of action of retinoids are made. Some clinical results on the treatment of acne, psoriasis and precancerous conditions are reported.

Topics: Animals; Carcinoma; Humans; Neoplasms, Experimental; Papilloma; Retinaldehyde; Skin Diseases; Skin Neoplasms; Structure-Activity Relationship; Tretinoin; Vitamin A

Sun exposure may lead to actinic keratoses (AKs), field cancerization, and skin cancer. Effective treatment of AKs and field cancerization is important. Oral and topical retinoids can be used for this purpose. To compare clinical, histological, and immunohistochemical effects of oral and topical retinoid for AKs and field cancerization on face and upper limbs of immunocompetent patients, as well as the impact on quality of life, safety, and tolerability.. This study compared 10 mg/day oral isotretinoin (ISO) to 0.05% tretinoin cream (TRE) every other night, associated with sunscreen (SPF 60). Patients of both genders, aged 50-75 years, underwent cryotherapy with liquid nitrogen for AKs at baseline and after 120 days when they were randomized into two groups, TRE (n = 31) and ISO (n = 30), for 6 months. Outcome measures were: number of AKs, histological (thickness of stratum corneum and epithelium) and immunohistochemical parameters (p53, Bcl-2 and Bax), dermatology life quality index (DLQI), and adverse events.. Both treatments reduced the number of AKs (around 28%), the thickness of stratum corneum, and expression of p53 and Bax. By contrast, the epithelium thickness and Bcl-2 expression increased. There was no difference in the outcomes between TRE and ISO. Both treatments improved quality of life and were well tolerated with minimal side effects.. Retinoids are effective and safe for field cancerization. Classical treatments for field cancerization (imiquimod and ingenol mebutate) are used for a short period; retinoids may be a good choice to intercalate with them and can be used continuously.

Topics: Administration, Cutaneous; Administration, Oral; Aged; Antineoplastic Agents; bcl-2-Associated X Protein; Facial Dermatoses; Female; Humans; Immunohistochemistry; Isotretinoin; Keratosis, Actinic; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Quality of Life; Skin Cream; Skin Neoplasms; Tretinoin; Tumor Suppressor Protein p53; Upper Extremity

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; 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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; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Treatment of refractory/relapsed cutaneous T-cell lymphoma (CTCL) remains controversial, most studies included a few patients with a short follow-up. Previously, we performed two small studies employing interferon alpha 2b (IFN) combined with low doses of methotrexate (MTX) or retinoids. Thus, we conducted an open-label clinical trial to assess the benefit and toxicity of the two mentioned regimens in a large number of patients with a longer follow-up of the treatment of refractory/relapsed CTCL.. Three-hundred and seventy-seven patients with refractory/relapsed, pathologically confirmed, CTCL, with advanced stages and at least treated with two previous effective regimens in CTCL, were randomized to receive IFN and low doses of MTX compared with IFN and all trans-retinoid acid during 6 months; if a complete response (CR) was not achieved, treatment was continued until 12 months in both arms. At this time, if patient achieves CR, MTX or retinoid was stopped, and the patient continues to receive IFN until progression disease or toxicity. One-hundred and eight patients received IFN for more than 5 years.. Toxicity was minimal and well tolerated, no patients needed to modify the administration of IFN secondary to toxicity. The overall complete response was achieved 80% in both arms. Actuarial curves at 5 years showed that progression-free survival was 60% in the IFN/MTX group and 62% in the IFN/retinoids group (P = 0.8) that were not statistically different and overall survival (OS) rates were 70 and 67%, respectively (P = 0.03).. Both present schedules showed good tolerance and an excellent OS at 5 years, which is better than the other, more expensive and toxic, regimens. Considering the indolent course of CTCL, we suggested that those regimens, mentioned in this paper, will be regarded as the standard therapy, for patients of this setting.. The use of IFN and retinoids or low dose of cytotoxic drugs will be preferred in patients with refractory/relapse CTCL, because OS is good and toxicity is minimal.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Interferon alpha-2; Interferon-alpha; Lymphoma, T-Cell, Cutaneous; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Recombinant Proteins; Remission Induction; Skin Neoplasms; Survival Analysis; T-Lymphocytes; Treatment Outcome; Tretinoin

Topics: Administration, Topical; Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Antineoplastic Agents; Carcinoma, Basal Cell; Chemoprevention; Female; Fluorouracil; Hospitals, Veterans; Humans; Incidence; Logistic Models; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Risk Assessment; Skin Neoplasms; Tretinoin

Topical tretinoin is commonly prescribed, but its frequent adverse effects are barriers to use. Predictors of resistance or susceptibility to retinoid irritation are not known.. To identify baseline patient characteristics associated with adverse effects of topical tretinoin.. This cohort study used data collected from 324 participants in the Veterans Affairs Topical Tretinoin Chemoprevention trial who were randomized to apply tretinoin cream on the face and ears. Univariate and multivariate logistic regression models were used to examine the associations between baseline characteristics and local adverse effects.. One hundred and ninety-seven patients (61% of those randomized to tretinoin) reported local adverse effects within 6 months. Clinical signs of severe photodamage at baseline [odds ratio (OR) 0·15, 95% confidence interval (CI) 0·04-0·54] and history of acne (OR 0·46, 95% CI 0·27-0·77) were associated with a decreased risk of adverse effects to tretinoin. The use of other topical medications at enrolment (OR 1·88, 95% CI 1·15-3·08) predicted an increase in adverse effects.. In this study population, the common indications of topical tretinoin treatment were associated with lower risks of adverse effects. The concurrent use of other topical medications may worsen irritation caused by tretinoin.

Topics: Acne Vulgaris; Aged; Anticarcinogenic Agents; Carcinoma; Drug Eruptions; Female; Humans; Keratinocytes; Male; Ointments; Photosensitivity Disorders; Risk Factors; Skin Neoplasms; Tretinoin

Invasive squamous cell carcinoma (SCC) of the skin is one of the most common cancers in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. We sought to determine the risk factors for invasive SCC on the face or ears in a high-risk population comprising 1,131 veterans in the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial. Participants were required to have been diagnosed with at least two keratinocyte carcinomas (KCs) in the 5 years prior to enrollment. The median duration of follow-up was 3.7 years. Twenty-three percent of the participants developed a new invasive SCC, and the cumulative risk of invasive SCC was 30% at 5 years. The following factors independently predicted for new invasive SCCs: number of invasive SCCs and number of in situ SCCs in the 5 years prior to enrollment, actinic keratoses count at enrollment, a history of ever use of topical 5-fluorouracil, and total occupational time spent outdoors. In contrast, the use of angiotensin-convering enzyme inhibitors or angiotensin receptor blockers during the study and a history of warts anywhere on the body were found to protect against new invasive SCCs. These independent predictors remained the same for all SCCs (invasive and in situ combined). The number of basal cell carcinomas in the 5 years prior to enrollment, sunburns, sun sensitivity, and recreational sun exposure were not associated with new SCCs. These findings identify key risk factors for additional SCCs in patients with multiple prior KCs, and suggest that a history of warts may be associated with reduced SCC risk.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Risk Factors; Skin Neoplasms; Sunburn; Sunscreening Agents; Tretinoin; Veterans; Warts

Glucorticosteroids (GC) are potent anti-inflammatory medications with immunosuppressive property. Few retrospective studies have reported the increased risk of development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with GC use.. We aimed to assess the effect of oral GC use on the risk of BCC and SCC using prospective data.. We analysed data from the Veterans Affairs Topical Tretinoin Chemoprevention Trial, which followed up patients from 1998 to 2004. Exposure to oral GCs was defined as (1) use of any oral GCs at any point during follow-up and (2) use of GCs for a month or longer. Outcome was occurrence of new BCC or SCC. Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).. Among the 1051 study participants, 148 patients (14%) had prednisone prescription filled during study period, and 63 (6%) used prednisone for over a month. A total of 472 patients (45%) developed at least one BCC during study: 394 (44%) among non-users of prednisone and 78 (53%) among any time users. The total number of new SCC was 309 (29%): 258 (29%) among non-users of prednisone and 51 (34%) among users. Among any time prednisone users, the adjusted HR was 1.11 (95% CI, 0.87-1.42) for BCC, and 1.05 (95% CI, 0.76-1.45) for SCC. Among those who used prednisone for 30 or more days, the HR was 1.26 (95% CI, 0.90-1.78) for BCC, and 1.03 (95% CI, 0.66-1.60) for SCC.. This study does not support the existence of association between use of oral GCs and risk of BCC or SCC.

Topics: Administration, Oral; Aged; Aged, 80 and over; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Male; Middle Aged; Prednisone; Skin Neoplasms; Tretinoin

Keratinocyte carcinoma (KC) is the most common cancer in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. Topical tretinoin has been used for KC chemoprevention, although this use is unproven. Hence, we conducted the randomized Veterans Affairs Topical Tretinoin Chemoprevention Trial of high-dose topical tretinoin for KC prevention. We randomized 1,131 patients to topical 0.1% tretinoin or a matching vehicle control for 1.5-5.5 years. The primary outcomes were time to development of new basal cell carcinoma (BCC) and new invasive squamous cell carcinoma (SCC) on the face or ears. The effects were not significant (P=0.3 for BCC and P=0.4 for SCC). The proportions of the tretinoin and control groups who developed a BCC at 5 years were 53 and 54% and an invasive SCC at 5 years were 28 and 31%. These differences (95% confidence intervals) were: for BCC, 1.0% (-6.5, 8.6%); for SCC, 3.6% (-3.1, 10.3%). No differences were observed in any cancer-related end points or in actinic keratosis counts. The only quality of life difference was worse symptoms in the tretinoin group at 12 months after randomization. This trial in high-risk patients demonstrates that high-dose topical tretinoin is ineffective at reducing risk of KCs.

Topics: Administration, Topical; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Keratinocytes; Male; Middle Aged; Quality of Health Care; Risk Factors; Skin Neoplasms; Tretinoin; Veterans

Basal cell carcinoma (BCC) is the most common cancer in the United States today, and patients who have had one are likely to have multiple carcinomas over time. Predictors of new BCCs on the face and ears among those at very high risk have not been studied in detail. We sought to do so prospectively in the context of a 6-year trial. We found that the number of BCCs in the prior 5 years was the most important predictor. Age, sun sensitivity, occupational sun exposure before the age of 30 years (but not afterward), lower educational level, history of eczema, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and more sunscreen use in the week, but not the 6 months, before enrollment were also independent predictors, but sunburns, baseline sun exposure, and other sun-protective measures, other skin cancers, and actinic keratoses were not. None of the eczema patients had a history of topical calcineurin use. The cumulative risk of BCC was 55% at 5 years. These findings document the key risk factors in this very high-risk population, suggesting that the history of eczema may increase the risk in those at high risk and that early sun exposure is important even in this group, and underscoring the need for chemopreventive strategies.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Basal Cell; Eczema; Educational Status; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Keratosis, Actinic; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Risk Factors; Skin Neoplasms; Sunlight; Sunscreening Agents; Tretinoin; Veterans

Topics: Administration, Topical; Aged; Chemoprevention; Female; Humans; Keratolytic Agents; Keratosis, Actinic; Male; Quality of Life; Skin Neoplasms; Tretinoin

Observational studies have reported significant negative associations between sporadic non-steroidal anti-inflammatory drug (NSAID) use and keratinocyte carcinoma (KC) while reporting null results for regular use. This pattern may be partially explained by the operational expression of NSAID exposure and analytic model assumptions. Our goals were to quantify the association between NSAIDs and KC and to explore the impact of exposure metrics and modeling assumptions on observed associations.. We conducted a prospective cohort study by linking data from the Veterans Affairs Topical Tretinoin Chemoprevention Trial and the VA Pharmacy Benefits Management database. NSAID use was categorized according to cyclooxygenase selectivity, timing of initiation, and frequency of use. Data were analyzed using time-varying and time-fixed multivariable-adjusted Cox proportional hazard models [Correction made here after initial online publication]. Simulated null data were generated and analyzed to explore potential biases introduced by the models and the exposure metrics.. During a median follow-up time of 2 years for basal cell carcinoma and 2.5 years for squamous cell carcinoma, 472 occurrences of BCC and 309 occurrences of SCC were observed. Time-fixed analyses of NSAID exposure metrics produced significant negative associations, whereas time-varying analyses produced null results. Analysis of simulated null data revealed the potential for strong bias in the time-fixed analyses.. This study did not identify a negative association between NSAIDs and KC. The disparity between the time-fixed and the time-varying analyses highlights the extent to which operational definitions of drug exposures and reliance on time-fixed methods may introduce bias.

Topics: Administration, Topical; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Carcinoma; Cohort Studies; Double-Blind Method; Female; Humans; Keratinocytes; Male; Middle Aged; Skin Neoplasms; Tretinoin; United States; United States Department of Veterans Affairs

Recent evidence suggests that statins may prevent cancer.. To quantify the association between statin use and the occurrence of keratinocyte carcinoma in high-risk veterans.. Cohort study.. 6 Veterans Affairs medical centers.. 1037 participants of the Veterans Affairs Topical Tretinoin Chemoprevention Trial, a randomized, multicenter, double-blind, vehicle-controlled trial of topical tretinoin, 0.1%, for prevention of keratinocyte carcinoma conducted from November 1998 to November 2004.. Time to first occurrence of keratinocyte carcinoma on the face or ears. Participants using a statin at randomization, according to the Veterans Affairs Pharmacy Benefits Management database, were considered exposed. Study dermatologists conducted physical examinations at baseline and every 6 months during follow-up. The association between statin use at randomization and the outcome was evaluated by using propensity score matching (n = 608) and Cox proportional hazards regression (n = 1037).. Among the 1037 participants, 37% used a statin at randomization (n = 397) for a median duration of at least 900 days over a median follow-up of 3.5 years. In the propensity score-matched analysis, statin use at randomization was not associated with keratinocyte carcinoma (rate ratio, 0.92 [95% CI, 0.73 to 1.16]), a finding that was consistent with the estimates derived from the Cox proportional hazards regression (rate ratio, 0.84 [CI, 0.70 to 1.02]).. The extent of residual confounding is unknown, and the confidence bounds around the measures of association were wide. These data may not be generalizable to lower-risk populations.. These data show no conclusive or consistent relationship between long-term statin use and risk for keratinocyte carcinoma.

Topics: Administration, Topical; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Confounding Factors, Epidemiologic; Double-Blind Method; Drug Administration Schedule; Ear Neoplasms; Facial Neoplasms; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Risk Factors; Skin Neoplasms; Tretinoin

To evaluate the relation of topical tretinoin, a commonly used retinoid cream, with all-cause mortality in the Veterans Affairs Topical Tretinoin Chemoprevention Trial (VATTC). The planned outcome of this trial was risk of keratinocyte carcinoma, and systemic administration of certain retinoid compounds has been shown to reduce risk of this cancer but has also been associated with increased mortality risk among smokers.. The VATTC Trial was a blinded randomized chemoprevention trial, with 2- to 6-year follow-up. Oversight was provided by multiple independent committees.. US Department of Veterans Affairs medical centers. Patients A total of 1131 veterans were randomized. Their mean age was 71 years. Patients with a very high estimated short-term risk of death were excluded. Interventions Application of tretinoin, 0.1%, or vehicle control cream twice daily to the face and ears.. Death, which was not contemplated as an end point in the original study design.. The intervention was terminated 6 months early because of an excessive number of deaths in the tretinoin-treated group. Post hoc analysis of this difference revealed minor imbalances in age, comorbidity, and smoking status, all of which were important predictors of death. After adjusting for these imbalances, the difference in mortality between the randomized groups remained statistically significant.. We observed an association of topical tretinoin therapy with death, but we do not infer a causal association that current evidence suggests is unlikely.

Topics: Administration, Topical; Aged; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cause of Death; Double-Blind Method; Female; Humans; Male; Skin Neoplasms; Tretinoin

Keratinocyte carcinomas (KCs) are the most common malignancies of the skin. As lesions have a low mortality rate, understanding quality-of-life (QoL) factors is necessary in their management.. To assess QoL and associated patient characteristics in those with a history of keratinocyte carcinomas.. We conducted a cross-sectional study of veterans with a history of KCs enrolled in a randomized controlled trial for chemoprevention of keratinocyte carcinomas. Study dermatologists counted actinic keratoses (AKs) and assessed for skin photodamage. QoL was assessed using Skindex-29 and KC-specific questions. Demographics were self-reported.. Participants (n = 931) enrolled at 5 clinical sites had worse QoL on all subscales (emotions, functioning, and symptoms) compared to a reference group of patients without skin disease. Univariate analysis demonstrated worse QoL associated with higher AK count, past 5-fluorouracil (5-FU) use, and greater sun sensitivity. Multivariate analysis demonstrated that higher AK count and past 5-FU use were independently related to diminished QoL. Higher comorbidities showed modest associations on the symptoms and functioning subscales. Number of previous KCs was not independently associated with any QoL differences.. Study population may not be generalizable to the general population. Counting of AKs is of limited reliability. Previous 5-FU use is self reported.. A history of ever use of 5-FU and present AKs was strongly associated with worse QoL. We find it more useful to consider these patients as having the chronic condition "actinic neoplasia syndrome," whose burden may be best measured by factors other than their history of KCs.

Topics: Administration, Topical; Aged; Aged, 80 and over; Analysis of Variance; Carcinoma, Squamous Cell; Chemoprevention; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hospitals, Veterans; Humans; Immunohistochemistry; Keratosis, Actinic; Male; Middle Aged; Multivariate Analysis; Precancerous Conditions; Probability; Quality of Life; Risk Assessment; Severity of Illness Index; Skin Neoplasms; Treatment Outcome; Tretinoin

Topical tretinoin is a medication commonly used for acne that has potential application in the long-term treatment of photodamaged skin. However, there are few published data regarding the tolerability of high-dose tretinoin with long-term use.. To assess the long-term tolerability of tretinoin 0.1% cream.. A randomized, multicentre, double-blind, controlled trial for chemoprevention of keratinocyte carcinomas (i.e. basal cell or squamous cell carcinomas) using topical tretinoin cream to the face and ears was conducted. All participants were veterans and had a history of two or more keratinocyte carcinomas over the previous 5 years. Participants were examined (by a study dermatologist) and interviewed every 6 months (for up to 5.5 years to May 2004). Treatment comprised tretinoin 0.1% cream or vehicle control cream once daily, then twice daily as tolerated. Participants were instructed to step down application frequency to once daily or less if twice daily was not tolerated. The main outcome measures were reported side-effects, frequency of cream application and attendance at study visits. Appropriate data were available for four of the six clinical sites of this trial.. Data from 736 randomized participants (mean age 71 years; 97% men) from four clinical sites were analysed. The tretinoin group more commonly reported one or more side-effects at the 6-month follow-up than the control group (61% vs. 42%, P < 0.0001). Side-effects decreased over time in both groups, but to a greater extent in the tretinoin group, and the difference became nonsignificant at 30 months. Burning was the most common side-effect (39% tretinoin vs. 17% control, P < 0.0001). There was no difference in severity of side-effects among those affected. Of the participants who reported burning in either group, most reported mild burning; only 11% of those with burning in the tretinoin group reported it as severe (mild 62% tretinoin vs. 70% placebo; severe 11% vs. 5%; P = 0.4). Itching (24% vs. 16%, P = 0.01) and other local cutaneous reactions (12% vs. 6%, P = 0.01) were also more commonly reported by the tretinoin group at 6 months. There was no difference in numbness (2% vs. 2%, P = 0.9). Participants in the tretinoin group were less likely to apply cream twice daily at 6 months (29% vs. 43%, P = 0.0002). This difference persisted over the entire duration of follow-up. There was little difference between groups in attendance at study visits or completion of telephone interviews (92% vs. 95%, P = 0.06). No unexpected adverse events were reported.. Overall, the tolerability level of topical tretinoin was high in this study population, with almost 40% of the tretinoin group reporting no side-effects, and the majority (67%) tolerating at least once-daily dosing at 6-month follow-up. High-dose topical tretinoin is feasible for long-term use in this population.

Topics: Administration, Topical; Aged; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Ear Neoplasms; Ear, External; Facial Neoplasms; Female; Humans; Male; Skin Neoplasms; Time Factors; Treatment Outcome; Tretinoin; Veterans

To evaluate the safety, dose tolerance, and anti-tumor effects of 9-cis-retinoic acid in the treatment of Kaposi sarcoma (KS) related to acquired immunodeficiency syndrome (AIDS).. Phase 2, open-label clinical trial of oral doses of 9-cis-retinoic acid increasing in 40-mg increments every 2 weeks from 60 mg/m(2) per day to a maximum of 140 mg/m( 2) per day.. Five hospital or health maintenance organization outpatient clinics.. Fifty-seven adult male patients with human immunodeficiency virus and biopsy-proven KS.. Safety was evaluated by adverse events, physical examination, laboratory test abnormalities, treatment-limiting toxic effects, and reasons for early withdrawal. Response (>/=50% improvement) was evaluated by an overall KS response and by the area and height from 6 index lesions selected at baseline.. Patients tolerated 60 and 100 mg/m(2) per day. Most patients found 140 mg/m(2) per day intolerable owing to headache. Common treatment-related adverse events were headache, xerosis, rash, alopecia, and hyperlipemia. The patient response rate for the overall KS disease was 19% (11/57), including 1 patient with clinically complete response. The response rate assessed by measuring 6 index lesions during treatment was 39% (22/57). Sixteen responding patients (73%) were refractory to at least 1 previous anti-KS therapy. Patients with CD4( +) counts of 150 cells/ micro L or lower were as likely to respond as patients with counts of higher than 150 cells/ micro L. The median time to response was 8.5 weeks (range, 4.0-21.1 weeks). The median duration of treatment was 15.1 weeks (range, 0.14 to >/=62 weeks).. 9-cis-retinoic acid capsules have moderate activity and provide durable responses, but substantial toxic effects at higher doses limit its suitability as an anti-KS therapy.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Alitretinoin; Antineoplastic Agents; Biopsy, Needle; Capsules; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Risk Assessment; Sarcoma, Kaposi; Single-Blind Method; Skin Neoplasms; Survival Rate; Treatment Outcome; Tretinoin

This randomized, double-blind and vehicle-controlled phase III study was conducted to evaluate the efficacy and safety of alitretinoin gel 0.1% for the topical treatment of the cutaneous lesions of AIDS-related Kaposi's sarcoma (KS).. Patients received treatment with alitretinoin gel (n = 62) or vehicle gel (n = 72) twice daily for 12 weeks. The primary efficacy endpoint was the cutaneous KS tumor response rate according to AIDS Clinical Trials Group (ACTG) objective criteria applied to topical therapy, with the patient as the unit of analysis.. Treatment of patients with alitretinoin gel resulted in a significant antitumor effect. The overall patient response rate (complete plus partial response) was 37% (23 of 62) for the alitretinoin-treated patients and 7% (5 of 72) for the vehicle-treated patients (p = 0.00003). The difference in response rates for the 2 treatment groups remained significant even after taking into consideration numerous variables, including age (p = 0.00001), Eastern Cooperative Oncology Group (ECOG) status (p = 0.00002), CD4+ cell count (p = 0.00002), history of opportunistic infection (p = 0.00002), aggregate area of indicator lesions (p = 0.00005), number of raised indicator lesions (p = 0.00002), prior therapy for KS (p = 0.00003), and number of drugs (p = 0.00002) used in concomitant antiretroviral therapy. Generally, treatment with alitretinoin gel was well tolerated. The overall incidence of adverse events was similar for the 2 treatment groups. Adverse events related to treatment with alitretinoin gel tended to be mild to moderate in severity and limited to the site of application. The most frequent adverse event occurring at the application site following alitretinoin gel treatment was irritation coded as rash (32%).. The results of this study provide convincing evidence of the superiority of alitretinoin gel over vehicle gel for the treatment of the cutaneous lesions of AIDS-related KS.

Topics: Administration, Topical; Adult; Alitretinoin; Antineoplastic Agents; Double-Blind Method; Drug Administration Schedule; Female; Gels; Herpesvirus 8, Human; Humans; Male; Palliative Care; Pharmaceutical Vehicles; Sarcoma, Kaposi; Skin Neoplasms; Treatment Outcome; Tretinoin

To evaluate the efficacy and safety of topical alitretinoin gel (9-cis-retinoic acid [LGD1057], Panretin gel; Ligand Pharmaceuticals, Inc, San Diego, Calif) in cutaneous Kaposi sarcoma (KS).. Open-label, within-patient, controlled, dose-escalating phase 1 and 2 clinical trials. In all patients, 1 or more cutaneous KS lesions were treated with alitretinoin gel, and at least 2 other lesions served as untreated controls for up to 16 weeks. Alitretinoin (0.05% or 0.1% gel) was applied twice daily for the first 2 weeks and up to 4 times daily thereafter, if tolerated.. Nine academic clinical centers.. One hundred fifteen patients with biopsy-proven acquired immunodeficiency syndrome (AIDS)-related KS.. AIDS Clinical Trials Group response criteria.. Statistically significant clinical responses were observed in 31 (27%) of 115 patients for the group of treated index lesions compared with 13 (11%) for the group of untreated control lesions (P<.001). Responses occurred with low CD4(+) lymphocyte counts (<200 cells/microL) and in some patients with refractory response to previous systemic anti-KS therapy. The incidence of disease progression was significantly lower for treated index lesions compared with untreated control lesions (39/115 [34%] vs 53/115 [46%]; P =.02). Alitretinoin gel generally was well tolerated, with 90% of treatment-related adverse events confined to the application site and only mild or moderate in severity.. Alitretinoin gel has significant antitumor activity as a topical treatment for AIDS-related KS lesions, substantially reduces the incidence of disease progression in treated lesions, and is generally well tolerated.

Topics: Administration, Cutaneous; Adult; AIDS-Related Opportunistic Infections; Alitretinoin; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Gels; Humans; Male; Middle Aged; Sarcoma, Kaposi; Skin Neoplasms; Treatment Outcome; Tretinoin; United States

Atypical naevi are potential precursors of melanoma and markers of increased melanoma risk. To examine the possibility of chemoprevention of melanoma by retinoids, we studied the effect of topical tretinoin 0.1% (all-transretinoic acid; vitamin A acid) and tretinoin 0.1% with hydrocortisone on atypical naevi. Thirty patients with atypical naevi were enrolled in a prospective randomized double blind study. For each patient three comparable naevi were selected and randomized to receive tretinoin 0.1% (T), tretinoin 0.1% with hydrocortisone 1% (C) or a placebo cream (P) once a week under Actiderm occlusion for 4 months. Baseline views of the naevi, taken with a videomicroscope (magnification 20 x), were assessed for morphological changes compared with views taken 2 months after the beginning of treatment, 1 week after completion of treatment and 6 months later. After completion of the study all naevi in the T and C groups and six naevi in the P group were removed and evaluated histologically for the presence of atypia. The number of naevi that had changed in colour or size was significantly higher in the T and C groups compared with the placebo group. A size reduction took place in 42.9% (T) and 40.0% (C) of the naevi and the colour changed in 75.0% (T) and 66.7% (C). The effect of treatment, in general subtle, did not differ significantly between groups T and C, but naevi treated with C became significantly less irritated. Histologically, 75.0% of the naevi treated with T and 69.6% of the naevi treated with C were atypical. Therefore, no major change was seen in the clinical aspect of atypical naevi after treatment with tretinoin 0.1% or tretinoin with hydrocortisone 1%, and most of the treated naevi still met the histological criteria for atypia after the treatment period. The current management of follow-up of atypical naevi and excision when change to melanoma is suspected is therefore still recommended. Nevertheless, some response was seen, which may justify a further exploration of tretinoin and hydrocortisone 1% therapy for a longer treatment period in combination with research to clarify its mechanism.

Topics: Adult; Antineoplastic Agents; Female; Humans; Hydrocortisone; Male; Melanoma; Middle Aged; Nevus; Occlusive Dressings; Pigmentation; Placebos; Prospective Studies; Skin Neoplasms; Tretinoin

Photodamaged skin typically displays lentigines, actinic keratoses, wrinkles, and textural alteration. Chemical peeling has been used to treat these, but few controlled studies have been performed to determine its efficacy.. Our purpose was to compare the efficacy of a medium-depth chemical peel with and without tretinoin before and after treatment.. Sixteen men with actinic damage including actinic keratoses were treated with a 40% trichloroacetic acid(TCA) chemical peel. Half were pretreated for 6 weeks with topical tretinoin; they also used tretinoin after the peel. Photographs were obtained at baseline and at 6 weeks and 6 months after treatment. Changes in specific features were rated by a panel of three examiners.. Some improvement was noted in all patients. More rapid and even frosting was observed in the patients pretreated with tretinoin. Solar lentigines, actinic keratoses, and skin texture were the features of photoaging most affected; wrinkles were least affected. No statistically significant difference was found between patients treated with TCA and tretinoin (before and after peel) and those with TCA alone.. A medium-depth chemical peel with 40% TCA alone produced moderate improvement in some manifestations of actinic damage but had little effect on wrinkles. Treatment with tretinoin before and after TCA did not significantly enhance the efficacy of the peel.

Topics: Administration, Cutaneous; Bacteria; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Chemexfoliation; Follow-Up Studies; Humans; Keratolytic Agents; Keratosis; Lentigo; Male; Patient Satisfaction; Photography; Premedication; Sebum; Skin; Skin Aging; Skin Neoplasms; Tretinoin; Trichloroacetic Acid

Renal transplant recipients experience a greatly increased frequency of neoplastic skin lesions, including aggressive squamous cell carcinomas. Recent reports suggest that high doses of systemic retinoids may exert a chemotherapeutic and chemoprophylactic effect. Similarly, topical retinoid, especially tretinoin, has also been shown to be anti-tumoragenic in various settings. Because of the serious toxicity of high-dose systemic retinoid, a protocol was developed that combined topical tretinoin with low-dose etretinate (10 mg daily) for the treatment of frequently occurring dysplastic skin lesions in renal transplant recipients. Seven patients elected to receive combined tretinoin and etretinate therapy, and 4 were treated with tretinoin alone. Clinical evaluations were performed monthly. By 3 months of therapy, 9 of 11 patients exhibited at least a 25% decrease in the number of neoplastic growths. After 6 months, 6 of 8 evaluable patients, including 2 of 3 individuals receiving tretinoin alone, exhibited at least a 50% decrease. Three of 4 patients on the combined regimen and 2 of 3 receiving tretinoin alone for at least 9 months, exhibited a significant decrease in the rate of development of new squamous cell cancers. At the start of treatment, epidermal specimens were almost completely devoid of Langerhans cells (CD1+ cells). Their density increased greatly and in proportion to the duration of therapy. Long term topical tretinoin with or without low-dose oral etretinate seems to be an effective regimen to suppress the development of new tumors and to reduce the numbers of existing lesions in renal transplant recipients.

Topics: Administration, Topical; Adult; Biopsy; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Drug Therapy, Combination; Etretinate; Humans; Immunohistochemistry; Kidney Transplantation; Pilot Projects; Precancerous Conditions; Skin; Skin Neoplasms; Tretinoin

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; HIV Seropositivity; Humans; Male; Middle Aged; Prospective Studies; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin

Orally administered all-trans-retinoic acid (all-trans-RA) can induce complete remission in a high proportion of patients with acute promyelocytic leukemia. A previous pharmacokinetic study in patients with acute promyelocytic leukemia raised the possibility that the absorption of orally administered all-trans-RA is a saturable process that would have significant clinical impact on dosing strategies.. This study was specifically designed to examine the saturability of all-trans-RA absorption by measuring the effect of doubling the oral dose of all-trans-RA on plasma drug concentration in patients receiving long-term oral therapy.. Six patients with solid tumors received oral doses of 10-mg gelatin capsules of all-trans-RA. Patients were studied on 2 consecutive days after they received 28 days of all-trans-RA administered as two daily 78-mg/m2 doses. The study assigned the patients to two groups. Three patients took a 156-mg/m2 dose on day 28 and a 78-mg/m2 dose on day 29; the other three patients took the lower dose on day 28 and the double dose on day 29. Blood samples for the determination of all-trans-RA plasma concentration were obtained at 30-minute intervals starting just prior to drug administration and continuing for a total of 7 hours. The plasma concentration of all-trans-RA was measured by high-performance liquid chromatography.. Plasma concentrations following an oral dose of all-trans-RA were highly variable, with peak concentrations ranging from 0.07 to 1.2 microM for the 78-mg/m2 dose level. Doubling the dose from 78 to 156 mg/m2 increased plasma concentration in all six patients, but the increase was unpredictable and not related to dose, ranging from less than a 1.2-fold to more than a 10-fold increase.. The current study does not support the hypothesis that the gastrointestinal absorption of all-trans-RA involves a saturable process but instead suggests that absorption is highly variable among patients. This wide interpatient variability suggests that pharmacokinetic drug monitoring may have an important role in the management of patients receiving all-trans-RA.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Biological Availability; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Dose-Response Relationship, Drug; Esophageal Neoplasms; Female; Half-Life; Humans; Intestinal Absorption; Lung Neoplasms; Male; Middle Aged; Skin Neoplasms; Time Factors; Tretinoin

Twenty-one patients were enrolled in a randomized, double-blind study that examined the effects of topical 0.05% tretinoin (all-trans-retinoic acid; vitamin A acid; Retin-A) solution on dysplastic nevi. Following histologic confirmation of the diagnosis of dysplastic nevus in three representative lesions, patients applied either tretinoin or a placebo containing 50% alcohol to selected dysplastic nevi once a day under tape occlusion, or twice a day unoccluded, for 4 months. Immediate posttreatment comparative photographs showed marked fading or elimination of some dysplastic nevi clinically, and histologic examination of excisional biopsy specimens showed disappearance or reversion to benign nevi in many of the treated lesions. There were no clinical or histologic changes in those dysplastic nevi treated with placebo. This study shows a definite biological effect of topical tretinoin on some dysplastic nevi.

Topics: Administration, Cutaneous; Adolescent; Adult; Bandages; Dermatitis; Double-Blind Method; Dysplastic Nevus Syndrome; Ethanol; Female; Humans; Male; Middle Aged; Placebos; Random Allocation; Skin; Skin Neoplasms; Tretinoin

To confirm reports that skin cancer can be prevented with retinoids, we conducted a three-year controlled prospective study of oral isotretinoin (also called 13-cis retinoic acid) in five patients with xeroderma pigmentosum who had a history of multiple cutaneous basal-cell or squamous-cell carcinomas. Patients were treated with isotretinoin at a dosage of 2 mg per kilogram of body weight per day for two years and then followed for an additional year, without the drug. Before, during, and after treatment, biopsies of all suspicious lesions were performed, and skin cancers were surgically removed. The patients had a total of 121 tumors (mean, 24; range, 8 to 43) in the two-year interval before treatment. During two years of treatment with isotretinoin, there were 25 tumors (mean, 5; range, 3 to 9), with an average reduction in skin cancers of 63 percent (P = 0.019). After the drug was discontinued, the tumor frequency increased a mean of 8.5-fold (range, 2- to 19-fold) over the frequency during treatment (P = 0.007). Although all patients experienced mucocutaneous toxic effects, and triglyceride, liver-function, or skeletal abnormalities developed in some, high-dose oral isotretinoin was effective in the chemoprophylaxis of skin cancers in patients with xeroderma pigmentosum.

Topics: Administration, Oral; Adolescent; Adult; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Child; Clinical Trials as Topic; Female; Humans; Isotretinoin; Male; Prospective Studies; Skin Neoplasms; Tretinoin; Xeroderma Pigmentosum

Thirty-nine patients with mycosis fungoides in various stages or Sézary syndrome were treated with isotretinoin and 29 with etretinate as single drug therapy. Complete remission within 2 months was obtained with isotretinoin in 8 cases (21%) and partial remission in another 15 cases (38%). Etretinate induced complete remission in 5 cases (21%) and partial remission in 11 (46%). Only 1 case with Sézary syndrome went into partial remission. The first sign of remission occurred in 2 to 4 weeks. During continued treatment remissions could not always be maintained. Isotretinoin and etretinate were considered to be of equal potency in the treatment of mycosis fungoides.

Topics: Drug Eruptions; Etretinate; Humans; Isotretinoin; Lymphatic Metastasis; Mycosis Fungoides; Remission Induction; Sezary Syndrome; Skin Neoplasms; Tretinoin

Peplomycin was given in a dose of 5 mg daily, divided into two equal parts for intramuscular administration each morning and evening. This schedule not only augments the antitumour effect but also reduces adverse reactions to the drug. Peplomycin-mitomycin C (P-M) therapy improves the response rates in T3 and T4 cases of skin cancer, and is also effective in some N1, N3 and M1 cases. Continuous intra-arterial infusion of peplomycin, though requiring somewhat complicated procedures, is very effective against squamous cell carcinoma of the head, neck and extremities. Multidisciplinary therapy incorporating peplomycin has given a considerably higher five-year survival rate than that found in historical controls.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Clinical Trials as Topic; Humans; Infusions, Intra-Arterial; Japan; Kinetics; Lung; Mitomycin; Mitomycins; Peplomycin; Skin Neoplasms; Tretinoin

The retinoids have been investigated extensively as chemopreventive and therapeutic agents in a variety of neoplasms. They have been shown to inhibit the proliferation of transformed cell lines in vitro and transplanted tumors in vivo. In cultured murine melanoma cells, retinoids inhibit proliferation and induce differentiation. Human melanoma cell lines have shown a mixed response. The clinical experience with retinoids in melanoma has been limited. Previously we investigated the activity of topical B-all-trans-retinoic acid (Retin-A, vitamin A acid, retinoic acid, and tretinoin) against intracutaneous metastases from malignant melanoma. We saw complete remission of multiple lesions in one individual and regression of several lesions in a second patient. This experience led us to conduct the present pilot trial of topical tretinoin in dysplastic nevus syndrome. The latter is a precursor of malignant melanoma. We saw regression of some of the treated lesions to benign nevi showing minimal or no dysplasia. Thus topical tretinoin appears to possess some activity against melanoma and at least one of its precursor conditions. In view of these preliminary results, more extensive trials are warranted to better define the role of tretinoin in the chemoprevention of malignant melanoma in high-risk lesions.

Topics: Administration, Topical; Adolescent; Clinical Trials as Topic; Dysplastic Nevus Syndrome; Humans; Male; Melanoma; Middle Aged; Pilot Projects; Skin Neoplasms; Tretinoin

In several studies between 1962 and 1978, topical tretinoin was proved capable of producing complete regression of actinic keratosis and basal cell carcinoma. But because its efficacy is not comparable to that of other modalities, topical tretinoin is currently used only as an adjunct to topical 5-fluorouracil in the treatment of actinic keratosis. One recent report found topical tretinoin ineffective in the chemoprevention of actinic keratosis. Although the oral synthetic retinoids isotretinoin and etretinate have been used in the prevention and treatment of cutaneous malignancy, the potential exists for chronic toxicity from the prolonged systemic therapy that appears necessary for maintaining the chemopreventive effect. For this reason, it may be appropriate to study further the preventive as well as therapeutic effects of topical tretinoin and other retinoids for actinic keratosis and skin cancer. If they prove safe and effective, the use of topical retinoids in the prevention and treatment of cutaneous tumors may be the most significant clinical application of these drugs.

Topics: Carcinoma, Basal Cell; Clinical Trials as Topic; Etretinate; Humans; Isotretinoin; Keratosis; Photosensitivity Disorders; Skin Neoplasms; Tretinoin; Urinary Bladder Neoplasms

Topics: Clinical Trials as Topic; Humans; Isotretinoin; Skin Neoplasms; Tretinoin; Vitamin A

Viaminate, a vitamin A acid drug developed in China, has been clinically used in acne treatment to regulate epithelial cell differentiation and proliferation, inhibit keratinization, reduce sebum secretion, and control immunological and anti-inflammatory actions; however, the exact method by which it works is unknown.. In the present study, acne was induced in the ears of rats using. After 30 days of treatment with viaminate, the symptoms of epidermal thickening and keratin overproduction in the ears of rats were significantly improved. Transcriptomic analysis of rat skin tissues suggested that viaminate significantly regulated the biological pathways of cellular keratinization. Gene differential analysis revealed that the S100A8 and S100A9 genes were significantly downregulated after viaminate treatment. The results of qPCR and Western blotting confirmed that viaminate inhibited the expression of S100A8 and S100A9 genes and proteins in rat and HaCat cell acne models, while its downstream pathway MAPK (MAPK p38/JNK/ERK1/2) protein expression levels were suppressed. Additional administration of the S100A8 and S100A9 complex protein significantly reversed the inhibitory effect of viaminate on abnormal proliferation and keratinization levels in acne cell models.. In summary, viaminate can improve acne by modulating S100A8 and S100A9 to inhibit MAPK pathway activation and inhibit keratinocyte proliferation and keratinization levels.

Topics: Acne Vulgaris; Animals; Calgranulin B; Cell Differentiation; Cell Proliferation; HaCaT Cells; Humans; MAP Kinase Signaling System; Propionibacterium acnes; Rats; Skin Neoplasms; Tretinoin

With the growing incidence of cutaneous squamous cell carcinoma (CSCC), the treatment-resistant invasive CSCC should be taken seriously. Retinoic acid receptor β (RARβ) functions as a tumor suppressor gene and is associated with the proliferation inhibition to retinoic acid. Demethylase TET2 directed epigenetic landscape contributes to cell malignant transform and is involved in therapeutic resistance in tumors. Whether aberrant TET2 participated in the deficient RARβ remains largely unknown. Hereby, we identified the aberrant-TET2 directed epigenetic landscape contribute to the deficient RARβ in CSCC.. The immunohistochemistry was used to detect the expression of RARβ and TET2. The bisulfite sequencing PCR was used to detect the RARβ promoter methylation. Plasmid transfection was used to upregulate TET2 in CSCC cells. Stable overxpressed TET2 cells were used to detect the effect of TET2 on RARβ and drug sensitivity in the CCSC.. We observed RARβ decreased with promoter hypermethylation in CSCC and aberrant TET2 associated with deficient RARβ. We upregulated TET2 could reverse promoter hypermethylation and showed a significantly increased expression of RARβ, which enhanced the sensitivity of tumor cells to retinoic acid treatment.. Aberrant TET2 leaded to the hypermethylation of RARβ promoter, which contributed to the deficient RARβ in CSCC. While reversing the hypermethylation of the RARβ promoter by recovering the TET2 could enhance tumor cells to be sensitive to retinoic acid.

Topics: Carcinoma, Squamous Cell; Dioxygenases; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Humans; Receptors, Retinoic Acid; Skin Neoplasms; Tretinoin

Melanoma originates from the malignant transformation of melanocytes. Compared with other skin cancers, melanoma has a higher fatality rate. The 5-year survival rate of patients with early-stage primary melanoma through surgical resection can reach more than 90%. However, the 5-year survival rate of patients with metastatic melanoma is only 25%. Therefore, accurate assessment of melanoma progression is critical. Previous studies have found that Retinoic Acid Induced 14(RAI14) is critical in tumorigenesis. However, the biological function of RAI14 for the development of melanoma is unclear. In this study, RAI14 is highly expressed in melanoma and correlated with prognosis. The expression of RAI14 can affect the proliferation, migration and invasion of melanoma cells. F-Box Protein 32(FBXO32) is an E3 ubiquitin ligase of c-MYC. We found that RAI14 affects the transcriptional expression of FBXO32 and regulates the stability of c-MYC. These results suggest that RAI14 play an important role in the growth of melanoma and is expected to be a therapeutic target for melanoma.

Topics: Cell Proliferation; Cell Transformation, Neoplastic; Cytoskeletal Proteins; F-Box Proteins; Humans; Melanoma; Muscle Proteins; Proto-Oncogene Proteins c-myc; Skin Neoplasms; SKP Cullin F-Box Protein Ligases; Transcription Factors; Tretinoin; Ubiquitin-Protein Ligases

Compound

Topics: Humans; Inflammation; Ligands; Retinoid X Receptors; Skin Neoplasms; Tetrahydronaphthalenes; Tretinoin; Triglycerides

Surgical excision is standard-of-care for primary invasive melanoma, but best care can be unclear for patients who are surgically high-risk or for whom resection may be excessively morbid. Alternatives to surgical excision have emerged for treatment of metastatic melanoma but have not yet been explored for primary invasive melanoma. Two elderly patients with primary invasive melanoma with many medical co-morbidities who were not surgical candidates were determined to be appropriate candidates for an intralesional IL-2 based regimen. Herein we report their clinical and histological outcome. An intralesional-based regimen (intralesional IL-2, topical imiquimod cream 5%, and tretinoin cream 0.1% under occlusion to the treatment site) was administered over the course of six to seven weeks, followed by two weeks of topical-only therapy. A complete response was seen after eight to nine weeks of treating invasive melanomas that were ≥1.85 mm and 5.5 mm thick. For patients with primary invasive melanoma on high morbidity sites and patients who are poor surgical candidates, a neoadjuvant intralesional IL-2-based approach may be a reasonable alternative. The two cases presented here suggest that alternative intralesional-based treatment modalities may minimize the size of the excision site and can be associated with complete histological clearance of invasive melanoma.

Topics: Aged; Aminoquinolines; Antineoplastic Agents; Humans; Imiquimod; Melanoma; Skin Neoplasms; Treatment Outcome; Tretinoin

Topics: Administration, Topical; Aminoquinolines; Antineoplastic Agents; Humans; Imiquimod; Melanoma; Skin Neoplasms; Tretinoin

Minimally invasive alternative approaches to treat non-melanoma skin cancers remain limited and unproven.. We aim to assess the efficacy of varying combinations of anti-tumor agents—imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream—with brief cryotherapy in treating non-melanoma skin cancers.. This retrospective study included 690 cases of non-melanoma skin cancers in 480 patients who received a diagnosis of a basal cell carcinoma or squamous cell carcinoma during a ten-year period. During treatment period, patients applied 30 applications of one of three combinations (imiquimod/tretinoin, 5-fluorouracil/tretinoin, or imiquimod/5-fluorouracil/tretinoin) and had cryotherapy every 2 weeks. Each patient had a clinical examination at least three years post-treatment or documented treatment failure. Clearance was defined by a lack of persistence or recurrence for 3 years following the completion of treatment. The likelihood of lesion clearance was evaluated using multivariable logistic regression analysis.. A total of 186 cases (97; basal cell carcinoma and 89; squamous cell carcinoma) in 133 patients [37% women and 63% men; median (interquartile range) age, 77 (69, 83) years] met the inclusion criteria. Multivariable logistic regression analysis adjusting for clinical and lesion variables demonstrated that, relative to the imiquimod/5-fluorouracil/tretinoin treatment approach, imiquimod/ tretinoin (odds ratio, 0.05; 95% confidence interval, 0.00-0.99) and 5-fluorouracil/tretinoin (0.02; 0.00–0.45) were associated with lower likelihoods of lesion clearance. Likewise, morpheaform basal cell carcinoma had a lower probability of clearance (0.05; 0.00–0.72).. The combination of imiquimod/5-fluorouracil/tretinoin with cryotherapy had high clearance rates and was the most effective treatment regimen. J Drugs Dermatol. 2021;20(3):260-267. doi:10.36849/JDD.5427.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Combined Modality Therapy; Cost-Benefit Analysis; Cryotherapy; Female; Fluorouracil; Humans; Imiquimod; Male; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Tretinoin

We analyzed the role of WIF1 in normal and acanthotic epidermis of 12-O-tetradecanoylphorbol-13-acetate (TPA) or all-trans-retinoic acid (ATRA)-treated and basal cell carcinoma (BCC)-bearing mice. WIF1 protein is located in the follicular infundibulum and interfollicular epidermis (IFE) in murine back skin. Within the hyperplastic epidermis of TPA- or ATRA-treated or BCC-bearing murine skin, WIF1 and Keratin 10 overlap in Ki67

Topics: Adaptor Proteins, Signal Transducing; Animals; Carcinoma, Basal Cell; Cell Proliferation; Culture Media, Conditioned; Epidermis; Gene Knockdown Techniques; HEK293 Cells; Humans; Keratinocytes; Mice; Neoplasms, Experimental; Primary Cell Culture; Skin Neoplasms; Tamoxifen; Tetradecanoylphorbol Acetate; Tretinoin

Xeroderma pigmentosum (XP) is a rare autosomal recessive dermatosis that is often complicated by multiple skin tumours at exposed locations, which are difficult to treat. We report a case of a 12-year-old girl with XP treated with oral retinoic acid and photodynamic therapy (PDT) with good clinical results. She had an 8-year history of multiple skin lesions that first appeared on her nasal dorsum, but gradually increased in size and spread to her entire face, neck, and upper limbs. Notably, the lesions became evidently aggravated after sun exposure. When she was 6 years old, sesame-seed-sized papules and plaques appeared, which were fragile and irregular in shape and would self-rupture, accompanied with slight itchiness and bloody exudate. Examination revealed multiple basal cell carcinomas. The tumours were treated with local carbon dioxide laser therapy combined with PDT. On the follow-up visit 2 months after the surgery, most of the skin lesions on her face had subsided. In cases of multiple tumours, PDT can be the treatment method of choice because it is less invasive, has less side effects, and does not damage the surrounding normal tissues.

Topics: Carcinoma, Basal Cell; Child; Drug Therapy, Combination; Face; Female; Hematoporphyrins; Humans; Lasers, Gas; Photochemotherapy; Photosensitizing Agents; Skin Neoplasms; Tretinoin; Xeroderma Pigmentosum

Malignant melanoma is a common form of skin cancer that contains different cell types recognized by various cell surface markers. Dacarbazine-based combination chemotherapy is frequently used for the treatment of melanoma. Despite its potent anticancer properties, resistance to dacarbazine develops in malignant melanoma. Here, we aim to improve response to dacarbazine therapy by pretreatment with all-trans retinoic acid (ATRA) in CD117. Collectively, combined treatment with ATRA and dacarbazine induced more apoptosis and enhanced the cell cycle arrest of CD117

Topics: Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dacarbazine; Drug Synergism; G1 Phase; Humans; Melanoma; Melanoma, Cutaneous Malignant; Proto-Oncogene Proteins c-kit; Resting Phase, Cell Cycle; Skin Neoplasms; Tretinoin

Down-regulated chemerin expression has been reported to correlate with poor prognosis of several types of cancer including melanoma. All-trans retinoic acid (atRA) is a potent inducer of chemerin, and we previously reported that atRA inhibited murine melanoma growth through enhancement of anti-tumor T-cell immunity. Here, we aimed to investigate whether loss of endogenous chemerin accelerated melanoma growth and whether chemerin was involved in the melanoma-inhibitory effect of atRA. We demonstrated that chemerin was constitutively expressed in the skin, which was down-regulated during murine melanoma growth. Rarres2

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chemokines; Intercellular Signaling Peptides and Proteins; Killer Cells, Natural; Melanoma, Experimental; Mice, Inbred C57BL; Mice, Knockout; Receptors, Chemokine; Receptors, G-Protein-Coupled; Skin Neoplasms; Tretinoin; Tumor Burden; Tumor Escape; Tumor Microenvironment

All-trans retinoic acid (atRA), the main biologically active metabolite of vitamin A, has been implicated in immunoregulation and anti-cancer. A recent finding that vitamin A could decrease the risk of melanoma in humans indicates the beneficial role of atRA in melanoma. However, it remains unknown whether topical application of atRA could inhibit melanoma growth by influencing tumour immunity. We demonstrate topical application of tretinoin ointment (atRA as the active ingredient) effectively inhibited B16F10 melanoma growth. This is accompanied by markedly enhanced CD8

Topics: Administration, Cutaneous; Animals; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Female; Granzymes; Histocompatibility Antigens Class I; Interferon-gamma; Ki-67 Antigen; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Melanoma, Experimental; Mice, Inbred C57BL; Signal Transduction; Skin Neoplasms; T-Lymphocytes, Cytotoxic; Time Factors; Tretinoin; Tumor Burden; Tumor Escape; Tumor Microenvironment; Tumor Necrosis Factor-alpha

Topics: Acute Generalized Exanthematous Pustulosis; Aged; Diagnosis, Differential; Humans; Keratolytic Agents; Keratosis; Male; Mycosis Fungoides; Neoplasm Staging; Skin Neoplasms; Tretinoin

Topics: Alitretinoin; Antineoplastic Agents; Cell Transformation, Neoplastic; Humans; Ki-1 Antigen; Male; Middle Aged; Mycosis Fungoides; Skin Neoplasms; Tretinoin

Vemurafenib is a selected BRAF kinase inhibitor approved for treating metastatic or unresectable melanoma, which has numerous cutaneous side effects unfortunately, including three previously reported cases of asymptomatic areola and/or nipple hyperkeratosis. We present the first case of painful bilateral nipple hyperkeratosis secondary to vemurafenib in an 84-year-old woman. She was successfully treated with tretinoin 0.05% cream that allowed her to comfortably continue treatment. With increased awareness of this condition, we found a second case of asymptomatic nipple hyperkeratosis secondary to vemurafenib in our clinic. As this medication gains acceptance for treatment of metastatic melanoma, it is imperative that dermatologists are aware of this potentially uncomfortable side effect that can result in decreased compliance and impaired quality of life.

Topics: Aged, 80 and over; Antineoplastic Agents; Female; Humans; Indoles; Keratosis; Melanoma; Nipples; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Quality of Life; Skin Neoplasms; Sulfonamides; Tretinoin; Vemurafenib

Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by widespread human papillomavirus (HPV) associated lesions and an increase susceptibility to cutaneous malignancies. A host of medications traditionally used to treat warty lesions have been used with variable results and limited success. To our knowledge, we describe the first reported case of a patient with Imiquimod resistant EV successfully treated with topical ingenol mebutate (Picato).. A patient with a 5 year history of EV failed to respond to a 6 week course of 5% imiquimod on the forehead and was subsequently treated with a 3 day course of 0.015% Picato gel which resulted in significant clinical improvement. A one month follow-up examination showed no reoccurrence of the lesions with the patient reporting continued satisfaction of the outcome.. Our case provides insight into the potential use of ingenol mebutate for EV patients unresponsive to traditional medical treatments.

Topics: Acitretin; Adult; Aminoquinolines; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Drug Resistance; Epidermodysplasia Verruciformis; Female; Gels; Humans; Imiquimod; Keratolytic Agents; Rare Diseases; Skin Neoplasms; Treatment Outcome; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Carcinoma, Squamous Cell; Humans; Immunocompromised Host; Kidney Transplantation; Leukemia, Promyelocytic, Acute; Lung Transplantation; Male; Middle Aged; Neoplasms, Second Primary; Oxides; Postoperative Complications; Skin Neoplasms; Tretinoin

Topics: Alitretinoin; Antineoplastic Agents; Female; Foot Dermatoses; Hand Dermatoses; Humans; Middle Aged; Mycosis Fungoides; Skin Neoplasms; Treatment Outcome; Tretinoin

Skin cancer burden is significant as treatment costs have skyrocketed to $8.1 million annually and some forms metastasize, such as cutaneous squamous cell carcinoma (cSCC) and melanoma. cSCC is caused by altered growth factor signaling induced by chemical carcinogens, ultraviolet light (UV) exposure, and infections with papillomaviruses (PVs). One of the few options for preventing cSCC in high-risk patients is oral retinoids. While much is understood about retinoid treatments and metabolism in mouse models of chemically and UV exposure induced cSCC, little is known about the role of retinoids in PV-induced cSCC. To better understand how retinoid metabolism is altered in cSCC, we examined the expression of this pathway in the newly discovered mouse papillomavirus (MmuPV1), which produces trichoblastomas in dorsal skin but not cSCC. We found significant increases in a rate-limiting enzyme involved in retinoic acid synthesis and retinoic acid binding proteins, suggestive of increased RA synthesis, in MmuPV1-induced tumors in B6.Cg-Foxn1(nu)/J mice. Similar increases in these proteins were seen after acute UVB exposure in Crl:SKH1-Hr(hr) mice and in regressing pre-cancerous lesions in a chemically-induced mouse model, suggesting a common mechanism in limiting the progression of papillomas to full blown cSCC.

Topics: Animals; Carcinoma, Squamous Cell; Disease Models, Animal; Female; Immunohistochemistry; Mice; Oligonucleotide Array Sequence Analysis; Papillomaviridae; Papillomavirus Infections; Skin Neoplasms; Transcriptome; Tretinoin

Topics: Aged; Alitretinoin; Antineoplastic Agents; Female; Forearm; Humans; Indoles; Keratoacanthoma; Melanoma; Proto-Oncogene Proteins B-raf; Retinoids; Skin Neoplasms; Sulfonamides; Tretinoin; Vemurafenib

All-trans retinoic acid (ATRA) has been tried for the treatment and prevention of a number of epithelial cancers. However, the precise mechanism by which ATRA inhibits the growth of cutaneous squamous cell carcinoma (cSCC) remains elusive.. To determine the suppressive effects of ATRA on the human cSCC cell line SCL-1, and explore the possible mechanisms involved.. SCL-1 cells were treated with ATRA, then cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while apoptosis and cell cycle progression were analysed by flow cytometry. Protein levels of cell-cycle regulatory proteins and the activation of extracellular signal-regulated kinase (ERK) and Jun kinase (JNK) were detected by western blotting analysis. Transcriptional activity of activator protein (AP)-1 was examined by luciferase reporter assay.. ATRA inhibited the proliferation of SCL-1 cells and had modest proapoptotic effects. ATRA also induced G1 cell-cycle arrest, inhibited the expression of cyclin D1/cyclin-dependent kinase (CDK)4 and cyclinE/CDK2, and increased the expression of the cyclin-dependent kinase inhibitors p21 and p27. In addition, ATRA significantly decreased the phosphorylation of ERK1/2 and JNK1/2, and inhibited AP-1 transcriptional activity.. ATRA induces cell-cycle arrest in human cSCC cells by inhibiting the mitogen-activated protein kinase (MAPK)-AP1 pathway, and could be effective in the prevention and chemotherapy of human cSCC.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Humans; Mitogen-Activated Protein Kinase 1; Skin Neoplasms; Tretinoin

A fundamental goal in cancer biology is to identify the cells and signalling pathways that are keys to induce tumour regression. Here we use a spontaneously self-regressing tumour, cutaneous keratoacanthoma (KAs), to identify physiological mechanisms that drive tumour regression. By using a mouse model system that recapitulates the behaviour of human KAs, we show that self-regressing tumours shift their balance to a differentiation programme during regression. Furthermore, we demonstrate that developmental programs utilized for skin hair follicle regeneration, such as Wnt, are hijacked to sustain tumour growth and that the retinoic acid (RA) signalling pathway promotes tumour regression by inhibiting Wnt signalling. Finally, we find that RA signalling can induce regression of malignant tumours that do not normally spontaneously regress, such as squamous cell carcinomas. These findings provide new insights into the physiological mechanisms of tumour regression and suggest therapeutic strategies to induce tumour regression.

Topics: Animals; Carcinoma, Squamous Cell; Disease Models, Animal; Hair Follicle; Keratoacanthoma; Mice; Remission, Spontaneous; Skin Neoplasms; Stem Cells; Tretinoin; Wnt Signaling Pathway

Retinoic acid (RA) and its analogues (retinoids) are promising agents in skin cancer prevention following either topical application or oral administration. However, long-term in vivo effects of RA on chemically induced hyperplastic epidermal foci in adult mouse skin have also been described, casting some doubt with regard to its chemopreventive activity.. To characterize chemically induced skin tumours and to investigate the in vivo long-term action and preventive effect of RA on adult mouse skin carcinogenesis.. Fifty-six adult Naval Medical Research Institute mice, exposed (n = 28) or not exposed (n = 28) to RA in utero.. Mice were treated with a standard two-stage skin carcinogenesis protocol, which included an initiating application of 7,12-dimethylbenz(a)anthracene followed by promotion with 12-O-tetradecanoylphorbol 13-acetate.. Retinoic acid administered to pregnant mice showed a long-term inhibitory action on cell differentiation and development of chemically induced tumours on the adult skin of their offspring, as well as a stimulatory effect on cell proliferation and expression of an early marker of malignant progression (keratin 13).. The results suggest that RA exposure in utero confers long-lasting effects on adult mouse skin carcinogenesis. These include chemopreventive activity (reduced number of tumours), as well as enhancement of squamous papilloma progression, which appears to be due to enhanced keratinocyte proliferation and suppression of epidermal maturation. The clinical significance of these findings is not known for other routes of RA administration at this time.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Carcinogens; Carcinoma, Squamous Cell; Drug Administration Schedule; Female; Keratoacanthoma; Male; Mice; Papilloma; Pregnancy; Skin Neoplasms; Tetradecanoylphorbol Acetate; Treatment Outcome; Tretinoin

Retinoids such as all-trans retinoic acid (ATRA) influence cell growth, differentiation and apoptosis and may play decisive roles in tumor development and progression. An essential retinoid-metabolizing enzyme known as lecithin retinol acyltransferase (LRAT) is expressed in melanoma cells but not in melanocytes catalysing the esterification of all-trans retinol (ATRol). In this study, we show that a stable LRAT knockdown (KD) in the human melanoma cell line SkMel23 leads to significantly increased levels of the substrate ATRol and biologically active ATRA. LRAT KD restored cellular sensitivity to retinoids analysed in cell culture assays and melanoma 3D skin models. Furthermore, ATRA-induced gene regulatory mechanisms drive depletion of added ATRol in LRAT KD cells. PCR analysis revealed a significant upregulation of retinoid-regulated genes such as CYP26A1 and STRA6 in LRAT KD cells, suggesting their possible involvement in mediating retinoid resistance in melanoma cells. In conclusion, LRAT seems to be important for melanoma progression. We propose that reduction in ATRol levels in melanoma cells by LRAT leads to a disturbance in cellular retinoid level. Balanced LRAT expression and activity may provide protection against melanoma development and progression. Pharmacological inhibition of LRAT activity could be a promising strategy for overcoming retinoid insensitivity in human melanoma cells.

Topics: Acyltransferases; Catalysis; Cell Line, Tumor; Cells, Cultured; Disease Progression; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Keratinocytes; Melanocytes; Melanoma; Melanoma, Cutaneous Malignant; Skin Neoplasms; Tretinoin; Vitamin A

We hereby report a rare case of a 14-year-old girl presenting with asymptomatic pitted papules over the flexor aspect of her right 4th and 5th digits. This was histopathologically proven to be porokeratotic eccrine ostial and dermal duct nevus (PEODDN).

Topics: Administration, Cutaneous; Adolescent; Antineoplastic Agents; Eccrine Glands; Female; Fingers; Humans; Keratolytic Agents; Nevus, Intradermal; Porokeratosis; Skin Neoplasms; Tretinoin

Aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that catalyses the conversion of lipid aldehydes to lipid carboxylic acids, plays pleiotropic roles in UV-radiation resistance, melanogenesis and stem cell maintenance. In this study, a combination of RNAi and pharmacologic approaches were used to determine which ALDH1A1 substrates and products regulate melanogenesis. Initial studies revealed that neither the UV-induced lipid aldehyde 4-hydroxy-2-nonenal nor the ALDH1A1 product all-trans retinoic acid appreciably induced melanogenesis. In contrast, both the ALDH1A1 substrate 9-cis retinal and its corresponding product 9-cis retinoic acid potently induced the accumulation of MITF mRNA, Tyrosinase mRNA and melanin. ALDH1A1 depletion inhibited the ability of 9-cis retinal but not 9-cis retinoic acid to stimulate melanogenesis, indicating that ALDH1A1 regulates melanogenesis by catalysing the conversion of 9-cis retinal to 9-cis retinoic acid. The addition of potent ALDH1A inhibitors (cyanamide or Angeli's salt) suppressed Tyrosinase and MITF mRNA accumulation in vitro and also melanin accumulation in skin equivalents, suggesting that 9-cis retinoids regulate melanogenesis in the intact epidermis. Taken together, these studies not only identify cyanamide as a potential novel treatment for hyperpigmentary disorders, but also identify 9-cis retinoic acid as a pigment stimulatory agent that may have clinical utility in the treatment of hypopigmentary disorders, such as vitiligo.

Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Alitretinoin; Cell Line, Tumor; Cells, Cultured; Cyanamide; Humans; Melanins; Melanocytes; Melanoma; Microphthalmia-Associated Transcription Factor; Monophenol Monooxygenase; Retinal Dehydrogenase; Skin; Skin Neoplasms; Skin Pigmentation; Tretinoin

Topics: Aged; Alitretinoin; Antineoplastic Agents; Hand; Humans; Male; Pagetoid Reticulosis; Skin Neoplasms; Treatment Outcome; Tretinoin

A 64-year-old man presented with a three-year history of an enlarging, pruritic, linear, verrucous plaque on his left lower extremity. Histopathologic examination was consistent with a verrucous epidermal nevus, which is a benign epidermal hamartoma, most commonly observed in the pediatric population. Verrucous epidermal nevi are often refractory to treatment and have high rates of recurrences, causing them to be therapeutic challenges. We review the treatment modalities reported to be effective in verrucous epidermal nevi.

Topics: Administration, Cutaneous; Antineoplastic Agents; Cryotherapy; Fluorouracil; Humans; Laser Therapy; Male; Middle Aged; Nevus, Sebaceous of Jadassohn; Skin Neoplasms; Tretinoin

Confluent and reticulate papillomatosis (CRP) is a rare disorder that has mostly been described in case reports and limited case series. Studies on this condition from our region are lacking.. To describe the clinical and histopathological findings, as well as response to treatment of all patients diagnosed with CRP at the American University of Beirut Medical Center (AUB-MC) between 1999 and 2009, and to compare our findings with those published in the literature.. Confluent and reticulate papillomatosis was diagnosed in 10 patients (five men, five women). Mean age at diagnosis was 19 years. Duration of lesions ranged from few months to several years. Skin lesions mainly consisted of reticulated, pigmented macules, patches and plaques. The most common area of involvement was the chest in five cases. The rash was asymptomatic in eight patients. Skin biopsy specimens from all patients revealed hyperkeratosis, papillomatosis and variable acanthosis. Whereas follicular plugging was observed in nine cases, anastomosis of the rete ridges was noted in three. Periodic acid Schiff stains highlighted yeast forms in six cases.. The clinical and histopathological features of the CRP patients in our study are generally comparable to those published in the literature, with minor differences. Clinically, one case had an atypical clinical presentation, and microscopically follicular plugging was seen in the majority of cases. Yeast-like spores were seen in six cases further supporting a role of Malassezia furfur in the pathogenesis of CRP.

Topics: Administration, Oral; Administration, Topical; Adolescent; Adult; Biopsy, Needle; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunohistochemistry; Lebanon; Male; Minocycline; Papilloma; Rare Diseases; Retrospective Studies; Skin Neoplasms; Steroids; Treatment Outcome; Tretinoin

Topics: Carcinoma, Basal Cell; Female; Humans; Male; Skin Neoplasms; Tretinoin

The effect of all-trans retinoic acid (ATRA) on cutaneous squamous cell carcinomas (c-SCC) has been poorly described. Because the imbalance of CRABP-II-mediated anticancer signalling and FABP5-mediated growth-promoting signalling was supposed to be related with ATRA sensitivities of cancer cells, COLO16 human c-SCC cell line was selected to check underlying mechanism leading to ATRA resistance by multiple experimental approaches. The results revealed that COLO 16 cells were resistant to 15 μm ATRA treatment. FABP5 as well as the elements related with CRABP-II signalling (CYP26A1, CYP26B1, CRABP-I, RARα/β/γ and RXRα/β/γ) and with FABP5 signalling (PPARβ/δ) were expressed, but CRABP-II was undetectable in COLO 16 cells. 5-Aza treatment enhanced CRABP-II expression but further bisulfite sequencing PCR-DNA sequencing revealed no methylation in CRABP-II promoter region. Transfection of CRABP-II-expressing plasmids or FABP5 siRNA or both successfully manipulated the level(s) of target gene expression but failed to overcome ATRA resistance in the transfectants. In conclusion, CRABP-II and FABP5 expression were imbalanced in ATRA-resistant COLO 16 cells. 5-Aza-enhanced CRABP-II expression and unmethylation in CRABP-II promoter region suggest the methylation of certain CRABP-II regulatory gene(s) in COLO 16 cells. As neither restoration of CRABP-II expression nor the increased CRABP-II versus FABP5 ratio can overcome ATRA resistance of COLO 16 cells, additional ATRA-resistant mechanism(s) may present in human c-SCCs and COLO 16 cells would be of value in addressing this issue.

Topics: Antineoplastic Agents; Azacitidine; Carcinoma, Squamous Cell; Cell Line, Tumor; Cytochrome P-450 Enzyme System; Decitabine; DNA Methylation; Drug Resistance, Neoplasm; Fatty Acid-Binding Proteins; Humans; PPAR delta; Receptors, Retinoic Acid; Retinoic Acid 4-Hydroxylase; Skin Neoplasms; Tretinoin

Given the high incidence of non-melanoma skin cancer (NMSC), a preventative intervention would be desirable. Except for regular sunscreen use, the quest for chemoprevention of NMSC in the general population has been unsuccessful. Weinstock et al. assessed the effects of 0.1% topical tretinoin on NMSC. Like earlier efforts at chemoprevention, this study failed to show therapeutic benefit. Future successful preventative strategies will likely rely on short-term, intermittent therapy or treatments used for other common indications.

Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Keratinocytes; Male; Skin Neoplasms; Tretinoin

In the last three decades, the incidence of melanoma has increased worldwide and no effective treatment modalities have been developed yet. All-trans retinoic acid (ATRA) and polyinosinic:polycytidylic acid (polyI:C) are strong inducers of toll-like receptor 3 (TLR3) and MDA5 expression, and polyI:C-induced TLR3 and MDA5 signaling specifically causes cell death in melanoma cells in vitro. We addressed the question of whether ATRA pretreatment could enhance the efficacy of polyI:C and, if so, would ATRA have any additional effects on this process. We found that the combined treatment of human melanoma cells with ATRA and polyI:C strongly increased the expression of TLR3 and MDA5 in both WM35 and WM983A cells associated with significantly higher mRNA and secreted levels of interferon β (IFNβ), CXCL1, CXCL8/IL-8, CXCL9, and CXCL10 than cells treated with either ATRA or polyI:C. Silencing of MDA5 by siRNA moderately affected IFNβ secretion, whereas TLR3 knockdown interfered with both CXCL chemokine and IFNβ production. Furthermore, the supernatants of ATRA+polyI:C-activated cultures increased the migration of both human monocyte-derived macrophages and CD1a dendritic cells significantly as compared with the supernatants of cells treated with either ATRA or polyI:C, and this effect occurred in a TLR3-dependent manner. In conclusion, consecutive treatment with ATRA and polyI:C results in strong, TLR3/MDA5-mediated chemokine and IFN responses in cultured human melanoma cells, which triggers a functional migratory response in professional antigen-presenting cells. This novel mode of concomitant activation may represent a more efficient treatment option for future melanoma therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Chemokines; Drug Synergism; Gene Knockdown Techniques; Humans; Interferon Inducers; Interferon-beta; Macrophages; Melanoma; Poly I-C; RNA, Small Interfering; Signal Transduction; Skin Neoplasms; Toll-Like Receptor 3; Transcriptome; Tretinoin

Although the concept of cancer stem cells (CSCs) is well-accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In this study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis, decreased cell viability in vitro, and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer.

Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Aldehyde Oxidoreductases; Animals; Apoptosis; Cell Transformation, Neoplastic; Dacarbazine; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Isoenzymes; Melanoma; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Neoplastic Stem Cells; Response Elements; Retinal Dehydrogenase; RNA, Small Interfering; Skin Neoplasms; Temozolomide; Tretinoin

Topical retinoids, compounds that are metabolites, analogues, or derivatives of retinol and possess biological vitamin A activity, are among the most used adjunctive agents for the mitigation of fine wrinkles, mottled hyperpigmentation, and tactile roughness of photodamaged and chronically aged skin. Retinoic acid (RA) is the most active biological form of vitamin A and remains the medical treatment of choice for photoaged skin. Retinyl palmitate (RP) is the major storage form of vitamin A in the skin and, because RP is also the most stable of available vitamin A esters, it is readily incorporated into the oil phase of cosmetic creams or lotions. Therefore, the topical application of RP is a practical strategy for increasing the levels of vitamin A in the skin. Usual cosmetic product concentrations of RA range from 0.025% to 0.1% and those of RP range from 0.1% to 5%. With a maximum absorbance around 325 nm, RA and RP absorb both ultraviolet A and B radiation (UVA and UVB) in incident sunlight. A 1-year study was conducted in mice to determine whether RA and RP would alter the photocarcinogenicity of broad-UV spectrum light generated by xenon arc lamps, termed simulated solar light (SSL), or narrow spectrum UV light generated by UVA and UVB lamps.

Topics: Administration, Topical; Animals; Antineoplastic Agents; Carcinogenicity Tests; Carcinoma, Squamous Cell; Diterpenes; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Inbred Strains; Mice, Nude; Retinyl Esters; Skin; Skin Neoplasms; Sunlight; Tretinoin; Vitamin A

Dyer et al. (this issue) assess the risk of new basal cell carcinoma (BCC) in the Veterans Affairs topical tretinoin chemoprevention trial, which included individuals with a history of at least two prior keratinocyte carcinomas. In addition to known risk factors for a future BCC, such as number of prior BCCs, a history of eczema and lower education levels were also associated with greater risk.

Topics: Carcinoma, Basal Cell; Female; Humans; Male; Skin Neoplasms; Tretinoin

Topics: Alitretinoin; Antineoplastic Agents; Humans; Male; Middle Aged; Mycosis Fungoides; Skin Neoplasms; Tretinoin

Many melanoma cells are resistant to the anti-proliferative effect of all trans retinoic acid (ATRA). Retinoic Acid Receptor-beta2 (RAR-beta2) mediates the ATRA growth inhibition. We found a correlation between the anti-proliferative activity of ATRA and expression of RAR-beta2. There was not a strict correlation between DNA methylation of RAR-beta gene and its expression. There was no difference in global and RARbeta specific nucleosome repeat length (NRL) in melanoma and melanocytes or between control and ATRA treated cells. Pan-acetylation of H3 and H4 within the RAR-beta gene promoter was higher in cells expressing RAR-beta2. All trans retinoic acid treatment of responsive cells did not change pan-acetylation of H3/H4, but addition of ATRA to non-responsive cells increased H4 pan-acetylation. Phytochemicals or the histone deacetylase inhibitor Trichostatin A did not restore expression of RAR-beta2. Treatment of WM1366 melanoma cells with 5-aza 2'-deoxycytidine reactivated RAR-beta2 gene expression and restored the ability of ATRA to further induce the expression of this gene. Therefore, promoter methylation is responsible for silencing of RAR-beta2 in some melanoma cells and pan-acetylation of H3 likely plays a permissive role in expression of RAR-beta2.

Topics: Acetylation; Cell Line, Tumor; Cell Proliferation; Chromatin Immunoprecipitation; Disease Progression; DNA Methylation; Gene Expression Regulation, Neoplastic; Gene Silencing; Histones; Humans; Melanocytes; Melanoma; Nucleosomes; Promoter Regions, Genetic; Protein Processing, Post-Translational; Receptors, Retinoic Acid; RNA, Messenger; Skin Neoplasms; Tretinoin

Eight cases of the acanthosis nigricans form of epidermal nevus have been described in literature. The present case is impressive and has an extensive segmental distribution. Although etiological factors, such as mutations in the FGFR3 gene, are becoming recognized, treatment options remain limited. We present a case of a 14-year-old male with multiple hyperpigmented, hyperkeratotic plaques on the upper body, axillae, and groin with a segmental distribution following Blaschko lines. Histopathological investigation showed aspects of both acanthosis nigricans and epidermal nevus. So far, screening has not revealed any internal abnormalities. As previous cases show a clear association with internal diseases, repetitive screening for internal diseases and syndromes is suggested in the case of the acanthosis nigricans form of epidermal nevus. Treatment of the condition remains a challenge.

Topics: Acanthosis Nigricans; Adolescent; Antineoplastic Agents; Humans; Male; Nevus; Skin Neoplasms; Tretinoin

NF-kappaB is a survival signaling transcription factor complex involved in the malignant phenotype of many cancers, including squamous cell carcinomas (SCC). The citrus coumarin, auraptene (AUR), and the ethno-medicinal ginger (Alpinia galanga) phenylpropanoid, 1'-acetoxychavicol acetate (ACA), were previously shown to suppress 12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse skin tumor promotion. The goal of the present study was to determine whether AUR and ACA are effective either alone or in combination with all-trans retinoic acid (ATRA) for suppressing SCC tumor growth.. We first determined the effects of orally administered ACA (100 mg/kg bw) and AUR (200 mg/kg bw) on lipopolysaccharide (LPS)-induced NF-kappaB activation in NF-kappaB-RE-luc (Oslo) luciferase reporter mice. Dietary administration of AUR and ACA +/- ATRA was next evaluated in a xenograft mouse model. Female SCID/bg mice were fed diets containing the experimental compounds, injected with 1 x 106 SRB12-p9 cells s.c., palpated and weighed twice a week for 28 days following injection.. Both ACA and AUR suppressed LPS-induced NF-kappaB activation in the report mice. In the xenograft model, AUR (1000 ppm) and ACA (500 ppm) modestly suppressed tumor volume. However, in combination with ATRA at 5, 10, and 30 ppm, ACA 500 ppm significantly inhibited tumor volume by 56%, 62%, and 98%, respectively. The effect of ATRA alone was 37%, 33%, and 93% inhibition, respectively. AUR 1000 ppm and ATRA 10 ppm were not very effective when administered alone, but when combined, strongly suppressed tumor volume by 84%.. Citrus AUR may synergize the tumor suppressive effects of ATRA, while ACA may prolong the inhibitory effects of ATRA. Further studies will be necessary to determine whether these combinations may be useful in the control of human SCC.

Topics: Animals; Antineoplastic Agents; Benzyl Alcohols; Blotting, Western; Carcinoma, Squamous Cell; Citrus; Coumarins; Drug Synergism; Drug Therapy, Combination; Female; Humans; Lipopolysaccharides; Luciferases; Male; Mice; Mice, SCID; NF-kappa B; Plant Extracts; Skin Neoplasms; Tretinoin; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Zingiber officinale

Topics: Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Humans; Keratinocytes; Quality of Life; Randomized Controlled Trials as Topic; Skin Neoplasms; Tretinoin; United States; United States Department of Veterans Affairs

Topics: Administration, Topical; Antineoplastic Agents; Cause of Death; Humans; Randomized Controlled Trials as Topic; Skin Neoplasms; Tretinoin

The transcription factor KLF4 acts in post-mitotic epithelial cells to promote differentiation and functions in a context-dependent fashion as an oncogene. In the skin KLF4 is co-expressed with the nuclear receptors RARgamma and RXRalpha, and formation of the skin permeability barrier is a shared function of these three proteins. We utilized a KLF4-transgenic mouse model of skin cancer in combination with cultured epithelial cells to examine functional interactions between KLF4 and retinoic acid receptors. In cultured cells, activation of a conditional, KLF4-estrogen receptor fusion protein by 4-hydroxytamoxifen resulted in rapid upregulation of transcripts for nuclear receptors including RARgamma and RXRalpha. We tested retinoids in epithelial cell transformation assays, including an RAR-selective agonist (all-trans RA), an RXR-selective agonist (9-cis UAB30, rexinoid), and a pan agonist (9-cis RA). Unlike for several other genes, transformation by KLF4 was inhibited by each retinoid, implicating distinct nuclear receptor heterodimers as modulators of KLF4 transforming activity. When RXRalpha expression was suppressed by RNAi in cultured cells, transformation was promoted and the inhibitory effect of 9-cis UAB30 was attenuated. Similarly as shown for other mouse models of skin cancer, rexinoid prevented skin tumor initiation resulting from induction of KLF4 in basal keratinocytes. Rexinoid permitted KLF4 expression and KLF4-induced cell cycling, but attenuated the KLF4-induced misexpression of cytokeratin 1 in basal cells. Neoplastic lesions including hyperplasia, dysplasia and squamous cell carcinoma-like lesions were prevented for up to 30 days. Taken together, the results identify retinoid receptors including RXRalpha as ligand-dependent inhibitors of KLF4-mediated transformation or tumorigenesis.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Cell Line; Fatty Acids, Unsaturated; Gene Expression Regulation, Neoplastic; Humans; Keratins; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Mice; Naphthalenes; Neoplasms, Squamous Cell; Rats; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoic Acid Receptor gamma; Retinoid X Receptor alpha; Skin Neoplasms; Tretinoin

Treatments for primary and metastatic melanomas are rarely effective. Even therapeutics such as retinoic acid (RA) that are successfully used to treat several other forms of cancer are ineffective. Recent evidence indicates that the antiproliferative effects of RA are mediated by the transcription factor SOX9 in human cancer cell lines. As we have previously shown that SOX9 is expressed in normal melanocytes, here we investigated SOX9 expression and function in human melanomas. Although SOX9 was expressed in normal human skin, it was increasingly downregulated as melanocytes progressed to the premalignant and then the malignant and metastatic states. Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. Furthermore, SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 increased SOX9 expression and restored sensitivity to RA. Thus, combined treatment with PGD2 and RA substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. The results of our experiments targeting SOX9 provide insight into the pathophysiology of melanoma. Further, the effects of SOX9 on melanoma cell proliferation and RA sensitivity suggest the encouraging possibility of a noncytotoxic approach to the treatment of melanoma.

Topics: Animals; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Down-Regulation; Humans; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Nude; Microphthalmia-Associated Transcription Factor; Nevus; Prostaglandin D2; Skin Neoplasms; SOX9 Transcription Factor; Tretinoin; Up-Regulation

Retinoids have been studied extensively for their potential as therapeutic and chemopreventive agents for a variety of cancers, including nonmelanoma skin cancer (NMSC). Despite their use for many years, the mechanism of action of retinoids in the prevention of NMSC is still unclear. In this study we have attempted to understand the chemopreventive mechanism of all-trans retinoic acid (ATRA), a primary biologically active retinoid, in order to more efficiently utilize retinoids in the clinic.. We have used the 2-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis model to investigate the chemopreventive effects of ATRA. We have compared the gene expression profiles of control skin to skin subjected to the 2-stage protocol, with or without ATRA, using Affymetrix 430 2.0 DNA microarrays. Approximately 49% of the genes showing altered expression with TPA treatment are conversely affected when ATRA is co-administered. The activity of these genes, which we refer to as 'counter-regulated', may contribute to chemoprevention by ATRA. The counter-regulated genes have been clustered into functional categories and bioinformatic analysis has identified the B-Raf/Mek/Erk branch of the MAP kinase pathway as one containing several genes whose upregulation by TPA is blocked by ATRA. We also show that ATRA blocks signaling through this pathway, as revealed by immunohistochemistry and Western blotting. Finally, we found that blocking the B-Raf/Mek/Erk pathway with a pharmacological inhibitor, Sorafenib (BAY43-9006), induces squamous differentiation of existing skin SCCs formed in the 2-stage model.. These results indicate that ATRA targets the B-Raf/Mek/Erk signaling pathway in the 2-stage mouse skin carcinogenesis model and this activity coincides with its chemopreventive action. This demonstrates the potential for targeting the B-Raf/Mek/Erk pathway for chemoprevention and therapy of skin SCC in humans. In addition our DNA microarray results provide the first expression signature for the chemopreventive effect of ATRA in a mouse skin cancer model. This is a potential source for novel targets for ATRA and other chemopreventive and therapeutic agents that can eventually be tested in the clinic.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Blotting, Western; Carcinogens; Cell Transformation, Neoplastic; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression; Immunohistochemistry; MAP Kinase Kinase Kinases; Mice; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins B-raf; Signal Transduction; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Topics: Administration, Topical; Antineoplastic Agents; Follow-Up Studies; Humans; Skin Neoplasms; Time Factors; Treatment Outcome; Tretinoin

Topics: Aged; Alitretinoin; Antineoplastic Agents; Humans; Keratoderma, Palmoplantar; Male; Mycosis Fungoides; Photopheresis; Sezary Syndrome; Skin Neoplasms; Treatment Outcome; Tretinoin

Squamous cell carcinoma (SCC) of the skin is the most clinically aggressive form of nonmelanoma skin cancer. We have determined the effects of all-trans retinoic acid (ATRA), a naturally occurring chemopreventive retinoid, on signal transducer and activator of transcription 3 (Stat3) signaling during the development of skin SCC. Stat3 is a transcription factor that plays a critical role in cell proliferation and survival, and it is constitutively active in several malignant cell types. We have previously shown that Stat3 is required for the initiation, promotion, and progression of skin SCC. ATRA is a highly efficient suppressor of tumor formation in the two-stage mouse skin carcinogenesis model and we have shown that this effect correlates with the suppression of the B-Raf/Mek/Erk signaling pathway. In this study, we have determined the pattern of Stat3 phosphorylation throughout the course of the two-stage protocol, both in the presence and absence of ATRA. We have used both SENCAR mice and K5.Stat3C transgenic mice, which express the Stat3C protein, a constitutively active form of Stat3, in the skin. Using Western blotting and immunohistochemical staining with phosphospecific antibodies, we show that coadministration of ATRA suppressed the 12-O-tetradecanoylphorbol-13-acetate-induced phosphorylation of Stat3 in both models, but was only able to suppress tumor formation in the SENCAR mice. Surprisingly, ATRA actually enhanced tumor formation in 12-O-tetradecanoylphorbol-13-acetate-treated K5.Stat3C mice. We hypothesize that ATRA blocks tumor formation, at least in part, by targeting events upstream of Stat3, such as the B-Raf/Mek/Erk pathway, and that in the K5.Stat3C mice, in which Stat3 activity is constitutive, it cannot suppress tumor formation.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Carcinogens; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Extracellular Signal-Regulated MAP Kinases; Female; Immunohistochemistry; MAP Kinase Kinase Kinases; Mice; Mice, Inbred SENCAR; Mice, Transgenic; raf Kinases; Signal Transduction; Skin Neoplasms; STAT3 Transcription Factor; Tetradecanoylphorbol Acetate; Tretinoin

Topics: Administration, Cutaneous; Antineoplastic Agents; Humans; Lung Neoplasms; Randomized Controlled Trials as Topic; Skin Neoplasms; Tretinoin

Retinoic acid (RA) signalling is essential for epidermal differentiation; however, the mechanisms by which it acts are largely unexplored. Partitioning of RA between different nuclear receptors is regulated by RA-binding proteins. We show that cellular RA-binding proteins CRABP1 and CRABP2 and the fatty acid-binding protein FABP5 are dynamically expressed during skin development and in adult tissue. CRABP1 is expressed in embryonic dermis and in the stroma of skin tumours, but confined to the hair follicle dermal papilla in normal postnatal skin. CRABP2 and FABP5 are expressed in the differentiating cells of sebaceous gland, interfollicular epidermis and hair follicles, with FABP5 being a prominent marker of sebaceous glands and anagen follicle bulbs. All three proteins are upregulated in response to RA treatment or Notch activation and are negatively regulated by Wnt/beta-catenin signalling. Ectopic follicles induced by beta-catenin arise from areas of the sebaceous gland that have lost CRABP2 and FABP5; conversely, inhibition of hair follicle formation by N-terminally truncated Lef1 results in upregulation of CRABP2 and FABP5. Our findings demonstrate that there is dynamic regulation of RA signalling in different regions of the skin and provide evidence for interactions between the RA, beta-catenin and Notch pathways.

Topics: Animals; beta Catenin; Carcinoma, Squamous Cell; Cell Differentiation; Epidermis; Fatty Acid-Binding Proteins; Hair Follicle; Lymphoid Enhancer-Binding Factor 1; Mice; Mice, Transgenic; Neoplasm Proteins; Papilloma; Receptor, Notch1; Receptors, Retinoic Acid; Signal Transduction; Skin; Skin Neoplasms; Stromal Cells; Tretinoin; Up-Regulation

The diversity of neuroblastoma and its clinical course depends on histology, biology and clinical features. We report a male presenting at 4 months of age with an abdominal mass and multiple subcutaneous nodules. The diagnosis was made by histological examination of a subcutaneous nodule and elevated urinary markers. The patient remained well during the subsequent 9 years. During that time no cytostatic treatment was given. Attempt to treat with cis-retinoic acid 10 years later did not result in any significant change of the clinical course. The patient has remained in good clinical condition for a 15-year observation period, having both progressing and regressing distant subcutaneous metastases. Skin nodules are the hallmarks of the indolent clinical course of the disease. We suggest the use of the "chronic neuroblastoma" as a term to describe patients with neuroblastoma showing indolent disease course over a very long period of time, but never achieving complete remission.

Topics: Abdominal Neoplasms; Adolescent; Adrenal Gland Neoplasms; Antineoplastic Agents; Child; Child, Preschool; Chronic Disease; Humans; Immunohistochemistry; Infant; Liver Neoplasms; Male; Neuroblastoma; Skin Neoplasms; Tretinoin

Incidence of melanoma continues to rise, and a better understanding of its genetics will be critical to improve diagnosis and develop new treatments. Here, we search for novel melanoma-specific genes that may serve as biomarkers and therapeutic targets by using an in vitro genetic screen. One identified cDNA encoded TROY, a member of the tumor necrosis factor receptor superfamily (TNFRSF). TROY is widely expressed during embryogenesis, but in adults expression is restricted to hair follicles and brain. However, TROY had never been associated with melanoma, and it was selected for further study. First we show that expression in melanoma is specific by semiquantitative RT-PCR analysis of a large panel of established tumor cell lines. Next, specificity of expression was evaluated by immunohistochemistry analysis of primary cell cultures and patient tissues. TROY is expressed in 2/2 primary melanoma cells and 45/45 melanoma tissue samples (p < 0.0001). With the exception of sebaceous glands, TROY is not expressed in normal skin biopsies (p < 0.0001) or primary skin cell cultures that contain keratinocytes and epidermal melanocytes, nor is it expressed in other skin tumor cells (p < 0.0001). Finally, we show that TROY regulates melanoma growth, because replication of melanoma cells with reduced TROY levels through treatment with short-interfering RNA was significantly decreased relative to control cells (p < 0.004). In summary, TROY is the first TNFRSF member that is a biomarker for melanoma. TROY also presents a potentially novel cell surface signaling target for inhibitors, cell and/or antibody-based immunotherapies.

Topics: Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Melanocytes; Melanoma; Receptors, Tumor Necrosis Factor; RNA, Messenger; Skin; Skin Neoplasms; TNF Receptor-Associated Factor 6; Tretinoin

Natural killer (NK) cells play a role in the innate and adaptive antitumor immune responses. The activity of NK cells is regulated by functionally opposing, activating and inhibitory receptors whose balance ultimately determines whether target cells will be susceptible to NK cell mediated lysis. As melanoma is an immunogenic tumor, the effect of immunomodulating agents is consistently investigated. In this study in 79 metastatic melanoma (MM) patients and 52 controls NK activity, expression of activating NKG2D and CD161 receptors and KIR receptors, CD158a and CD158b, on freshly isolated PBL and NK cells were evaluated. Native NK cell activity of melanoma patients in clinical stage I-III and MM patients was determined against NK sensitive K562, NK resistant Daudi, human melanoma FemX, HeLa and HL 60 target tumor cell lines. In addition, predictive pretherapy immunomodulating effect after 18 h in vitro treatments of PBL of MM patients with rh IL-2, IFN-alpha (IFN), 13-cis retinoic acid (RA) and combination IFN-alpha and RA was evaluated with respect to NK cell lyses against K562 and FemX cell lines. In this study we show for the first time that low expression of CD161 and activating NKG2D receptors, without increased expression of KIR receptors CD158a and CD158b, as well as a decrease in the cytotoxic, CD16(bright) NK cell subset, is associated with a significant impairment in NK cell activity in MM patients. Furthermore, the predictive pretherapy finding that IL-2, IFN, IFN and RA, unlike RA alone, can enhance NK cell activity of MM patients against FemX melanoma tumor cell line can be of help in the design and development of therapeutic regimens, considering that it has recently been shown that low-dose combination of different immunomodulators represents the most promising approach in the therapy of MM.

Topics: Adult; Aged; Antigens, Surface; Antineoplastic Agents; Cell Line, Tumor; Cytotoxicity, Immunologic; Female; Flow Cytometry; History, 17th Century; Humans; Interferon-alpha; Interleukin-2; Killer Cells, Natural; Lectins, C-Type; Lymphocytes; Male; Melanoma; Neoplasm Metastasis; NK Cell Lectin-Like Receptor Subfamily B; NK Cell Lectin-Like Receptor Subfamily K; Receptors, Immunologic; Receptors, KIR; Receptors, KIR2DL1; Receptors, KIR2DL3; Receptors, Natural Killer Cell; Recombinant Proteins; Skin Neoplasms; Tretinoin

TR3 was originally recognized for its role in the regulation of cell survival and differentiation, however, it was recently found to be a potent pro-apoptotic protein. In order to characterize the role of TR3 in melanoma cell apoptosis, we studied expression of TR3 in melanoma cell lines and tissues, its subcellular distribution and function during apoptosis using various expression and RNA interference vectors. We found that TR3 was constitutively expressed in both cultured melanoma cells and melanoma tissues. TR3 expression was significantly decreased in advanced melanomas comparing to benign nevi. Over-expression of wild type TR3 or mutant TR3 lacking the DNA binding domain resulted in massive apoptosis in melanoma cells, whereas stable knockdown of TR3 using RNA interference resulted in melanoma cell resistance to apoptosis induced by chemotherapeutic agents ATRA and cisplatin. We further demonstrated that apoptosis in melanoma cells was mediated, at least partially, through TR3 mitochondrial translocation but not alteration in TR3 expression levels. Our results suggest that TR3 is an important apoptosis inducing factor in melanoma cells. Decreased expression of TR3 in metastatic melanoma cells may contribute to their reduced apoptotic potential and increased resistance to chemotherapy.

Topics: Apoptosis; Cell Line, Tumor; Cisplatin; Cytochromes c; DNA-Binding Proteins; Humans; Melanoma; Mitochondria; Nuclear Receptor Subfamily 4, Group A, Member 1; Proto-Oncogene Proteins c-bcl-2; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Skin Neoplasms; Transcription Factors; Tretinoin

Topics: Antineoplastic Agents; Apoptosis; Bexarotene; CD4-Positive T-Lymphocytes; Cell Culture Techniques; Drug Resistance, Neoplasm; Humans; Sezary Syndrome; Skin Neoplasms; Tetrahydronaphthalenes; Tretinoin

The TAF4 subunit of transcription factor TFIID was inactivated in the basal keratinocytes of foetal and adult mouse epidermis. Loss of TAF4 in the foetal epidermis results in reduced expression of the genes required for skin barrier function, leading to early neonatal death. By contrast, TAF4 inactivation in adult epidermis leads to extensive fur loss and an aberrant hair cycle characterised by a defective anagen phase. Although the mutant epidermis contains few normal anagen-phase hair follicles, many genes expressed at this stage are strongly upregulated indicating desynchronized and inappropriate gene expression. The TAF4 mutant adult epidermis also displays interfollicular hyperplasia associated with a potent upregulation of several members of the EGF family of mitogens. Moreover, loss of TAF4 leads to malignant transformation of chemically induced papillomas and the appearance of invasive melanocytic tumours. Together, our results show that TAF4 is an important regulator of keratinocyte proliferation and has cell-autonomous and non-cell-autonomous tumour suppressor activity.

Topics: Animals; Cell Differentiation; Cell Proliferation; Epidermis; Female; Genetic Predisposition to Disease; Hair; Hyperplasia; Keratinocytes; Male; Mice; Mice, Knockout; Nevus, Pigmented; Protein Subunits; Skin Neoplasms; TATA-Binding Protein Associated Factors; Transcription Factor TFIID; Tretinoin; Tumor Suppressor Proteins

Adult Naval Medical Research Institute (NMRI) mice, after prenatal exposure to retinoic acid (RA), were treated with a standard two-stage skin carcinogenesis regime to characterize hyperplastic epidermal foci that precede the appearance of cutaneous papillomas, and to investigate the in vivo long-term action of RA on adult mouse skin treated with DMBA (7,12 dimethyl benz[a]anthracene) and TPA (12-O-tetradecanoylphorbol 13-acetate). The results demonstrate that RA administered to pregnant mice had a long-term inhibitory action on the cell differentiation and development of hyperplastic lesions occurring prior to cancer on the adult skin of their offspring as well as a stimulatory effect on cell proliferation of these hyperplastic lesions.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Animals; Carcinogens; Cell Differentiation; Disease Models, Animal; Female; Keratolytic Agents; Mice; Papilloma; Pregnancy; Prenatal Exposure Delayed Effects; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

The few chemoimmunotherapy trials that together with dacarbazine (DTIC) and interferon-alpha 2a (IFNalpha), include retinoic acid (RA), did not include detailed immunological evaluation of functional and phenotypic natural killer (NK) cell characteristics, and have shown contradictory clinical results.. Malignant melanoma (MM) patients undergoing phase II-randomized chemoimmunotherapy trials were treated with DTIC, IFNalpha (Hoffmann-La Roche) (group A, n = 31), and with DTIC, IFNalpha and 13-cis-RA (Isotretinoin, Hoffmann-La Roche, Basel, Switzerland) (group B, n = 29). Patients and 42 healthy controls were evaluated by FACS flow analyses for CD3/CD56/CD69 positive cells, NK cytotoxicity in fresh peripheral blood lymphocytes (PBL) and for interferon regulatory factor-1 mRNA expression by reverse transcriptase polymerase chain reaction in treated PBL.. The addition of RA to a DTIC-IFN regime did not bring any therapeutical benefit in terms of response or survival. Immunological follow-up on days 1, 6 and 27 of each therapy cycle shows a significant increase in NK cell activity in both groups, only on day 6 of the first cycle, while CD69+CD56+ expression increased significantly on day 6 of each therapy cycle, in both groups. Evaluation of the dynamics of expression of IRF-1 of in vitro treated PBL, shows its strong and prompt up-regulation by IFNalpha and synergistic effect of IFNalpha and RA combination.. The dynamics of the increase in CD69 early activation antigen expression on CD56+ NK cells is systematic and serial with the increase being significantly higher on day six of the first cycle in group B patients with clinical response, compared to those without, indicating possible predictive value of CD69 expression for clinical response to chemoimmunotherapy.

Topics: Adult; Aged; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; CD56 Antigen; Dacarbazine; Female; Humans; Immunotherapy; Interferon alpha-2; Interferon Regulatory Factor-1; Interferon-alpha; Killer Cells, Natural; Lectins, C-Type; Male; Melanoma; Middle Aged; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Skin Neoplasms; Tretinoin

AQP3 (aquaporin 3) in the skin is important for skin moisture as demonstrated by the studies of AQP3-null mice, which have accelerated skin drying. Prevention of dry skin is important not only from a cosmetic but also from a clinical point of view. Primary keratinocyte cultures are cumbersome for screening substances that modulate AQP3 expression.. A human keratocarcinoma cell line was found to express AQP3 mRNA and protein, which responded to hypertonic stimulation with sorbitol, suggesting that the AQP3 expression is normally regulated in this cell line. This cell line also expressed the type 1 keratinocyte transglutaminase gene. The AQP3 expression was unaffected by all-trans-retinoic acid up to 10(-6) M. Similarly, the retinoic acid did not increase the AQP3 expression up to 1% concentration in rat skin.. This cell line is useful for the screening of candidate substances that modulate AQP3 expression.

Topics: Animals; Aquaporin 3; Cell Line, Tumor; Humans; Keratinocytes; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Skin Neoplasms; Sorbitol; Transglutaminases; Tretinoin

Fenretinide [N-(4-hydroxyphenyl)retinamide or 4-HPR] is a synthetic retinoid analogue with antitumor and chemopreventive activities. N-(4-Methoxyphenyl)retinamide (4-MPR) is the most abundant metabolite of 4-HPR detected in human serum following 4-HPR therapy. We have shown in in vitro studies that 4-HPR and 4-MPR can act independent of the classic nuclear retinoid receptor pathway and that 4-HPR, but not 4-MPR, can also activate nuclear retinoid receptors. In this study, we have compared the chemopreventive effects of topically applied 4-HPR and 4-MPR with the primary biologically active retinoid, all-trans retinoic acid (ATRA), in vivo in the mouse skin two-stage chemical carcinogenesis model. All three retinoids suppressed tumor formation but the effect of 4-HPR and 4-MPR, and not of ATRA, was sustained after their discontinuation. The tumor-suppressive effects of 4-HPR and 4-MPR were quantitatively and qualitatively similar, suggesting that the two may be acting through the same retinoid receptor-independent mechanism(s). We further explored this effect in vitro by analyzing primary cultures of mouse keratinocytes treated with the same retinoids. All three could induce apoptosis with a 48-hour treatment and only ATRA and 4-HPR induced an accumulation of cells in the G1 phase of the cell cycle. This finding is consistent with our previous results showing that the effects of phenylretinamides on the cell cycle are retinoid receptor dependent whereas apoptosis induction is not. A microarray-based comparison of gene expression profiles for mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) alone and TPA + 4-HPR or TPA + 4-MPR reveals a high degree of coincidence between the genes regulated by the two phenylretinamides. We propose that 4-HPR may exert therapeutic and chemopreventive effects by acting primarily through a retinoid receptor-independent mechanism(s) and that 4-MPR may contribute to the therapeutic effect of 4-HPR by acting through the same retinoid receptor-independent mechanism(s).

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Chemoprevention; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Fenretinide; G1 Phase; Gene Expression Profiling; In Vitro Techniques; Keratinocytes; Mice; Mice, Inbred SENCAR; Oligonucleotide Array Sequence Analysis; Retinoid X Receptors; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Suppressor Proteins

Melasma and acquired dermal melanocytosis (ADM; acquired bilateral nevus of Ota-like macules) are both seen most commonly symmetrically on the face of women with darker skin and are also known as difficult conditions to treat.. Our topical bleaching protocol with 0.1 to 0.4% tretinoin gel and 5% hydroquinone was performed repeatedly (1-3 times) for melasma (n=163), and a combination treatment with topical bleaching and Q-switched ruby (QSR) laser was performed repeatedly (1-3 times) for ADM (n=62).. There is a significant correlation between clinical results (clearance of pigmentation) and the number of sessions in both melasma (p=.019) and ADM (p<.0001).. The repeated treatment protocol for melasma and ADM showed successful clinical results compared with conventional ones, and they may be applied to other pigment conditions. It may be better that epidermal and dermal pigmentations are treated separately, especially in dark-skinned people who are more likely to suffer postinflammatory hyperpigmentation after inflammation-inducing therapies.

Topics: Adult; Antioxidants; Asian People; Combined Modality Therapy; Drug Therapy, Combination; Facial Neoplasms; Female; Follow-Up Studies; Humans; Hydroquinones; Keratolytic Agents; Low-Level Light Therapy; Male; Melanosis; Middle Aged; Nevus, Pigmented; Retreatment; Skin Neoplasms; Treatment Outcome; Tretinoin

Topics: Aged; Alitretinoin; Antineoplastic Agents; Gels; Humans; Male; Sarcoma, Kaposi; Skin Neoplasms; Treatment Failure; Tretinoin

The main cause of skin cancer and photo-aging is chronic exposure to ultraviolet B (UVB) radiation. Such damage can be ameliorated by retinoid treatment. UVB-radiation-induced skin carcinogenesis is associated with the induction of activator protein 1 (AP1) signaling and factors, namely FOS and JUN family members. We investigated the effects of several retinoids, all-trans-retinoic acid (tRA), 9-cis-retinoic acid (cRA), and N-(4-hydroxyphenyl)-retinamide (HPR), on UVB-induced damage in primary mouse keratinocytes. In addition, the interplay between UVB radiation, retinoid receptors, and AP1 signaling was assessed using Western blot analysis and ribonuclease protection and gene reporter assays. Exposure of keratinocytes to UVB radiation caused a down-regulation of the retinoid receptor protein levels in a proteasome-mediated manner. In contrast, FOS and JUN proteins were transiently induced shortly after exposure to UVB radiation. Retinoid treatment caused a dose-dependent reduction in the levels of retinoid receptor proteins. When irradiated cells were treated with retinoids, no significant effects on AP1 protein expression were noted. Interestingly, pretreatments with tRA and cRA, but not HPR, suppressed UVB-radiation-induced AP1 activity by more than 50%, whereas post-treatment failed to produce similar effects. Our findings indicate that the inhibition of AP1 activity by retinoids explains, at least in part, the chemopreventive potential of retinoids in UV-radiation-associated epidermal damage.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Cell Line; Dose-Response Relationship, Radiation; Down-Regulation; Epidermis; Fenretinide; Gene Expression Regulation; Genes, Reporter; Keratinocytes; Luciferases; Mice; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Retinoids; Signal Transduction; Skin Neoplasms; Time Factors; Transcription Factor AP-1; Transfection; Tretinoin; Ultraviolet Rays

Topics: Administration, Topical; Biopsy, Needle; Combined Modality Therapy; Humans; Immunohistochemistry; Laser Therapy; Male; Middle Aged; Osteoma; Prognosis; Rare Diseases; Skin Neoplasms; Tretinoin

Activation of telomerase is crucial for the continued growth and progression of cancer cells. In a previous study, we showed that telomerase is frequently activated in skin tumours.. Because retinoic acid (RA) plays an important role in the growth and differentiation of keratinocytes and as RA has some preventive and therapeutic effects on human skin cancers, we examined the effect of RA on the telomerase activity of HSC-1 human cutaneous squamous cell carcinoma cells.. Treatment of HSC-1 cells with all-trans RA (ATRA) significantly suppressed their telomerase activity. The suppression of telomerase activity was obvious at day 4 and was maximal at day 5 after the start of treatment with RA. This suppression was reversible as removal of ATRA allowed the recovery of telomerase activity. The suppression of telomerase activity correlated with the decreased expression of mRNA of human telomerase catalytic subunit (hTERT), the rate-limiting determinant of enzyme activity. The production of c-myc and of Sp1 proteins, transcription factors regulating hTERT expression, was not suppressed in HSC-1 cells by ATRA, but phosphorylation of extracellular signal-regulated kinases (ERK)1/2 and of the serine/threonine kinase Akt was significantly suppressed. Phosphorylation of the epidermal growth factor receptor, which regulates hTERT expression in HSC-1 cells, was not altered by ATRA.. These data indicate that RA is effective in inhibiting telomerase activity in HSC-1 cells. Suppression of ERK1/2 and Akt activation is presumed to be involved in the RA-induced suppression of hTERT.

Topics: Carcinoma, Squamous Cell; Cell Division; DNA-Binding Proteins; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Enzymologic; Humans; Neoplasm Proteins; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Skin Neoplasms; Telomerase; Tretinoin; Tumor Cells, Cultured

Topics: Adult; Amoxicillin-Potassium Clavulanate Combination; Benzoyl Peroxide; Carcinoma, Basal Cell; Cryosurgery; Dermatologic Agents; Drug Therapy, Combination; Humans; Male; Nevus, Pigmented; Skin Neoplasms; Syndrome; Toes; Tretinoin

To investigate the effects of all-trans retinoic acid (ATRA), acitretin and tazarotene on apoptosis and Bax/Bcl-2 protein expressions of human melanoma A375 cells.. The effects of retinoids on apoptosis and Bax/Bcl-2 protein expressions of A375 cells in vitro were examined. Apoptosis analysis with double staining with annexin V-FITC and PI was performed using flow cytometer. SABC immunocytochemistry was employed for detection of Bax/Bcl-2 protein expressions.. At the concentration of 1 x 10(-5) mol/L, ATRA, acitretin and tazarotene all induced apoptosis of A375 cells with apoptosis ratio of 5.03% (P<0.05), 13.42% (P<0.05) and 2.88% (P>0.05), respectively, and acitretin induced more significant apoptosis than the other two agents (P<0.05). In addition, all the three agents significantly increased the number of cells positive for Bax expression and decreased the number of cells expressing Bcl-2 (P<0.05), among which acitretin had the strongest effects.. ATRA, acitretin and tazarotene mediate apoptosis of A375 cells possibly through, at least partially, the mitochondrial pathway. Acitretin may be utilized as a valuable alternative for treating melanoma.

Topics: Acitretin; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Humans; Melanoma; Nicotinic Acids; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; Tretinoin; Tumor Cells, Cultured

All-trans retinoic acid (RA), the principle biologically active form of vitamin A, is essential for many developmental process as well as homeostasis in the adult. Many lines of evidence also suggest that RA, acting through the RA receptors (RARs), can also suppress growth of tumors of diverse origin. To assess directly the role of the RARs in a model of epidermal tumorigenesis, we investigated the incidence of tumor formation using keratinocytes lacking specific RAR types. Our data suggest that loss of RARgamma, but not RARalpha, predisposed keratinocytes to v-Ha-Ras-induced squamous cell carcinoma. We also found that ablation of RARgamma, but not RARalpha, abolished RA-induced cell cycle arrest and apoptosis in these keratinocytes. Reconstitution of receptor expression into RAR-null cells restored sensitivity to RA, and reversed the tumorigenic potential of receptor-deficient keratinocytes. These data strongly support a tumor suppressor effect for the RARs, in particular endogenous RARgamma, in murine keratinocytes.

Topics: Animals; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Cell Nucleus; COS Cells; Genes, Reporter; Genes, Tumor Suppressor; Genotype; Keratinocytes; Mice; Mice, Transgenic; ras Proteins; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Retroviridae; Skin Neoplasms; Time Factors; Tretinoin

Retinoids influence growth and differentiation of keratinocytes (KCs) and are widely used for the management of skin diseases and for prevention of nonmelanoma skin cancer (NMSC) in predisposed patients. Here we investigated the effect of all-trans-retinoic acid (ATRA) on KC apoptosis. When KCs were cultured in confluent monolayers for several days, they acquired resistance against UVB-induced apoptosis. In contrast, when the cells were treated with 1 micromol/L ATRA for 6 days and subsequently irradiated with different doses of UVB, they underwent massive apoptosis as assessed by morphology, expression of activated caspase-3, and DNA fragmentation. The same effect was observed when doxorubicin was used instead of UVB. Analysis by real-time PCR and Western blot revealed that ATRA treatment strongly increased the mRNA and protein expression of p53 and caspase-3, -6, -7, and -9, which are key regulators of apoptosis. UVB irradiation of ATRA-treated cells but not of control cells led to the accumulation of p53 protein and of its target gene Noxa. Inhibition of p53 and caspases with alpha-pifithrin and z-Val-Ala-Asp-fluoromethyl ketone, respectively, blocked UVB- and doxorubicin-induced apoptosis in ATRA-treated KCs. Analogous to the observed ATRA effects in monolayer cultures, in vitro-generated organotypic skin cultures reacted with up-regulation of p53 and proapoptotic caspases and displayed increased sensitivity to UVB-induced apoptosis. The ability of retinoic acid to regulate the expression of proapoptotic genes and to sensitize KCs to apoptosis may play a role in their prevention of NMSC in transplant patients and patients with DNA-repair deficiencies.

Topics: Antibiotics, Antineoplastic; Apoptosis; Caspase Inhibitors; Caspases; Cells, Cultured; Down-Regulation; Doxorubicin; Drug Synergism; Humans; Isoenzymes; Keratinocytes; Skin Neoplasms; Tretinoin; Tumor Suppressor Protein p53; Ultraviolet Rays; Up-Regulation

Germline mutations in the Exostoses-1 gene (EXT1) are found in hereditary multiple exostoses syndrome, which is characterized by the formation of osteochondromas and an increased risk of chondrosarcomas and osteosarcomas. However, despite its putative tumor-suppressor function, little is known of the contribution of EXT1 to human sporadic malignancies. Here, we report that EXT1 function is abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of EXT1, a glycosyltransferase, leads to the loss of heparan sulfate (HS) synthesis. Reduced HS production can be reversed by the use of a DNA demethylating agent. Furthermore, the re-introduction of EXT1 into cancer cell lines displaying methylation-dependent silencing of EXT1 induces tumor-suppressor-like features, e.g. reduced colony formation density and tumor growth in nude mouse xenograft models. Screening a large collection of human cancer cell lines (n=79) and primary tumors (n=454) from different cell types, we found that EXT1 CpG island hypermethylation was common in leukemia, especially acute promyelocytic leukemia and acute lymphoblastic leukemia, and non-melanoma skin cancer. These findings highlight the importance of EXT1 epigenetic inactivation, leading to an abrogation of HS biosynthesis, in the processes of tumor onset and progression.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; CpG Islands; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, Tumor Suppressor; Heparitin Sulfate; Humans; Leukemia, Promyelocytic, Acute; Mice; Mice, Nude; Mutation, Missense; N-Acetylglucosaminyltransferases; Neoplasms, Experimental; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; Skin Neoplasms; Transplantation, Heterologous; Tretinoin

We investigated whether p27 and mitogen-activated protein kinase (MAPK) proteins were involved in all-trans retinoic acid (atRA)-induced apoptosis and cell cycle arrest. Matched primary and metastatic melanoma cells were exposed to atRA. Apoptosis and cell cycle were detected by flow cytometry. Expression of p27, Ras, B-raf, Mek and Erk proteins was examined. Results showed that atRA induced apoptosis and cell cycle arrest in both primary and metastatic melanoma cells. The primary melanoma cells were more vulnerable than their matched metastatic cells. Expression of p27 was increased, while MAPK proteins were decreased, this response was dose- and time-dependent. Alterations of these proteins were more pronounced in primary melanoma cells than in the matched metastases. These data indicate that up-regulation of p27 and down-regulation of MAPK proteins were involved in atRA-induced apoptosis and cell cycle arrest in melanoma.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p27; Dose-Response Relationship, Drug; Enzyme Inhibitors; Genes, Tumor Suppressor; Humans; Melanoma; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Skin Neoplasms; Tretinoin; Tumor Suppressor Proteins

Retinoids have been studied extensively for their chemopreventive properties. The biological activity of retinoids is acquired through their conversion to retinoic acid (RA). Characterization of endogenous circulating RA concentrations after supplementation with vitamin A over longer time periods has not been done previously. Our investigation was conducted to determine whether vitamin A (retinyl palmitate) supplementation significantly increases circulating RA concentrations of all-trans-, 9-cis-, and 13-cis-RA. Using plasma samples from 41 participants enrolled in a randomized clinical trial of placebo, 25,000, 50,000, or 75,000 IU supplemental retinyl palmitate daily, high-performance liquid chromatography analyses were conducted for concentrations of three RA isomers. Seven plasma samples were analyzed for each participant over a 16-month period. Based on an intention-to-treat analysis, results obtained using linear mixed models showed that supplementation with retinyl palmitate statistically significantly increased concentrations of all three RA isomers from baseline levels. This study suggests that supplementation with retinyl palmitate is an effective means to increase circulating all-trans, 9-cis-, and 13-cis-RA concentrations among humans.

Topics: Aged; Anticarcinogenic Agents; Chromatography, High Pressure Liquid; Diterpenes; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Retinyl Esters; Skin Neoplasms; Stereoisomerism; Tretinoin; Vitamin A

The design of analogues of 7,8-dihydroretinoic acid (7,8-dihydro-RA) was based on reported biological activities of this retinoid and its dihydro-TMMP(1) analogue and on structural hypotheses. 7-Oxa-7,8-dihydroretinoids (5, 6) were prepared by O-alkylation of phenoxides by methyl 8-bromo-3,7-dimethyl-2,4,6-octatrienoate. In some cases, C-alkylation also occurred. 7-Aza-8-oxo-7,8-dihydroretinoids (12, 13) were synthesized from benzeneamines and the acyl cyano or bromo derivative of the monomethyl ester of 3,7-dimethyl-2,4,6-octatriene-1,8-dioic acid. These monomethyl ester precursors were synthesized from the known analogous aldehyde via an O-trimethylsilyl cyanohydrin. 7-(2,3,5-Trimethylphenoxy)-3,5-dimethyl-2,4,6-octatrienoic acid (6b) was the most active of the 7-oxa-7,8-dihydro-RAs in inhibiting DMBA-initiated and TPA-promoted mouse-skin papillomas. The ED(50) was about 4-fold that of etretinate. Two additional 7-oxa-7,8-dihydro-RAs exhibited modest activity in the papilloma assay. Some of the 7-oxa-7,8-dihydro-RAs bind to CRABP and RARalpha.

Topics: Animals; Anticarcinogenic Agents; Fatty Acids, Unsaturated; Mice; Papilloma; Protein Binding; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Skin Neoplasms

The construction of transgenic FVB/N mice targeting the PMLRARA fusion gene under the control of a human MRP8 promoter recapitulated the phenotype of acute promyelocytic leukemia but had the unexpected result of multiple squamous papillomas of the skin (Brown et al., PROC: Natl. Acad. Sci. USA, 94:2551-2556, 1997). In addition, transgenic MRP8-PMLRARA mice exhibited a skin phenotype characteristic of vitamin A deficiency. The severity of the skin phenotype and spontaneous papilloma development correlated with the level of transgene expression. Papilloma formation was preceded by follicular hyperplasia and the expression of epidermal differentiation markers in the follicular epithelium. Mutations in the Ha or Ki alleles of ras were not detected in papillomas that developed on transgenic skin, and papilloma formation was accentuated on the C57/Bl6 background, unlike the usual resistance of this strain to skin tumor induction. Analysis of liver extracts from transgenic mice indicated a deficiency in the production of retinoic acid. Furthermore, affected transgenic epidermis had reduced levels of retinoic acid receptoralpha (RARalpha) and retinoic X receptor (RXRalpha), and supplementation with exogenous retinoic acid prevented the skin phenotype. When transgenic keratinocytes were grafted to nude mice, the resulting integument was normal, and conversely, when transgenic bone marrow was grafted to normal mice, a skin phenotype did not develop. Together these results suggest that local interruption of PML and RARalpha signaling in the skin, together with a systemic retinoid deficiency, initiates a tumor induction pathway that is independent of ras activation.

Topics: Animals; Calgranulin A; Cell Differentiation; Diterpenes; Genes, ras; Genetic Predisposition to Disease; Hair Follicle; Humans; Liver; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neoplasm Proteins; Oncogene Proteins, Fusion; Papilloma; Promoter Regions, Genetic; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoid X Receptors; Retinoids; Retinyl Esters; Skin Neoplasms; Transcription Factors; Transgenes; Tretinoin; Vitamin A

Retinoids have been shown to inhibit the growth of squamous cell carcinoma and other malignancies. They have also been shown to alter gap junctional intercellular communication (GJIC) and the expression of connexins, the protein subunits of gap junctions. We report in this study that the alteration of GJIC by retinoids may be directly related to inhibitory effects on cell growth.. SCC-13 cells were treated with all-trans retinoic acid (tRA) and 13-cis retinoic acid (cRA) at 10(-7) and 10(-6) M concentrations in culture. No treatment and ethanol vehicle controls were included for each experiment. Serial cell counts of parallel cultures were performed to determine cell growth. The parachute technique was performed in combination with fluorescence activated cell sorting (FACS) analysis to determine GJIC. Northern and Western blot analysis were performed to assess connexin mRNA and protein expression.. The growth rate was inhibited for cells treated with tRA (10(-6) M) (P < 0.05) and cRA (10(-6) M) (P = 0.068) vs. vehicle control. GJIC was significantly inhibited with both tRA (10(-7) and 10(-6) M) (P < 0.001) and cRA (10(-7) and 10(-6) M) (P < 0.001) at 24, 48, and 96 h as determined by FACS analysis. To correlate GJIC with cell growth, we studied the effect of glycyrrhetinic acid, a known inhibitor of GJIC. Glycyrrhetinic acid also significantly inhibited cell growth (P < 0.05) vs. control. Connexin 26 and connexin 43 mRNA and protein expression were not significantly altered after retinoid treatment.. Retinoic acids inhibit both cell growth and GJIC in SCC-13 cells. Retinoids may inhibit cell growth through alteration of GJIC in SCC-13 cells.

Topics: Blotting, Northern; Blotting, Western; Carcinoma, Squamous Cell; Cell Communication; Cell Division; Connexin 26; Connexin 43; Connexins; Flow Cytometry; Gap Junctions; Glycyrrhizic Acid; Isotretinoin; Logistic Models; Retinoids; RNA, Messenger; Skin Neoplasms; Tretinoin; Tumor Cells, Cultured

Topics: Administration, Topical; Aged; Aged, 80 and over; Alitretinoin; Antineoplastic Agents; Female; Gels; Humans; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin

Topics: Alitretinoin; Antineoplastic Agents; Gels; Humans; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Skin Neoplasms; Tretinoin

Four human cutaneous squamous cell carcinoma (SCC) cell lines and normal human epidermal keratinocyte (NHEK) cells from two donors were examined for sensitivity to the synthetic retinoid 6-[3-(1 -adamantyl)-4-hydroxyphenyl]-2-naph-thalene carboxylic acid (CD437) alone or in combination with other agents. CD437 promoted rapid (within 2 h) apoptosis in SCC cells and G1 arrest in NHEK cells. G1 arrest in NHEK cells was sustained for 48 h while apoptosis occurred in approximately 60% of SCC cell after 24 h. Apoptosis could not be inhibited by nuclear retinoic acid receptor antagonists or cycloheximide, indicating CD437 was functioning in a receptor-independent manner. All-trans retinoic acid not only failed to induce apoptosis in SCC cells even at 20-fold higher concentration relative to the effective concentration of CD437; it also decreased the efficacy of CD437. Because of its differential effects on normal versus malignant keratinocytes, CD437 may be useful for the prevention or treatment of cutaneous SCC.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle; Cell Division; Cell Line; DNA Fragmentation; Epidermis; G1 Phase; Humans; Keratinocytes; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Reactive Oxygen Species; Reference Values; Retinoids; Skin Neoplasms; Time Factors; Tretinoin

Topics: Administration, Topical; Antineoplastic Agents; Carcinoma, Squamous Cell; Humans; Isotretinoin; Organ Transplantation; Skin Neoplasms; Tretinoin

Retinoids are a fascinating class of compounds that exert control over cellular function from the time of conception to death. They play a critical role in such vital processes as fetal morphogenesis, cellular differentiation and apoptosis. Over the years synthetic retinoids have provided dermatologists with a spectrum of medications that have profound therapeutic effects on a variety of recalcitrant skin disorders. Moreover, retinoids are an expanding component of the treatment arsenal against hematologic and solid malignancies. Retinoids are poised to offer exciting new therapeutic options in the field of endocrinology for the treatment of diabetes and lipid disorders. Researchers and clinicians are only beginning to unveil the therapeutic potential of this class of medications. The development of new retinoid compounds targeting specific receptors promises a wealth of new therapies for the new millennium.

Topics: Acne Vulgaris; Humans; Keratosis; Leukemia, Promyelocytic, Acute; Lymphoma, T-Cell, Cutaneous; Psoriasis; Skin Neoplasms; Treatment Outcome; Tretinoin; Vitamin A

Retinoids are essential for normal epidermal differentiation and are used for the prevention and treatment of numerous skin disorders and cancers in humans. In previous studies, we have shown that retinoic acid receptors (RARs) -alpha and -gamma are down-regulated during skin tumor progression. The transduction of v-ras(Ha) into primary mouse keratinocytes is sufficient to reduce both RARalpha and RARgamma protein levels as well as inhibit their transactivation functions. Our primary objective is to investigate the roles that RARalpha and RARgamma play in keratinocyte tumor cell proliferation. Through retroviral gene transduction, we overexpressed RARalpha or RARgamma into neoplastic mouse epidermal cells with down-regulated endogenous RAR proteins. Following all-trans retinoic acid (RA) treatment, RARalpha- and RARgamma-transduced cell lines exhibit a progressive, dose-dependent growth inhibition relative to the control LXSN cell lines. Further characterization of RAR-transduced cells following RA treatment reveals that both RARalpha and RARgamma cause a decrease in S-phase population, while only RARalpha causes a simultaneous G(0)/G(1) block as evidenced by reduced [(3)H]-thymidine incorporation and flow cytometric analysis of DNA content. Following RA treatment, both receptors cause an early, transient increase in the cyclin-dependent kinase inhibitor (CDKI) p21 proteins, while only RARalpha causes a simultaneous sharp, brief increase in the CDKI p16 protein. A later decrease in cyclin D(1) protein is also evident in RARalpha- and RARgamma-transduced cells. Chromatin condensation and PARP cleavage are observed in both RARalpha- and RARgamma-transduced cells indicating an RA-induced apoptosis that may be caspase dependent. Furthermore, both receptors cause a late upregulation and apparent cleavage of the squamous differentiation marker protein kinase C (PKC)-eta. These results suggest that RARalpha and RARgamma enhance growth suppression and apoptosis of neoplastic epidermal keratinocytes. This growth inhibitory effect of both retinoid receptors in neoplastic keratinocytes may be achieved through distinct as well as overlapping mechanisms of cell cycle control.

Topics: Animals; Apoptosis; Cell Differentiation; Cell Division; Cell Line, Transformed; Cell Size; Electrophoretic Mobility Shift Assay; Epidermal Cells; Epidermis; Keratinocytes; Mice; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Skin Neoplasms; Transduction, Genetic; Tretinoin; Tumor Cells, Cultured

Studies into the effects of topical retinoic acid on photocarcinogenesis have yielded ambiguous findings. This may be due to different Experimental protocols and ultraviolet spectra. Retinoic acid is commonly used for a range of dermatologic conditions, and therefore it is important to resolve whether it affects skin tumor formation. To address this issue we used a protocol to mimic as closely as possible human use of retinoic acid. Two mouse strains were used: Skh:HR-1 (albino) and Skh:HR-2 (lightly pigmented). The pigmented mice more closely resemble Caucasian skin as they develop a light tan in response to ultraviolet radiation. This tan is greatly augmented by retinoic acid. As these are congenic mice, any differences can be attributed to the development of a tan. Mice were exposed to solar-simulated ultraviolet radiation, followed by treatment with 0.05% retinoic acid. This modeled exposure to sunlight during the day followed by retinoic acid treatment and a night-time period in the absence of sunlight. As it is recommended that ultraviolet exposure is minimized when using topical retinoic acid, the mice were only exposed to one-third of minimal edemal dose of ultraviolet radiation per day. This retinoic acid protocol augmented photocarcinogenesis. Retinoic acid decreased the latency period, reduced the probability that a mouse would survive without a tumor, and increased the number of tumors per mouse. All tumors induced were squamous cell carcinomas, and the skin between the tumors on mice treated with retinoic acid was found to contain carcinoma in situ upon histologic diagnosis. The light tan of the solvent-treated pigmented mice did not provide any protection, whereas the dark tan, which developed in Skh:HR-2 mice in response to retinoic acid, reduced photocarcinogenesis but did not overcome the augmenting effect of retinoic acid. Thus, using this experimental design, topical retinoic acid augmented photocarcinogenesis, and the ability to develop a dark but not light tan provided some, but limited, protection.

Topics: Administration, Topical; Animals; Carcinoma, Squamous Cell; Female; Melanins; Melanoma; Mice; Pigmentation; Skin Neoplasms; Sunlight; Tretinoin; Ultraviolet Rays

We recently demonstrated that the constitutive expression of cyclooxygenase (COX)-2 protein and prostaglandin E(2) (PGE(2)) biosynthesis were significantly enhanced in human skin epidermal cancer cells and that cancer cell growth was effectively inhibited by the suppression of COX-2 expression by transfection with COX-2 antisense oligonucleotide. The purpose of this study was to search for agents which suppress COX-2 expression and examine their effects on cell growth. Since retinoids and antioxidants have been used for chemoprevention of cancers in several tissues, the effects of these agents on COX-2 expression and PGE(2) biosynthesis in skin squamous carcinoma cells were investigated. Treatment with a retinoid (9-cis-retinoic acid (9-cis-RA)) or an antioxidant (pyrrolidinedithiocarbamate (PDTC)) suppressed COX-2 expression and PGE(2) biosynthesis in a concentration-dependent manner. Cell growth was significantly inhibited by 9-cis-RA and PDTC. These results suggest that 9-cis-RA and PDTC may be useful in preventing skin cancer growth and that COX-2 is involved in their protective effects on skin carcinogenesis.

Topics: Acetylcysteine; Alitretinoin; Antineoplastic Agents; Antioxidants; Blotting, Western; Carcinoma, Squamous Cell; Cell Division; Cell Line; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Free Radical Scavengers; Humans; Isoenzymes; Keratinocytes; Membrane Proteins; Oligonucleotides, Antisense; Prostaglandin-Endoperoxide Synthases; Pyrrolidines; Retinoids; Skin Neoplasms; Thiocarbamates; Time Factors; Transfection; Tretinoin; Tumor Cells, Cultured

Confluent and reticulate papillomatosis (CRP) of Gougerot and Carteaud is a rare cutaneous disorder characterized by persistent, usually asymptomatic, dark papules and plaques centrally located on the back, intermammary, and epigastric areas. The eruption spreads out peripherally into a fading reticulated pattern. The pathogenesis is poorly understood, but there are several theories. Many different treatments, with varying success rates, have been attempted. We present 3 patients with CRP who had excellent results in the areas treated with topical tretinoin. The only difficulty with therapy is applying the tretinoin to the back, which sometimes necessitates a second person. However, if this situation can be overcome, topical tretinoin provides an effective, safe alternative to systemic therapies. Response to tretinoin provides support that CRP is a disorder of keratinization. Finally, the fact that 2 of the patients were brothers may support the idea that CRP has a hereditary influence.

Topics: Administration, Topical; Adolescent; Adult; Antineoplastic Agents; Humans; Male; Papilloma; Skin Neoplasms; Tretinoin

Topics: Administration, Cutaneous; AIDS-Related Opportunistic Infections; Alitretinoin; Anti-HIV Agents; Dermatologic Agents; Drug Administration Schedule; Humans; Sarcoma, Kaposi; Skin Neoplasms; Treatment Outcome; Tretinoin

Interferon regulatory factor 1 (IRF-1) transcription factor binds to DNA sequence elements found in the promoters of type I IFN and IFN-inducible genes. Transient up-regulation of the IRF-1 gene by virus and IFN treatment causes the consequent induction of many IFN-inducible genes involved in cell growth control and apoptosis. We reported recently that IFN-alpha and all-trans retinoic Acid (RA) inhibit the cell proliferation of squamous carcinoma cell line ME-180 by inducing apoptotic cell death. IRF-1 expression correlates with the IFN-alpha-induced apoptosis phenomenon and, surprisingly, with the RA-induced apoptosis phenomenon. To study how these two different ligands cross-talk in the regulation of cellular antitumor responses, the signalling pathways involved in IRF-1 induction were analyzed in RA and/or IFN-alpha-treated ME-180 cells. We provide evidence indicating that RA-induced IRF-1 gene expression is independent of the STAT-1 activation pathway, despite the presence of the IFN-gamma activated sequence element in the gene promoter, but involves nuclear factor-kappaB activation. Thus, here we first describe the activation of nuclear factor-kappaB by both IFN-alpha and RA in the ME-180 cell line. The induced IRF-1 protein is successively able to bind the IFN-stimulated responsive element in the promoter of the target gene 2',5'-oligoadenylate synthetase.

Topics: Carcinoma, Squamous Cell; Dactinomycin; DNA Primers; DNA-Binding Proteins; Electrophoresis, Polyacrylamide Gel; Gene Expression Regulation; Humans; Immunoblotting; Interferon alpha-2; Interferon Regulatory Factor-1; Interferon-alpha; NF-kappa B; Phosphoproteins; Protein Synthesis Inhibitors; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Skin Neoplasms; STAT1 Transcription Factor; Time Factors; Trans-Activators; Transfection; Tretinoin; Tumor Cells, Cultured

Topics: Child; Humans; Laser Therapy; Male; Porokeratosis; Precancerous Conditions; Skin; Skin Diseases; Skin Neoplasms; Tretinoin

We have measured the levels of thioredoxin, thioredoxin reductase and glutaredoxin enzyme activity in mouse skin following topical application of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C (PKC) activator and tumor promoter. The specific activity of thioredoxin and thioredoxin reductase in extracts from normal epidermis increased by 40 and 50%, respectively, after single or multiple application of TPA. Multiple applications (twice per week for 2 weeks) of TPA increased glutaredoxin activity by >300%. Induction of the proteins lasted several days. Other PKC activators, like 12-O-retinoylphorbol 13-acetate, mezerein, 1-oleoyl-2-acetylglycerol and the calcium ionophore A23187, also induced all the enzyme activities. Phorbol and 4-O-methyl-12-O-tetradecanoylphorbol-13-acetate, weak activators of PKC, selectively induced the thioredoxin system only and did not influence glutaredoxin activity. Multiple applications of TPA to tumor initiated (7,12-dimethyl[a]benzanthracene-treated) skin resulted in elevated levels of both the thioredoxin and glutaredoxin systems when examined 6 days after the last phorbol ester treatment. Induction of thioredoxin, thioredoxin reductase and glutaredoxin activities by TPA and calcium ionophores may play a general role in the epigenetic mechanism of tumor promotion via thiol redox control mechanisms.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Calcimycin; Calcium; Carcinogens; Cocarcinogenesis; Diglycerides; Diterpenes; Enzyme Activation; Enzyme Induction; Epidermis; Female; Fluocinolone Acetonide; Gene Expression Regulation; Glutaredoxins; Glutathione; Ionophores; Mice; Oxidation-Reduction; Oxidoreductases; Phorbol Esters; Protein Kinase C; Proteins; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Thioredoxin-Disulfide Reductase; Thioredoxins; Tosylphenylalanyl Chloromethyl Ketone; Tretinoin

Topics: Aged; Antineoplastic Agents; Facial Neoplasms; Hemangiosarcoma; Humans; Interferon alpha-2; Interferon-alpha; Male; Neoplasm Recurrence, Local; Recombinant Proteins; Skin Neoplasms; Treatment Outcome; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Skin Neoplasms; Tretinoin

We recently synthesized several conformationally constrained retinoic acid (RA) analogues [8-(2'-cyclohexen-1'-ylidene)-3, 7-dimethyl-2,4,6-octatrienoic acids with different alkyl substituents at 2' (R1) and 3' (R2) positions on the cyclohexene ring] (Muccio et al. J. Med. Chem. 1996, 39, 3625) as cancer chemopreventive agents. UAB8 (R1 = Et; R2 = iPr), which contains sufficient steric bulk at the terminal end of the polyene chain to mimic the trimethylcyclohexenyl ring of RA, displayed biological properties similar to those of RA. To explore the efficacy of this retinoid in acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML), we evaluated UAB8 isomers in in vitro assays which measure the capacity of retinoids to inhibit aberrant myeloid colony growth from blood or bone marrow cells obtained from human JMML patients and in assays measuring the potential of retinoids to differentiate NB4 cells (an APL cell line). Both (all-E)- and (13Z)-UAB8 were 2-fold more active than RA in the NB4 cell differentiation assay; however, only (all-E)-UAB8 had comparable activity to the natural retinoids in the JMML cell assays. These results were compared to the biological effectiveness of a new retinoid, UAB30 [8-(3', 4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4, 6-octatrienoic acid], which had different nuclear receptor binding and transactivational properties than UAB8. Relative to (all-E)-RA and (all-E)-UAB8, (all-E)-UAB30 bound well to RARalpha but did not activate transcription-mediated RARalpha homodimers, even though it was effective in RARbeta- and RARgamma-mediated transactivational assays. In APL assays, this retinoid had much reduced activity and was only moderately effective in JMML assays and in cancer chemoprevention assays.

Topics: Animals; Antineoplastic Agents; Cell Line; Chickens; Child; Fatty Acids, Unsaturated; HL-60 Cells; Humans; In Vitro Techniques; Leukemia, Myelomonocytic, Chronic; Leukemia, Promyelocytic, Acute; Mice; Molecular Conformation; Naphthalenes; Papilloma; Radioligand Assay; Receptors, Retinoic Acid; Skin; Skin Neoplasms; Stereoisomerism; Transcription, Genetic; Tretinoin; Tumor Stem Cell Assay

Retinoids, metabolites and synthetic derivatives of vitamin A (retinol), have been shown to inhibit carcinogenesis in various epithelial tissues in animal model systems and to have clinical efficacy as chemotherapeutic agents against certain types of cancer, including squamous cell carcinomas (SCCs). We examined the metabolism of [3H]retinol in normal human cell strains and SCC lines from the oral cavity and skin, and we report here that the cultured normal human epithelial cell strains esterified [3H]retinol to a much greater extent than the SCC lines. Furthermore, microsomal extracts of normal cell strains (e.g., OKF4) exhibited about 7-fold more palmityl-CoA-dependent, phenylmethylsulfonyl fluoride-resistant retinol esterification activity than extracts from SCC lines (e.g., SCC25). The fact that the esteriflcation of retinol was phenylmethylsulfonyl fluoride resistant suggests that the enzyme acyl-CoA:retinol acyltransferase is involved. Culture of both the normal and SCC lines in the presence of 1 microM all-trans-retinoic acid (RA) for 48 h enhanced the formation of [3H]retinyl esters from [3H]retinol. All of the cell lines examined can also metabolize [3H]retinol to [3H]RA, [3H]14-hydroxy-4,14-retroretinol, [3H]retinaldehyde, and [3H]3,4-didehydroretinol, but this metabolism occurs to varying extents in different cell lines. Culture of the cells in the presence of RA for 48 h did not affect the subsequent metabolism of [3H]retinol to [3H]RA and [3H]14-hydroxy-4,14-retroretinol, but it did reduce the metabolism of [3H]retinol to [3H]3,4-didehydroretinol. When cultured for 6-10 h in the presence of nanomolar concentrations of exogenous [3H]retinol, both the normal and SCC lines had much higher intracellular [3H]retinol concentrations, in the micromolar range. No correlation was seen between CRABP II or CRBP I mRNA levels and the levels of either intracellular [3H]retinol or [3H]retinol metabolism in these lines. The reduced ability to esterify retinol in these tumor cells may result in inappropriate cell growth and the loss of normal differentiation responses because of the lack of a sufficient amount of internal retinol stored as retinyl esters.

Topics: Carcinoma, Squamous Cell; Humans; Mouth Neoplasms; Skin Neoplasms; Tretinoin; Tumor Cells, Cultured

Retinoic acid (RA) was topically applied to the skin of Sencar mice during the promotion phase of specific tumor induction protocols that produce papillomas at low (12-O-tetradecanoylphorbol-13-acetate promoted, TPA) or high (mezerein-promoted) risk for premalignant progression and malignant conversion. RA consistently reduced the yield of papillomas and carcinomas in both protocols, but the frequency of malignant conversion in papillomas that emerged during RA treatment was not reduced. When TPA was reapplied after cessation of RA treatment, the number of papillomas increased 2-fold, suggesting that RA had not eliminated initiated cells. In vitro, RA prevented the emergence of transformed keratinocytes in an assay that mimics malignant conversion, suggesting that RA can suppress conversion if applied during the stage of premalignant progression. Examination of tumor markers at weeks 14 and 22 of the tumor-induction experiments in vivo indicated that papillomas evolving during RA treatment exhibited a phenotype of high progression risk, even in the TPA-promoted groups. In the majority of these tumors, the alpha6beta4 integrin and retinoid X receptor alpha transcripts were detected suprabasally, indicating an advanced state of premalignant progression. RA-treated tumors also expressed higher levels of transcripts for transforming growth factor (TGF)-beta1 and localized TGF-beta1 peptide in the basal portions of the tumor fronds. Because up-regulated expression of TGF-beta1 suppresses papilloma formation, these studies suggest a mechanism whereby RA can prevent papilloma eruption via a TGF-beta intermediate, but papillomas resistant to RA may have altered TGF-beta signaling and progress to carcinomas at an increased frequency.

Topics: Administration, Topical; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Biomarkers, Tumor; Carcinogens; Carcinoma, Basal Cell; Cell Transformation, Neoplastic; Disease Progression; Diterpenes; Female; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Inbred SENCAR; Papilloma; Phenotype; Precancerous Conditions; Receptors, Retinoic Acid; Retinoid X Receptors; Risk Factors; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Transcription Factors; Transforming Growth Factor beta; Tretinoin

More than 100 years has passed since the first report of a nevus comedonicus. The earliest reports emphasized the inflammatory aspect of the nevus comedonicus as being the most significant problem. In the past 30 years, publications have ignored the inflammatory aspect of nevus comedonicus while emphasizing a variety of associated malformations. In this review, we describe five prepubertal children with prominent and persistent inflammatory changes limited to areas within a nevus comedonicus. In our experience, inflammation can be severe and resistant to treatment. Ultimately, surgical removal of the involved skin was required in two children.

Topics: Acne Vulgaris; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Antineoplastic Agents; Cheek; Child; Child, Preschool; Drug Therapy, Combination; Facial Neoplasms; Female; Humans; Infant; Male; Nevus; Shoulder; Skin Neoplasms; Thoracic Neoplasms; Tretinoin

Topics: Antimetabolites, Antineoplastic; Drug Therapy, Combination; Etretinate; Fluorouracil; Humans; Keratolytic Agents; Keratosis; Masoprocol; Neoplasms, Radiation-Induced; Retinoids; Skin Neoplasms; Tretinoin

Topics: Animals; Antineoplastic Agents; Apoptosis; Clinical Trials, Phase III as Topic; Humans; Isotretinoin; Keratolytic Agents; Neoplasms; Neoplasms, Experimental; Receptors, Retinoic Acid; Retinoids; Skin; Skin Neoplasms; Tretinoin

Extramedullary involvement is only occasionally observed in patients with acute promyelocytic leukemia (APL) but has been said to occur more frequently after treatment with all- trans retinoic acid (ATRA) than after treatment with cytotoxic drugs. In the literature, 37 well-documented cases have been reported.. The authors report 7 patients with extramedullary APL documented by cytologic, phenotypic, and molecular analyses among 120 adult APL patients referred to two different institutions during a period of 9 years.. In this APL series, extramedullary disease (EMD) occurred in 7 of 120 cases (5.8%). The extramedullary sites were the skin in five patients, the central nervous system in one, and the lymph nodes in one. Molecular analysis of the PML/RARalpha rearrangement was performed on four samples of skin and one of CSF; all patients exhibited the same molecular pattern in the bone marrow (BM) and EMD sites. Of 120 patients, 61 were treated with ATRA plus chemotherapy and 59 with chemotherapy alone. Relapses were observed in 38 patients, 6 of whom had EMD; 1 patient had developed EMD at the onset of APL. Of the relapsed EMD cases, 2 of 61 patients had received ATRA plus chemotherapy and 4 of 59 had received chemotherapy alone.. There is some controversy as to whether treatment of APL with ATRA may predispose patients to the development of extramedullary relapse. The data from this study do not contain evidence that EMD may occur more frequently in APL patients treated with ATRA.

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Brain Neoplasms; Cytarabine; Daunorubicin; Disease Progression; Fatal Outcome; Female; Gene Amplification; Gene Rearrangement; Humans; Idarubicin; Immunophenotyping; Leukemia, Promyelocytic, Acute; Lymph Nodes; Male; Middle Aged; Neoplasm Recurrence, Local; Polymerase Chain Reaction; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Skin Neoplasms; Translocation, Genetic; Tretinoin

Retinoic acid is one of the most promising drugs for chemotherapy and chemoprevention of cancer. Either blocking activator protein-1 (AP-1) activity or activating retinoic acid response element (RARE) have been proposed to be responsible for its antitumor activity. However, evidence for this hypothesis is lacking in vivo studies. To address this issue, we used an AP-1-luciferase transgenic mouse as a carcinogenesis model and new synthetic retinoids that are either selective inhibitors of AP-1 activation or selective activators of the RARE. The results showed that the SR11302, an AP-1 inhibition-specific retinoid, and other AP-1 inhibitors such as trans-retinoic acid and fluocinolone acetonide, markedly inhibit both 12-O-tetradecanoylphorbol-13-acetate-induced papilloma formation and AP-1 activation in 7,12-dimethyl benz(a)anthracene-initiated mouse skin (P < 0.05). In contrast, repeated applications of SR11235, a retinoid with RARE transactivating activity, but devoid of AP-1 inhibiting effect, did not cause significant inhibition of papilloma formation and AP-1 activation (P > 0.05). These results provide the first in vivo evidence that the antitumor effect of retinoids is mediated by blocking AP-1 activity, but not by activation of RARE.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Carcinogens; Female; Fluocinolone Acetonide; Luciferases; Male; Mice; Mice, Transgenic; Papilloma; Recombinant Fusion Proteins; Regulatory Sequences, Nucleic Acid; Retinoids; Skin Neoplasms; Tetradecanoylphorbol Acetate; Transcription Factor AP-1; Transcriptional Activation; Tretinoin

The hyaluronan-rich matrix that surrounds many tumours and facilitates tumour cell growth and invasion is thought to be predominantly synthesized by normal stromal cells stimulated by tumour cell-derived factors. This study examines the possibility that the production of tumour cell-derived factors that stimulate fibroblast glycosaminoglycan (GAG) synthesis may be blocked by exposure to differentiation-inducing agents such as retinoic acid. We have demonstrated that Hs294T, C8161 and A375 human melanoma cell lines release factors into their medium that stimulate normal fibroblast GAG synthesis. Exposure of these melanoma cells to retinoic acid failed to mediate any significant reduction in growth over a 7-day period. Retinoic acid failed to block the tumour cell production of GAG-stimulating activities and even enhanced the activities produced by the C8161 cell line, particularly at low retinoic acid concentrations (48% stimulation at 10(-9) M retinoic acid; P < 0.02). Addition of retinoic acid directly to fibroblast cultures exposed to fibroblast-conditioned medium resulted in an inhibition of GAG synthesis with a 33% inhibition observed at 10(-5) M. Addition of retinoic acid to fibroblast cultures exposed to the tumour cell-conditioned medium failed to inhibit the stimulation of GAG synthesis. Other differentiation-inducing agents, such as hexamethylene-bis-acetamide and butyrate, also failed to block the production of tumour cell-derived GAG-stimulating activities. These results demonstrate that retinoic acid and other differentiation-inducing agents fail to inhibit melanoma cell production of fibroblast GAG synthesis-stimulating factors or their action upon fibroblasts.

Topics: Acetamides; Adult; Antineoplastic Agents; Butyrates; Butyric Acid; Cell Count; Cell Differentiation; Cells, Cultured; Culture Media, Conditioned; Female; Fibroblasts; Glycosaminoglycans; Humans; Male; Melanoma; Middle Aged; Skin Neoplasms; Tretinoin

The retinoic acid (RA) signaling pathway was investigated by transient transfection of a chloramphenicol acetyltransferase (CAT) reporter gene construct containing the RA response element (RARE) of the murine (m) RARbeta2 gene into murine primary epidermal keratinocytes (PEK), papilloma-derived SP1 cells, and carcinoma-derived 3P2 cells. Murine PEK transfected in a low-Ca2+ medium (0.05 mM Ca2+) exhibited a strong transactivation of the CATgene after exposure of the cells to 0.1 microM RA. Transactivation of the CATgene could, however, also be achieved by shifting RAREbeta2-transfected low-Ca2+ PEK to high-Ca2+ conditions (0.15-1.2 mM Ca2+). Concomitantly, the Ca2+ raise also led to the induction of both cellular retinol (ROL)-binding protein I (CRBPI) and cellular RA-binding protein II (CRABPII), whereas expression of cellular RA-binding protein I (CRABPI) was not observed. Moreover, induction of in vitro differentiation also activated the ROL-->RA converting enzyme system in PEK. These findings suggest the following sequence of events involved in the high Ca2+-mediated activation of RAREbeta2. First, high Ca2+ induces the synthesis of mCRBPI, which binds ROL released from retinyl ester stores and makes it accessible to the ROL-RA converting enzyme system. Enzymatically generated RA is taken over by mCRABPII and transported to the nucleus, where it acts as ligand for nuclear receptors, which complex with RAREbeta2 to activate the reporter gene. This hypothetical cascade of RA signaling was supported by our findings that inhibition of the ROL-->RA converting enzyme system by citral abolished the Ca2+-mediated transactivation of the CAT gene in a nontoxic manner. Studies in transformed murine cell lines revealed that Ca2+-induced activation of RAREbeta2 was essentially maintained in papilloma-derived SP1 cells, although all parameters of the Ca2+-dependent RAREbeta2 activation cascade were induced to a much lower extent. In contrast, strong RAREbeta2 activity was already observed in low-Ca2+ carcinoma-derived 3P2 cells. Low-Ca2+ 3P2 cells also expressed high levels of both mCRBPI and mCRABPII and possessed a highly active ROL-->RA converting enzyme system. Again, inhibition of the enzyme by citral abolished RAREbeta2 activity in low-Ca2+ 3P2 cells. Our data show that Ca2+-induced differentiation in cultured murine PEK entails a series of events that ultimately lead to the activation of RARE-containing genes. These properties are maintained in transformed e

Topics: Animals; Calcium; Carcinoma; Cell Differentiation; Chloramphenicol O-Acetyltransferase; Genes, Reporter; Keratinocytes; Mice; Mice, Inbred Strains; Papilloma; Receptors, Retinoic Acid; Signal Transduction; Skin; Skin Neoplasms; Skin Physiological Phenomena; Transcriptional Activation; Transfection; Tretinoin; Vitamin A

We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med. Chem. 1994, 37, 4499-4507) and selective agonists for nuclear receptor binding and activation (Alam et al. J. Med. Chem. 1995, 38, 2302-2310). In order to probe important structure-activity relationships, we evaluated a homologous series of four 6-s-trans-retinoids that are 8-(2'-cyclohexen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acids with different substituents at 2' (R2) and 3' (R1) positions on the cyclohexene ring. UAB1 (R1 = R2 = H), UAB4 (R1 = R2 = Me), UAB7 (R1 = Me, R2 = iPr), and UAB8 (R1 = Et, R2 = iPr) contain alkyl R groups that mimic, to different extents, portions of the trimethylcyclohexenyl ring of RA. Both 9Z- and all-E-isomers of these retinoids were evaluated in binding assays for cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), a nuclear retinoic acid receptor (RAR alpha), and a nuclear retinoid X receptor (RXR alpha). The all-E-isomers of UAB retinoids bound tightly to CRABPs and RAR alpha, the binding affinity of the all-E-isomer increased systematically from UAB1 to UAB8, and binding for the latter was comparable to that of all-E-RA. In contrast to RA, the (9Z)-UAB retinoids were at least 200-fold less active than the all-E-isomers in binding to RAR alpha. The (9Z)-UAB isomers exhibited increasingly stronger binding to RXR alpha, and (9Z)-UAB8 was nearly as effective as (9Z)-RA in binding affinity. The retinoids were also evaluated in gene expression assays mediated by RAR alpha and RXR alpha homodimers or RAR alpha/RXR alpha heterodimers. Consistent with the binding affinities, the (all-E)-UAB retinoids activated gene transciption mediated by RAR alpha homodimers or RAR alpha/RXR alpha heterodimers, while the (9Z)-UAB isomers activated only the RXR alpha homodimer-mediated transcription. The all-E- and 9Z-isomers of the UAB retinoids were further evaluated for their capacity to prevent the induction of mouse skin papillomas. When compared to RA, only the (all-E)-UAB retinoids containing bulky R1 and R2 groups were effective in this chemoprevention assay. (9Z)-RA displayed equal capacity as RA to prevent papillomas, while the 9Z-isomers of the UAB retinoids were much less effective. Taken together, these studies demonstrate that the cyclohexenyl ring substituents of 6-s-trans-UAB retinoids are important for their biological activities and that the ch

Topics: Animals; Anticarcinogenic Agents; Cell Nucleus; Mice; Models, Molecular; Molecular Conformation; Molecular Structure; Papilloma; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Skin Neoplasms; Stereoisomerism; Structure-Activity Relationship; Thermodynamics; Transcription Factors; Transcription, Genetic

A 30-year-old woman with acute promyelocytic leukaemia (APL) went into complete remission following idarubicin and cytarabine chemotherapy; 18 months later she developed repeated skin relapse, with no bone marrow involvement. DNA and RNA analysis of skin lesions revealed the presence of the PML/RAR alpha hybrid gene, which was not detected at the same time in bone marrow. The skin relapses were successfully treated by all-trans-retinoic acid (ATRA) as single agent over 2 years. However, prolonged administration of ATRA caused pseudotumour cerebri, which disappeared upon drug withdrawal. The absence of the hybrid gene in the bone marrow by RT-PCR analysis led to the patient being autografted.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Base Sequence; Blotting, Southern; Cytarabine; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Molecular Sequence Data; Polymerase Chain Reaction; Pseudotumor Cerebri; Skin Neoplasms; Tretinoin

Topics: Adolescent; Adult; Female; Humans; Hypersensitivity, Immediate; Male; Papilloma; Skin Neoplasms; Tretinoin; Urea

In the two-stage protocol of skin carcinogenesis, the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) is applied to the skin of mice at around seven weeks of age. We previously performed DMBA initiation at three weeks of age to study the effect of pharmacological (30 micrograms/g diet) dietary retinoic acid (RA) on skin carcinogenesis. In this study we asked whether dietary pharmacological RA is equally effective against skin carcinogenesis when mice are initiated with (DMBA) at 7 weeks of age and then subjected to weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) or mezerein (MEZ) for 20 weeks. Similar to the three-week initiation protocol, high dietary RA inhibited papilloma incidence and yield in MEZ- but not in TPA-promoted female SENCAR mice. In addition, carcinoma incidence and yield were decreased by high dietary RA in TPA- as well as MEZ-treated mice. These data demonstrate that the high dietary RA diet is as effective in inhibiting papilloma and carcinoma formation when the DMBA is applied at seven weeks of age as at three weeks.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Aging; Animals; Antineoplastic Agents; Carcinogens; Diet; Diterpenes; Female; Mice; Papilloma; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Tretinoin

(2E, 4E, 6E)-8-[3'-Ethyl-2'-(1-methylethyl)-2'-cyclohexen-1'-ylidene] -3, 7-dimethyl-2,4,6-octatrienoic acid (UAB-8) has potent activity in preventing papillomas on the skin of mice similar to that determined in a previous study for the homolog containing one less carbon atom. To evaluate the toxicological profile for UAB-8, relative to all-trans-retinoic acid (RA), female mice were dosed by oral gavage for 29 days with amounts of 0.05, 0.1, or 0.2 mmol/kg/day. For the two compounds, the effects on body weights were similar. Mice dosed with UAB-8, however, had a lower incidence of clinical signs of toxicity (alopecia, scaly skin, and limping). At necropsy, bone fractures, skin abnormalities, and splenomegaly were observed in some mice dosed with RA but not in any dosed with UAB-8. Lymph node hyperplasia was noted in some mice dosed with either dose of RA but only in those dosed with the highest dose of UAB-8. All dose levels of RA produced microscopic lesions in the bones of mice; only the highest dose of UAB-8 had this effect. RA and UAB-8 had similar effects on chondrogenesis in cultures of cells from mouse limb buds, an indication of comparable teratogenic effects. For mice dosed i.v. (10 mg/kg), there was a saturated phase of elimination of RA from plasma (Km = 0.61 microgram/ml and Vmax = 2572 micrograms/hr); no such phase was noted when UAB-8 was administered. UAB-8 had values for t1/2 alpha and t1/2 beta of 0.47 and 17.1 hr, respectively. Relative to RA, UAB-8 has a favorable toxicological profile and different pharmacokinetics.

Topics: Animals; Body Weight; Calcification, Physiologic; Erythrocyte Count; Female; Hematocrit; Hemoglobins; Keratolytic Agents; Limb Buds; Lymph Nodes; Mice; Papilloma; Skin; Skin Neoplasms; Tretinoin

Using mouse skin papilloma as a model system, we examined whether the antitumorigenic activity of carotenoids was related to their provitamin A activity. Oral administration of canthaxanthin (CX) or beta-carotene at 200 mg/kg/day for 14 days significantly reduced the cumulative size of papillomas induced on the skin by 9,10-dimethyl-1,2-benzanthracene (p < 0.05), after the accumulation of these carotenoids in the tumors. The levels of a protooncogene, c-myc, were simultaneously suppressed in papillomas in carotenoid-treated mice. Because CX cannot be converted metabolically to retinoids, these results suggested that CX directly inhibited the growth of papillomas. Neither the accumulation of retinoids nor the expression of a retinoic acid-inducible gene, retinoic acid receptor-beta, was found in papillomas of CX- and beta-carotene-treated mice, suggesting that, like CX, beta-carotene might exert the tumor-suppressing effect without being converted to retinoids. Thus a certain antitumorigenic activity of carotenoids appears not necessarily to require their provitamin A activity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Canthaxanthin; Female; Gene Expression; Mice; Papilloma; Proto-Oncogene Proteins c-myc; Receptors, Retinoic Acid; RNA, Messenger; Skin Neoplasms; Tretinoin

Many studies have shown that all trans retinoic acid (RA) exhibits significant protective effects against mouse skin tumor promotion and spontaneous as well as enhanced malignant conversion. In a recently completed study, we showed that under treatments in which papillomas on SENCAR mouse skin are induced at low and high probabilities to convert to malignant carcinomas, RA affords significant protection against both tumor promotion and subsequent malignant conversion. More than 95% of these mouse skin papillomas and carcinomas have been shown to contain point mutation at the 61 codon of Ha-ras oncogene. The ras oncogene encodes a p21 protein that, in its mutated form, transforms mammalian cells only when p21 is at the inner surface of the plasma membrane, by a series of enzymatic reactions in which the initial step is catalyzed by farnesyltransferase (FTase). In this study, we assessed whether the protective effect of RA against malignant conversion involves the inhibition of ras p21 processing in those tumors that contain the activated ras oncogene. The FTase activity and the levels of cytosolic and membrane-bound Ha-ras p21 were determined in all papillomas and carcinomas obtained from acetone- or RA-treated animals. No matter how the data were analyzed and what comparisons were considered, in all the protocols used, compared with controls, papillomas and carcinomas obtained from RA-treated groups showed significantly decreased (P < 0.01-0.001) FTase activity. Furthermore, the tissue samples from RA-treated groups in different protocols also showed significantly diminished membrane localization of Ha-ras p21, with a concomitant increase in cytosolic Ha-ras p21 levels. The analysis of these data also showed that in all the protocols used, the increased FTase activity and membrane localization of Ha-ras p21 were associated with the induction of papillomas and their subsequent malignant conversion to squamous cell carcinomas. Taken together, these results indicate a strong correlation between the inhibition of ras p21 farnesylation because of a decrease in FTase activity by RA and its protective effect against malignant conversion of papillomas to carcinomas. Based on the results of this study, it is tempting to suggest that clinical trials evaluating the preventive or therapeutic potential of retinoids may be directed more toward those clinical malignancies that are known to contain the activated ras oncogene.

Topics: Alkyl and Aryl Transferases; Animals; Carcinoma; Cell Compartmentation; Cell Membrane; Cell Transformation, Neoplastic; Cytosol; Diterpenes; Enzyme Inhibitors; Mice; Papilloma; Proto-Oncogene Proteins p21(ras); Skin; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Transferases; Tretinoin

The role of retinoids in hairless mouse photocarcinogenesis has been studied extensively but remains controversial. By contrast, the role of corticosteroids has hardly been investigated. Many findings indicate an antagonism between the action of these two drugs. To examine these issues, we irradiated hairless mice thrice weekly for 10 weeks with 1.5 minimal erythema doses of solar simulating radiation (UVB + UVA). In the post-UV period, groups of mice were treated topically for 30 weeks with tretinoin, corticosteroid or emollient vehicle alone or with a sequential combination of corticosteroid and tretinoin. A control group remained topically untreated. All three agents, when used alone, significantly inhibited tumorigenesis. The sequential combination produced the greatest inhibition.

Topics: Administration, Topical; Adrenal Cortex Hormones; Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Drug Synergism; Female; Mice; Mice, Hairless; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Skin Neoplasms; Tretinoin; Ultraviolet Rays

Invasion of basement membranes is a key step in systemic spread of tumour cells. To analyze genetic mechanisms involved in this process, we have selected strongly and weakly invasive sublines with stable phenotypes from a primary human melanoma cell line by repeated passage through a reconstituted basement membrane in vitro. The sublines differed approximately 5-fold in their invasive potential. Invasiveness correlated with better attachment and overexpression of the integrin alpha v/beta 3 (vitronectin/laminin-receptor). Treatment with retinoic acid inhibited proliferation in both sublines and invasion in the weakly invasive cells but stimulated invasion in the strongly invasive subline. Northern-blot analyses revealed equal levels of mRNA expression regarding collagenase type-IV and retinoic-acid receptors but enhanced expression of TIMP-2 mRNA in weakly invasive cells. The 2 sublines differed significantly in their respective DNA ploidy when compared to the wild-type Mel Im cell line, suggesting that they represent heterogeneous clones present in the primary tumour. We have started to exploit this in vitro system for tumour heterogeneity to clone genes involved in invasion. By a subtractive cDNA cloning strategy, 12 partial cDNA clones were obtained that are specifically overexpressed in the strongly or weakly invasive subline. These results illustrate that stable genetic alterations lead to heterogeneous subpopulations within primary melanomas which differ in their ability to invade basement membranes and interact with components of the extracellular matrix.

Topics: Actins; Aneuploidy; Clone Cells; Cloning, Molecular; Collagen; Collagenases; Disease Progression; DNA, Complementary; DNA, Neoplasm; Drug Combinations; Gene Expression Regulation, Neoplastic; Humans; Integrins; Laminin; Melanoma; Neoplasm Invasiveness; Neoplasm Proteins; Protein Biosynthesis; Proteins; Proteoglycans; Receptors, Cytoadhesin; Receptors, Vitronectin; Selection, Genetic; Skin Neoplasms; Tissue Inhibitor of Metalloproteinase-2; Tretinoin; Tumor Cells, Cultured

Elevated levels of c-SRC activity have been found in human melanocytes and some human melanoma cell lines. We examined c-SRC in B16 murine melanoma cells. B16-F0 non-metastatic melanoma cells contained threefold more c-SRC activity and protein than NIH 3T3 murine fibroblasts. Differentiation of B16-F1 metastatic melanoma cells with retinoic acid resulted in an elevation in c-SRC activity, protein and mRNA. The increase in c-SRC was detectable after about 48 h of retinoic acid treatment, as were changes in cellular morphology and growth rate. Thus, there is a correlation between differentiation and expression of c-SRC in B16 murine melanoma cells. These findings suggest a role for c-SRC in murine melanocyte differentiation or function.

Topics: 3T3 Cells; Animals; Cell Differentiation; Fibroblasts; Melanocytes; Melanoma, Experimental; Mice; Proto-Oncogene Proteins pp60(c-src); RNA, Neoplasm; Skin Neoplasms; Tretinoin; Tumor Cells, Cultured

Mirex, a halogenated hydrocarbon, is a potent skin tumor promoter in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. In the present study retinoic acid (RA) and fluocinolone acetonide (FA), classical inhibitors of phorbol ester- and non-phorbol ester-type skin tumor promoters, were examined for their ability to inhibit mirex tumor promotion. Female CD-1 mice were initiated with 200 nmol DMBA and promoted with equipotent promoting doses of either 5 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) or 200 nmol mirex twice weekly for 25 weeks and RA (2(1 or 5 nmol), FA (0.5 or 2 nmol) or acetone were applied 30 min prior to each TPA or mirex dose. TPA-promoted papilloma formation was strongly inhibited by > 70% with both doses of RA and by > 90% with both doses of FA. In contrast, mirex-promoted papilloma formation was not inhibited by either dose of RA or 0.5 nmol FA and 2 nmol FA weakly inhibited mirex-promoted papillomas by only 32%. TPA- and mirex-promoted papillomas that were refractory to RA and FA demonstrated the same incidence of Ha-ras mutation as TPA- or mirex-promoted papillomas without RA and FA treatment, further indicating that the inhibitory activity of RA and FA is promoter-dependent and not solely dependent on mutant Ha-ras. FA (2 nmol) treatment completely abolished TPA-induced epidermal hyperplasia and proliferating cell nuclear antigen (PCNA) S phase-positive cells, however, FA had no inhibitory effect on the weak proliferative response induced by mirex. Collectively, these results indicate that the promotional activity of mirex, as well as its weak proliferative response, result from a distinct promoter mechanism and/or that mirex promotes a unique population of epidermal cells that are insensitive to FA and RA and cannot be distinguished by their mutant Ha-ras genotype.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Base Sequence; Carcinogens; Cell Division; Drug Interactions; Ear, External; Edema; Female; Fluocinolone Acetonide; Genes, ras; Genotype; Mice; Mice, Inbred Strains; Mirex; Molecular Sequence Data; Papilloma; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

A newly established cell line, designated NRS-1, was derived from an alveolar rhabdomyosarcoma that developed in the left forearm of a 7-year-old girl. The cell line had a t(2; 13) chromosomal translocation. Reverse transcription-polymerase chain reaction demonstrated that 5' PAX3-3' FKHR chimeric transcript was expressed in NRS-1 cells. NRS-1 cells showed myogenic differentiation without any particular stimulus in vitro and exhibited various kinds of muscle markers. All-trans retinoic acid promoted cell differentiation in the myogenic direction. Transforming growth factor-beta (TGF-beta) inhibited myogenic differentiation of those cells and promoted cell proliferation.

Topics: Base Sequence; Cell Differentiation; Cell Division; Cell Line, Transformed; Child; Female; Forearm; Humans; Karyotyping; Molecular Sequence Data; Rhabdomyosarcoma; Skin Neoplasms; Transforming Growth Factors; Tretinoin

We studied the effect of dietary retinoic acid (RA) in a two-stage protocol of skin carcinogenesis in female SENCAR mice. At 3 weeks of age mice were initiated with 7,12-dimethylbenz[a]anthracene (DMBA, 20 micrograms) and promoted with either 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 micrograms) once per week or mezerein (MEZ, 4 micrograms) twice per week for 20 weeks. At the week of DMBA initiation mice were also put on a purified diet containing either 3 (physiological dose) or 30 micrograms (pharmacological dose) of RA/g of diet. High dietary RA significantly inhibited papilloma yield but not incidence in the MEZ-promoted group. Papilloma incidence and yield were also lower in the MEZ- than in the TPA-treated groups. Cumulative carcinoma incidence and yield, and conversion efficiency (= (carcinomas/maximal papillomas) x 100%), were all decreased by high dietary RA in both MEZ- and TPA-treated groups. These results demonstrate that high dietary RA inhibited skin carcinogenesis in MEZ-promoted mice at the stages of tumor promotion and malignant conversion, while this inhibition occurred only at the malignant conversion stage in TPA-promoted mice.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Carcinoma; Diet; Diterpenes; Female; Mice; Mice, Inbred SENCAR; Papilloma; Skin Neoplasms; Terpenes; Tretinoin

The present study was directed to characterizing the reversion of neoplastic epidermal JB6 RT101 cells by AP-1 inhibiting drugs. Treatment of tumorigenic JB6 RT101 cells with retinoic acid (RA), fluocinolone acetonide (FA) or forskolin (FN) induced drug dependent (reversible) reversion of transformation. A synergistic effect on reversion was found with the three drugs in combination. Cells reverted by these three drugs also showed reduced levels of AP-1 transcription factor activity. After long term exposure of RT101 cells to FA, enrichment of flat revertants occurred in the population while a few unreverted cells formed foci. These unreverted cells appeared to be FA-resistant. Cloning of cells following RA treatment revealed stable reversion at least 2 months after drug withdrawal. Stable revertants showed lower basal AP-1 activity than RT101 cells (P < 0.01) and unstable revertants returned to transformed phenotype and elevated AP-1 activity within days following drug withdrawal. To our knowledge this is the first demonstration that drug induced reversion co-selects for reduced AP-1 activity. These data suggest that the JB6 RT101 cell line is a useful cell model for studying reversion of transformation and that inhibition of AP-1 activity may be one molecular mechanism of reversion. Considering the development of resistance with FA alone and the relative inefficiency of RA or FN alone, combinations of the three AP-1 activity inhibitors RA, FA and FN may be useful for further animal and clinical studies.

Topics: Animals; Anticarcinogenic Agents; Cell Transformation, Neoplastic; Cells, Cultured; Colforsin; Cyclic AMP; Drug Resistance; Fluocinolone Acetonide; Glucocorticoids; Mice; Phenotype; Sensitivity and Specificity; Skin; Skin Neoplasms; Time Factors; Transcription Factor AP-1; Transcriptional Activation; Tretinoin

The introduction of substituents at position 3 of methyl 4-oxoretinoate can be effected in good yields by alkylating the lithium dienolate. A second substituent can be introduced also, but the resulting 3,3-disubstituted-4-oxoretinoates were isolated in lower yields. Evidence was obtained for a slower rate of alkylation at the alpha-position (carbon 14) of the ester group. Some of these 4-oxoretinoic acid analogues showed high activity in assays in vivo for the inhibition of ornithine decarboxylase activity and carcinogen-induced papillomas in mouse skin.

Topics: Alkylation; Animals; Anticarcinogenic Agents; Cricetinae; Drug Stability; Enzyme Induction; Female; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred Strains; Ornithine Decarboxylase; Papilloma; Skin; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Tretinoin

Various retinoids and interferons exert anti-tumor effects both in experimental studies and in clinical trials. Recent reports indicate that they have a synergistic antineoplastic activity. Our study aimed to determine whether these synergistic anti-tumor effects are related to inhibition of tumor-cell-induced angiogenesis. A further aim was to compare the anti-angiogenic activity of various retinoids including 9-cis retinoic acid, a ligand for nuclear retinoic acid receptor RXR, given alone and in combination with interferon alpha-2a (IFN alpha-2a). An in vivo experimental model of cutaneous angiogenesis in the mouse was used. Angiogenesis was induced by intradermal injection of HPV16- or HPV18 DNA-harboring tumor-cell lines. All-trans retinoic acid (all-trans RA), 13-cis retinoic acid (13-cis RA) and 9-cis retinoic acid (9-cis RA) as well as IFN alpha-2a applied to mice intraperitoneally for 5 consecutive days before induction of angiogenesis resulted in significant inhibition of angiogenesis. Combination of retinoids with IFN alpha-2a led to a synergistic inhibition of angiogenesis, as compared to the effects of the drugs given alone. Similar results were obtained when tumor cells were preincubated in vitro with the compounds, before injection into untreated mice. Our findings on synergistic anti-angiogenic effects of retinoids and IFN alpha-2a could explain, at least partially, the anti-tumor efficacy of combined therapy with these agents, and provide support for the role of angiogenesis in tumor growth.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Drug Synergism; HeLa Cells; Humans; Interferon alpha-2; Interferon-alpha; Isomerism; Isotretinoin; Keratinocytes; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Papillomaviridae; Recombinant Proteins; Retinoids; Skin Neoplasms; Tretinoin; Tumor Cells, Cultured; Tumor Virus Infections

Interferon gamma (IFN-gamma) is a potent inducer of squamous differentiation in normal human epidermal keratinocytes. This induction is characterized by a > or = 95% decrease in the mRNA level of two growth regulatory genes, cdc2 and E2F-1, and a 7-15-fold increase in the expression of two squamous cell-specific genes, transglutaminase type I and cornifin. In contrast to the decrease in cdc2 and E2F-1 expression, the increase in transglutaminase type I and cornifin mRNAs by IFN-gamma occurs after a lagtime of more than 12 h. These results are consistent with the hypothesis that in normal human epidermal keratinocyte cells irreversible growth arrest precedes the expression of the squamous-differentiated phenotype. The action of IFN-gamma on the expression of squamous cell-specific genes is antagonized by retinoic acid and transforming growth factor beta 1. Both factors are potent suppressors of the induction of transglutaminase type I and cornifin; however, they do not prevent the commitment to irreversible growth arrest. Several squamous cell carcinoma cell lines do not show a detectable decrease in cdc2 or increase in transglutaminase type I mRNA levels after IFN-gamma treatment and appear to be altered in their control of squamous differentiation.

Topics: Carcinoma, Squamous Cell; CDC2 Protein Kinase; Cell Differentiation; Cell Division; Cells, Cultured; Cornified Envelope Proline-Rich Proteins; DNA Probes; Gene Expression Regulation; Growth Substances; Humans; Interferon-gamma; Keratinocytes; Kinetics; Male; Membrane Proteins; Recombinant Proteins; RNA, Messenger; Skin; Skin Neoplasms; Transforming Growth Factor beta; Transglutaminases; Tretinoin; Tumor Cells, Cultured

Using 7,12-dimethylbenz[a]anthracene as the initiator and 12-O-tetradecanoyl-13-acetate as the tumor promoter on the dorsal skin of Sencar mice, we previously showed that pharmacological dietary all-trans-retinoic acid and beta-carotene inhibit the conversion of papillomas to carcinomas in a two-stage system of chemical carcinogenesis. The purpose of this study was to determine the influence of dietary retinoic acid and beta-carotene on retinoid and beta-carotene concentrations in skin and other tissues. We were unable to measure tissue retinoic acid because of the relatively limited amount of tissue available for analysis and the fast rate of metabolism. Different dietary levels of retinoic acid or beta-carotene did not influence total retinol of skin, papilloma, and carcinoma tissues, which all showed a concentration of approximately 1 +/- 0.5 microgram/g wet wt. Equally refractory to dietary retinoic acid or beta-carotene was serum retinol concentration. In contrast, dietary retinoic acid protected loss of liver retinol and retinyl palmitate, and beta-carotene caused an increase in beta-carotene and retinyl palmitate in liver but did not affect serum and liver retinol. We further investigated metabolic and functional aspects of retinoic acid in cultured mouse epidermal keratinocytes (LC-8 cells) and found that these cells actively metabolized [10,11-14C]retinoic acid to polar compounds. Isomers of retinoic acid were a minor product in the presence of cells and the major product when incubated in serum-containing medium in the absence of cells. From the functional point of view, exposure of LC-8 cells to 3 x 10(-6) M all-trans-retinoic acid (RA) caused a 75-fold induction in tissue transglutaminase and an approximately 9-fold induction in 10(-6) M RA at three days of culture. We conclude that retinoic acid spares endogenous retinol and that beta-carotene greatly enhances liver retinyl palmitate levels. Moreover we show that although mouse epidermal cells metabolize retinoic acid at a very high rate, they respond functionally by induction of tissue transglutaminase activity. Because this enzyme has been suggested to be involved in programmed cell death, we are presently investigating the possibility that it may be involved in the inhibition of carcinogenesis in mice fed pharmacological doses of RA.

Topics: Animals; beta Carotene; Carcinoma; Carotenoids; Cell Division; Chromatography, High Pressure Liquid; Diet; Female; Keratinocytes; Liver; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Papilloma; Skin; Skin Neoplasms; Transglutaminases; Tretinoin; Tumor Cells, Cultured; Vitamin A

We have previously reported that high dietary retinoic acid (RA; 30 micrograms/g diet) inhibits carcinoma formation in a two-stage skin carcinogenesis protocol, using 7,12-dimethylbenz[a]anthracene (DMBA) as the initiator and 12-O-tetradecanoyl phorbol-13-acetate (TPA) as the tumor-promoter in female SENCAR mice. We next asked whether switching the diets from high to control levels of RA and vice versa would influence carcinoma formation. Mice at 3 weeks of age were initiated with DMBA (20 micrograms) once, followed by 20 weekly applications of TPA (2 micrograms). At 3 weeks of age mice were weaned onto a diet containing either 3 (control) or 30 (high) micrograms RA/g diet. Half of the mice from either dietary group were switched to the other diet at 20 weeks of age, when papilloma formation was at its peak. These four groups are designated RA 3 micrograms, RA 30 micrograms, RA 3/30 micrograms and RA 30/3 micrograms groups. As previously found, papilloma formation (including incidence and yield) was not significantly affected by dietary treatment. However, high dietary RA inhibited carcinoma formation; specifically cumulative carcinoma incidence (18.5-23.1% versus 50%) and yield (0.19-0.23 versus 0.68) were significantly lower (P < 0.05) in the high dietary RA treatment groups than the RA 3 micrograms control group, as was the carcinoma conversion efficiency (2.1-3.8% versus 9.4%). The beneficial effect on carcinoma formation was still evident when excess RA was given late during the carcinogenesis process (i.e. the RA 3/30 micrograms group). Moreover, a residual effect of excess RA was also seen after the dietary RA was switched to the control level at 20 weeks of age, when papilloma yield was highest (i.e. the RA 30/3 micrograms group). It is therefore concluded that the chemopreventive effect of high dietary RA on skin carcinogenesis induced by a two-stage carcinogenesis protocol with DMBA and TPA resides mainly at the step of conversion from benign papillomas to malignant carcinomas.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Inbred SENCAR; Papilloma; Pregnancy; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Previously, we have shown that dietary retinoic acid (RA) at pharmacological doses (30 micrograms/g of diet) inhibited the malignant conversion of skin papillomas to carcinomas induced by a two-stage carcinogenesis protocol with 7,12-dimethylbenz[a]anthracene as initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as promoter (De Luca et al., Carcinogenesis, 14 (1993) 539-542). The purpose of this study was to determine the effect of dietary RA on skin papilloma and carcinoma formation induced by a complete carcinogenesis protocol with repeated DMBA treatment in female Sencar mice. Mice at 3 weeks of age were weaned onto a diet containing either 3 (control) or 30 (excess) micrograms of RA/g of diet and treated topically with DMBA (25.5 micrograms) once per week for 20 weeks. Mice fed excess dietary RA did not significantly differ from control mice in the following parameters: body weight, survival rate, papilloma incidence, cumulative carcinoma incidence (19.4% versus 23.7%), carcinoma yield (0.19 versus 0.26 per mouse), carcinoma conversion efficiency (5.2% versus 3.9%), and average age of carcinoma development (22.7 +/- 4.7 versus 23.3 +/- 2.8 weeks). However, papilloma yield was decreased by about 50% (i.e. 3.7 versus 7.0 at week 20, P < 0.01) between weeks 17 and 22 of age by excess dietary RA treatment. Contrary to other routes of administration (i.e. topical and systemic) of RA (Verma et al., Cancer Res., 42 (1982) 3519-3525), excess dietary RA did not enhance skin tumor formation. In addition, excess dietary RA failed to inhibit malignant conversion of papillomas to carcinomas in the complete carcinogenesis protocol. Thus, the modulation of RA on skin papilloma and carcinoma formation is dependent on carcinogenesis protocol and route of RA administration.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma; Diet; Female; Mice; Papilloma; Skin Neoplasms; Tretinoin

The growth and differentiation response to retinoic acid (RA) was studied in the human keratinocyte line HaCaT and tumorigenic clones transfected with c-Ha-ras oncogene (HaCaT-ras). Differentiation (mainly keratin synthesis) was evaluated and correlated to cell proliferation in vitro but also growth behaviour in vivo (tumorigenicity). Comparable to normal keratinocytes, HaCaT cells and ras clones showed increased expression of the epidermal suprabasal keratins K1 and K10 upon RA depletion of the media (delipidized serum), while simple epithelial type keratins K7, K8 and K18 as well as K19 and K13 (typical of internal stratified epithelia) were almost completely suppressed. The cell density-dependent increase of K1 and K10 at intermediate RA levels (as in regular media with untreated serum) was also observed at Ca2+ levels below 0.1 mM, thus being clearly unrelated to stratification, whereas K13 synthesis was Ca(2+)-dependent and initiated with stratification. The effects on keratins were fully reversed by increasing RA concentrations. There was only mild stimulation of proliferation at RA doses (10(-10) to 10(-8) M) not directly corresponding to suppression of keratinization. Thus, the negative RA influence on K1 and K10, opposed to the effect on simple keratins, substantiates the preserved regulatory capacity rendering these cells appropriate models for biological testing. Among the various tumorigenic HaCaT-ras clones highly and moderately differentiating ones could be distinguished, accordingly induction in vitro led to a comparable spectrum of differentiation markers (K1 and K10 appearing early, and filaggrin late) as growth in vivo. These in vitro results demonstrate that, in spite of some differences in RA sensitivity, virtually all clones possess the epidermal differentiation repertoir which is regulated according to the same principles. Finally, this confirms our in vivo data that differentiation potential is not inversely related to the state of transformation or tumorigenicity.

Topics: Calcium; Cell Division; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Epidermal Cells; Epidermis; Filaggrin Proteins; Fluorescent Antibody Technique; Humans; Keratinocytes; Keratins; Precipitin Tests; Proto-Oncogene Proteins p21(ras); Skin Neoplasms; Tretinoin; Tumor Cells, Cultured

Human epidermal melanocytes were treated with all-trans-retinoic acid (RA) and examined for adhesion to bovine serum albumin-, fibronectin- and laminin-coated culture dishes. Control and treated cells were also examined for motility into micropore filters coated with the same proteins. Treatment of the cells with 3 x 10(-6) M RA for 3-4 days resulted in inhibition of attachment to all three substrates. Decreased attachment was observed within 1.5 h. Inhibition of attachment was not due to toxicity because differences between control and treated cells disappeared by 18 h, when most of the cells (approximately 75%) were attached and spread on all three substrates. The same treatment that inhibited adhesion also reduced migration into the interstices of micropore filters coated with the same three proteins. In additional experiments, human and mouse melanoma cell lines were examined in place of normal melanocytes. RA treatment also blocked adhesion and motility of these cells. The malignant melanoma cells were less sensitive to RA than normal melanocytes in the adhesion assay but were equally sensitive in the motility assay. The ability of RA to inhibit melanocyte adhesion and motility as well as melanocyte growth could explain, in part, the capacity of retinoids to modulate melanocyte function in hyperpigmented skin lesions.

Topics: Animals; Cattle; Cell Adhesion; Cell Line, Transformed; Cell Movement; Fibronectins; Humans; Infant, Newborn; Laminin; Melanocytes; Melanoma; Serum Albumin; Skin Neoplasms; Tretinoin

The efficiency of topical tretinoin was examined in a patient with basal cell carcinomas (BCC) for which conventional means of removal was inappropriate.. Topical tretinoin was used to treat multiple arsenic-induced superficial BCCs in a 64-year-old woman. Topical tretinoin (0.05% twice daily) was administered to four lesions for 3 weeks followed by a 3-week interruption.. After three cycles of treatment clinical healing of all the lesions was observed. Histopathological examination of the lesional biopsies showed no evidence of a tumor. However, 9 months later all four lesions relapsed and surgical excision disclosed BCC.. The data indicate that topical tretinoin treatment of multiple superficial BCCs induces clinical and pathological regression of the lesions with a high rate of relapse. This report suggests that topical tretinoin is not an effective therapy for the cure of arsenic-induced superficial BCCs.

Topics: Administration, Cutaneous; Carcinoma, Basal Cell; Female; Humans; Middle Aged; Skin Neoplasms; Tretinoin

Previously we have shown that dietary retinoids are essential for papilloma formation induced by either an initiation-promotion or a complete skin carcinogenesis protocol. The present study was conducted to further determine the effect of dietary retinoic acid (RA) on papilloma formation and the conversion of papillomas to carcinomas. Skin tumors were induced in 3 week old female SENCAR mice by an initiation-promotion protocol with one application of 20 micrograms of 7,12-dimethylbenz[a]anthracene (DMBA), followed by 20 weekly applications of 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice were fed RA at one of the three doses: 0.3 (nutritionally marginal dose), 3 (near physiological) and 30 (pharmacological) micrograms/g of diet. Mice fed 30 micrograms of RA/g of diet had the same survival rate as the other two groups despite a lower body weight and all three groups had similar papilloma incidence, which reached 100% at age 18 weeks. Mice fed 3 micrograms of RA/g of diet had the highest papilloma yield (approximately 14 papillomas/mouse) of all groups and it peaked between weeks 18 and 38 of age. These papillomas later regressed such that mice from all three groups had about the same papilloma yield at week 44 of age. Mice fed 30 micrograms of RA/g of diet failed to develop any visible carcinoma, while mice fed 0.3 or 3 micrograms/g showed 1.9% conversion of papillomas to carcinomas. Therefore, dietary RA at 30 micrograms/g of diet inhibited the conversion of papillomas to carcinomas without affecting papilloma incidence. In addition, dietary RA at 30 and 0.3 micrograms/g of diet lowered papilloma yield.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma; Diet; Female; Mice; Papilloma; Skin Neoplasms; Tretinoin

Early recognition of melanoma is directly related to improvement in survival. Patients, therefore, must not only be educated in recognition of abnormal skin lesions, but also in proper skin examination, ultraviolet radiation protection, effect of drugs on the development of malignancies, and dietary means of promoting wellness and preventing disease. Basic patient instruction should begin at the time of diagnosis and should include all health care team members to assure patient comprehension and compliance with recommendations.

Topics: Dietary Fats; Dietary Fiber; Humans; Melanoma; Patient Education as Topic; Skin Aging; Skin Neoplasms; Sunscreening Agents; Survival Rate; Tretinoin

The inhibitory effect of retinoic acid (RA) on 12-O-tetradecanoylphorbol-13-acetate- (TPA) induced mouse skin tumors was studied. Two subpopulations of tumors, small (< 2 mm) and large (> or = 2 mm) appeared after 12 weeks of cutaneous promotion by TPA (10 nmol), following initiation by application of 2 x 100 nmol of 7,12-dimethylbenz[a]anthracene (DMBA) to the skin. RA in the doses of 17 and 34 nmol, prior to each TPA treatment inhibited (P < 0.05) the formation of small tumors at 12 weeks of promotion. However, RA in either dose did not inhibit the formation of large (> or = 2 mm) tumors. Ten weeks following withdrawal of all treatments, the number of large tumors persisted in a significantly (P < 0.05) higher number as compared to small tumors in all groups. Our results provide evidence for the existence of tumor subpopulations with a differential response to RA. In addition, elevated levels of metallothionein (MT) expression were demonstrated in papillomas induced by TPA, 72 h after the last TPA treatment. Comparing papillomas treated with RA prior to each TPA treatment and papillomas treated with TPA only, demonstrated that the elevated MT expression in papillomas was unaffected by RA. This indicated that RA did not affect the expression of a protein that showed elevated level in TPA-induced papillomas.

Topics: Animals; Female; Metallothionein; Mice; Mice, Inbred Strains; Papilloma; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

The case of a child with basal cell nevus syndrome whose condition was successfully managed for 10 years with a combination of topical 5-fluorouracil and tretinoin is reported. The concurrent use of these two agents prevented the development of new tumors, inhibited the growth of existing tumors, and caused the regression of superficially invasive basal cell carcinomas.

Topics: Basal Cell Nevus Syndrome; Child, Preschool; Drug Synergism; Drug Therapy, Combination; Female; Fluorouracil; Humans; Skin Neoplasms; Time Factors; Tretinoin

Two lines of murine melanoma cells (B16 and Cloudman S91) were cultured on type I collagen gel and the effects of all-trans-retinoic acid on the growth and infiltration into the gel were assayed. In both lines, proliferation and the degree of infiltration were suppressed by the addition of all-trans-retinoic acid. The infiltration-inhibiting effect was expressed very rapidly and was dose-dependent at concentrations ranging from 10(-7) to 10(-5) M of all-trans-retinoic acid. These results suggest the anti-invasive effects of all-trans-retinoic acid on melanoma cells.

Topics: Animals; Cell Division; Collagen; Dose-Response Relationship, Drug; Gels; Melanoma; Mice; Neoplasm Invasiveness; Skin Neoplasms; Tretinoin; Tumor Cells, Cultured

It is becoming increasingly clear that cutaneous carcinogenesis in murine skin is a stepwise process comprising of initiation, promotion and progression. Most of the papillomas induced by an initiation-promotion protocol regress, while a few of them progress to malignant carcinomas. Progression of benign tumors into malignant cancer is critical since the latter lesions are capable of metastatic spread and eventual death. Inhibitors of the conversion process are therefore likely to be useful as cancer chemopreventive agents. All-trans retinoic acid (RA) is a known regulator of cellular proliferation and differentiation, and a known inhibitor of tumor promotion in murine skin. In this study we assessed the effect of topical application of RA on conversion of benign skin papillomas to malignant carcinomas. Papillomas were induced in SENCAR mice by topical application of 7,12-dimethylbenz[a]anthracene (DMBA) as tumor initiator followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) as tumor promoter. In SKH-1 hairless mice papillomas were induced by thrice weekly exposure to ultraviolet B (UVB) radiation. At 18 (DMBA/TPA group) and 25 (UVB group) weeks papilloma yield stabilized and no new tumors developed. Beginning at the 20th week (DMBA/TPA group) and at the 27th week (UVB group), malignant conversion was achieved by twice weekly topical application of TPA or free radical-generating compounds benzoyl peroxide (BPO), 2,2-azobis(2-amidinopropane) (ABP) and tert-butyl peroxybenzoate (BPB). Application of RA (10 micrograms/animal) 1 h prior to skin application of TPA, BPO, ABP or BPB afforded significant protection (up to 70%) only against malignant conversion mediated by free radical-generating compounds in both chemically induced and UVB-induced benign skin papillomas. On the other hand, preapplication of RA was less effective in the suppression of spontaneous malignant conversion in vehicle-treated animals. These results suggest that, in addition to their anti-tumor promoting effects, retinoids may also act as anti-carcinogens by inhibiting the process of malignant conversion induced by free radical-generating compounds.

Topics: Animals; Carcinoma; Female; Mice; Neoplasms, Radiation-Induced; Papilloma; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin; Ultraviolet Rays

A 35-year-old man with refractory cutaneous Ki-1 lymphoma was salvaged successfully with oral 13-cis-retinoic acid (1 mg/kg/day). He had a complete remission lasting for 20 months before a single nodule recurred on his skin. Excisional biopsy of the recurrent tumor revealed a distinct morphologic change, suggesting cellular differentiation toward a more benign phenotype. No significant side effects were noted except mild xerostomia, bone pain, and hyperlipidemia. The authors believe that 13-cis-retinoic acid should be considered in the treatment of cutaneous Ki-1 lymphoma.

Topics: Adult; Antigens, Differentiation; Antigens, Neoplasm; Cell Differentiation; Humans; Immunophenotyping; Ki-1 Antigen; Lymphoma, T-Cell, Cutaneous; Male; Remission Induction; Skin Neoplasms; Tretinoin

Tumor-promoting or antipromoting agents potentially may act directly on initiated squamous epithelial cells or indirectly through effects on normal keratinocytes or immune cells. The purpose of this study was to examine direct effects by comparing in vitro and in vivo treatment of initiated cell populations with 12-O-tetradecanoylphorbol-13-acetate (TPA) or retinoic acid. Keratinocytes were initiated by treatment in vitro with 7,12-dimethylbenz[alpha]anthracene. Replicate cultures of a cloned initiated cell line were exposed to TPA or retinoic acid with acetone as control. After an equivalent number of population doublings, cultured cell sheets were transplanted as skin grafts to athymic nude mice. Replicate grafts from each in vitro treatment group were then treated with TPA or retinoic acid for 8 months. Promotion was quantified by tumor incidence (graft sites with tumor per total sites) and by tumor growth rate. The findings were as follows: (a) TPA increased tumor incidence whether it was applied in vitro or in vivo; (b) TPA in vitro favored more progressive tumors than TPA in vivo; (c) stages of malignant progression from cloned keratinocytes treated in vitro were histologically identical to those following treatment of skin in vivo, including papilloma, dysplastic invasive papilloma, squamous cell carcinoma, and metastasis to lymph node and lung; (d) retinoic acid treatment in vivo reduced tumor incidence and tumor growth rate in initiated cells previously exposed to TPA but not in cells previously exposed to retinoic acid. The results indicated the following: (a) direct effects of TPA on initiated keratinocyte populations were a significant component of tumor promotion; (b) factors in vivo modified the TPA response toward less progressive growth; and (c) the effect of retinoic acid was modulated by prior treatment history.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Drug Synergism; Mice; Mice, Inbred BALB C; Papilloma; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Topics: Administration, Topical; Humans; Melanoma; Skin Neoplasms; Tretinoin

Topics: Adult; HIV Infections; Humans; Male; Middle Aged; Neoplasm Staging; Remission Induction; Sarcoma, Kaposi; Skin Neoplasms; Tretinoin

In the epidermis of skin, a fine balance exists between proliferating progenitor cells and terminally differentiating cells. We examined the effects of TGF-beta s and retinoic acid (RA) on controlling this balance in normal and malignant human epidermal keratinocytes cultured under conditions where most morphological and biochemical features of epidermis in vivo are retained. Our results revealed marked and pleiotropic effects of both TGF-beta and RA on keratinocytes. In contrast to retinoids, TGF-beta s acted on mitotically active basal cells to retard cell proliferation. Although withdrawal from the cell cycle is a necessary prerequisite for commitment to terminal differentiation, TGF-beta s inhibited normal keratinization in suprabasal cells and promoted the type of differentiation commonly associated with wound-healing and epidermal hyperproliferation. The actions of TGF-beta s and RA on normal keratinization were synergistic, whereas those on abnormal differentiation associated with hyperproliferation were antagonistic. These observations underscore the notion that environmental changes can act separately on proliferating and differentiating cells within the population. Under the conditions used here, the action of TGF-beta s on human keratinocytes was dominant over RA, and TGF-beta s did not seem to be induced as a consequence of RA treatment. This finding is consistent with the fact that RA accelerated, rather than inhibited, proliferation in raft cultures. Collectively, our data suggest that the effects of both factors on epidermal growth and differentiation are multifaceted and the extent to which their action is coupled in keratinocytes may vary under different conditions and/or in different species.

Topics: Carcinoma, Squamous Cell; Cell Differentiation; Cell Division; Cell Line; Cells, Cultured; DNA Replication; Epidermal Cells; Humans; Keratinocytes; Keratins; Molecular Weight; Skin Neoplasms; Transforming Growth Factor beta; Tretinoin

The preventive effect of vitamin A acid (13-cis-retinoic acid) on skin papillomas induced in rabbits (Oryctolagus cuniculus) by the bite of bed bugs (Cimex lectularius) pre-irradiated with gamma rays was investigated. Painting the papillomas with an oily 13-cis-retinoic acid suspension twice a week in a dose of 25 mg/kg body weight leads to significant regression of these structures.

Topics: Animals; Antineoplastic Agents; Bedbugs; Male; Papilloma; Rabbits; Skin Neoplasms; Tretinoin

Repeated promotion of 7,12-dimethylbenz[alpha]anthracene-initiated cells in mouse skin with 12-O-tetradecanoylphorbol-13-acetate (TPA) induces them to grow as premalignant skin papillomas and some of these subsequently progress to carcinomas. In this study, we demonstrate that this TPA-induced progression of initiated cells to papillomas and carcinomas could be prevented by exposing them previously to weak promoting regimens or to agents that mimic TPA activity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benzoflavones; Benzyl Alcohols; Cell Transformation, Neoplastic; Cortisone; Dose-Response Relationship, Drug; Indoles; Mice; Mice, Inbred BALB C; Papilloma; Precancerous Conditions; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin; Vitamin E

Experimental carcinogenesis has led to a concept that defines two discrete stages in the development of skin tumors: (i) initiation, which is accomplished by using a mutagen that presumably activates a protooncogene, and (ii) promotion, which is a reversible process brought about most commonly by repeated application of phorbol esters. We have created a transgenic mouse strain that carries the activated v-Ha-ras oncogene fused to the promoter of the mouse embryonic alpha-like, zeta-globin gene. Unexpectedly, these animals developed papillomas at areas of epidermal abrasion and, because abrasion can also serve as a tumor-promoting event in mutagen-treated mouse skin, we tested these mice for their ability to respond to phorbol ester application. Within 6 weeks virtually all treated carrier mice had developed multiple papillomas, some of which went on to develop squamous cell carcinomas and, more frequently, underlying sarcomas. We conclude that the oncogene "preinitiates" carrier mice, replacing the initiation/mutagenesis step and immediately sensitizing them to the action of tumor promoters. In addition, treatment of the mice with retinoic acid dramatically delays, reduces, and often completely inhibits the appearance of promoter-induced papillomas. This strain has use in screening tumor promoters and for assessing antitumor and antiproliferative agents.

Topics: Animals; Cell Transformation, Neoplastic; Cells, Cultured; Genes, ras; Keratinocytes; Mice; Mice, Inbred Strains; Mice, Transgenic; Plasmids; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Retinoids have chemopreventive activity for epithelial tumors in a variety of systems, including the two-stage tumorigenesis system of mouse skin in which only the promotion stage is inhibited. We asked whether dietary vitamin A deficiency could affect the skin tumorigenic response, prior to major changes in body weight or general health of the animals. Two regimens were tested to induce vitamin A deficiency. SENCAR mice were either (a) fed a vitamin A-deficient diet from 4 or 9 weeks of age or (b) their mothers were fed the diet from the time of birth of the experimental animals which were then weaned on the same diet. The latter regimen produced typical symptoms of vitamin A deficiency in the offspring by Weeks 12-14 and all the mice died by Week 19; the former regimen permitted sufficient accumulation of retinol and its esters to sustain life for up to 45 and 75 weeks, respectively, in the majority of mice. For our experiments, vitamin A depletion was produced by placing the mothers on the deficient diet at birth of the experimental animals. A single topical dose of 20 micrograms of 7,12-dimethylbenz(a)anthracene (DMBA) was used as the initiator at 3 weeks of age and 1 to 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) once weekly as the tumor promoter for 10 weeks (from Week 4 through 13 of the experiment). Fifty-five % of mice (n = 40) on Purina laboratory chow (mean body weight, 31.4 g) developed skin tumors (2.58 per mouse) at 12 weeks, versus 2.5% (0.05 papillomas per mouse) of mice (n = 40) kept on the purified vitamin A-deficient diet (mean body weight, 30.3 g), a 98% decrease in tumor/mouse. Retinoic acid (RA) (1-3 micrograms/g diet) supplementation after Week 12 caused a rapid tumorigenic response in 95% of the mice by week 22. This tumor response occurred to a reduced extent in the absence of continued TPA treatment up to Week 13. Even though tumor incidence increased within 1 week of RA and 95% of the mice showed the tumorigenic response, the number of tumors per mouse was about 50% of that observed in mice maintained on standard Purina diet. This was confirmed in an experiment in which the mice were maintained for life either on Purina or on the RA (3 micrograms/g) containing purified diet, the latter being the control group for the effect of vitamin A deficiency on skin tumorigenesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carotenoids; Cocarcinogenesis; Diet; Female; Liver; Male; Mice; Neoplasms, Experimental; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin; Vitamin A Deficiency; Weight Loss

A single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) was found to induce mRNA of a metallothionein (MT) gene or genes in the skin of Sencar mice, and papillomas produced by repeated applications of TPA were shown to have elevated levels of MT mRNA. Induction of MT mRNA was maximal 4-8 h after application of TPA and returned to the control level 24 h later. A dose-dependent increase of MT mRNA was observed with doses of TPA of 1-5 micrograms. Of the other promoters tested, phorbol-12, 13-didecanoate, mezerein, and the ionophore A23187 also induced MT mRNA, but 4-O-methyl-TPA and benzoyl peroxide did not. Phorbol and 4 alpha-phorbol-12,13-didecanoate, which are not promoters, also did not induce MT mRNA. Retinoic acid and 1 alpha, 25-dihydroxyvitamin D3, inhibitors of tumor promotion, did not induce MT mRNA themselves or inhibit the induction of MT mRNA by TPA. In C57BL/6 promotion-resistant mice, TPA caused only slight induction of MT mRNA. These data suggest a correlation between induction of MT mRNA and epidermal hyperplasia. The constitutive elevation of MT mRNA levels in papillomas may be due to the loss, during the process of tumor promotion, of some mechanism regulating MT gene expression.

Topics: Administration, Topical; Animals; Carcinogens; Cholecalciferol; Female; Gene Expression Regulation; Metallothionein; Mice; Mice, Inbred C57BL; Papilloma; RNA, Messenger; Skin Neoplasms; Tetradecanoylphorbol Acetate; Transcription, Genetic; Tretinoin

Topics: Administration, Topical; Humans; Male; Melanoma; Middle Aged; Neoplasm Recurrence, Local; Skin Neoplasms; Tretinoin

In view of the clinical trials of retinoids as therapeutic agents for premalignant skin lesions, a radiographic study was undertaken to measure skeletal toxicities after chronic dietary administration of retinoids in mice exposed to tumor initiation and promotion. CD-1 mice were initiated with 0.15 moles of 7,12-dimethylbenz[a]anthracene and promoted twice daily with 8 nmoles of 12-0-tetradecanoylphorbol-13-acetate for 23 weeks. Diets were supplemented with 60 IU, 200 IU, or 700 IU of retinyl palmitate (RP) per g diet. After 5 weeks, the 700 IU of RP /g diet was lowered to 350 IU/g diet. Administration of these diets to mice during the 23 weeks of tumor promotion resulted in a 0-fold, 2-fold, or 10-fold increase in bone fractures, respectively. Osteoporotic bone lesions identified on radiographs rose 0-fold, 0-fold, and 10-fold at the respective doses, whereas metaphyseal flares increased 0-fold, 1.4-fold, and 3.6-fold. Bone deformities were augmented 0-fold, 1.8-fold and 2.9-fold at the respective doses. Addition of selenium (2 ppm in the drinking water) did not alter the bone toxicity of RP. 13-cis-retinoic acid (CRA) was less toxic at 700 IU/g diet than was RP at that dose, as evidenced by the death of 12 of 70 mice by the 6th week of dietary RP and no deaths in the 35 mice fed 700 IU CRA/g diet for 23 weeks. CRA at 700 IU/g diet resulted in 3/4 as many osteoporotic bones, 1/3 as many bone fractures, 4/5 as many metaphyseal flares, and a similar number of bone deformities as mice fed 700/350 IU/g diet. At the dose of 200 IU/g food, osteotoxicities were similar in the mice fed diets supplemented with RP and CRA. Thus, the light dose of CRA (700 IU/g diet) was less toxic than the high dose of, RP but at a lower dose (200 IU/g), CRA was as osteotoxic as was RP. Bone fractures in mice exposed to prolonged dietary administration of retinoids was a more sensitive index of retinoid toxicity than was body weight. We have detected osteotoxicity in mice at a total dose of CRA which was about twice the total dose used clinically.

Topics: Administration, Oral; Animals; Bone and Bones; Bone Diseases; Carcinogens; Diterpenes; Dose-Response Relationship, Drug; Female; Mice; Mice, Inbred Strains; Osteoporosis; Retinyl Esters; Selenium; Skin Neoplasms; Tretinoin; Vitamin A

Malignant cells are known to be sensitive to increased temperature. The effects of hyperthermia (HT) on intradermally implanted S91 melanoma cells in syngeneic mice were investigated with a hand-held radiofrequency generator. The possible additive effects of topical retinoic acid (RA) in this system also were studied. Five millimeter diameter melanomas were treated with either HT alone, RA alone, or a combination of HT and RA and were then evaluated after 43 days and 59 days. Eighteen of 20 tumors treated with HT alone and all 20 melanomas treated with HT/RA were eradicated. RA alone caused complete regression in 11 of 19 treated tumors. It is concluded that radiofrequency HT is an effective treatment in intradermal murine melanoma and that the addition of RA does not significantly alter the outcome because of the extreme effectiveness of HT alone.

Topics: Administration, Cutaneous; Animals; Combined Modality Therapy; Hyperthermia, Induced; Male; Melanoma, Experimental; Mice; Mice, Inbred DBA; Radio Waves; Remission Induction; Skin Neoplasms; Tretinoin; Tumor Cells, Cultured

To confirm reports that skin cancer can be prevented with retinoid treatment, a three-year controlled prospective study was conducted of oral isotretinoin in five patients with xeroderma pigmentosum who had a history of multiple cutaneous basal cell or squamous cell carcinomas. Patients were treated with isotretinoin, 2 mg/kg per day for two years, and then evaluated for an additional year without using the drug. Before, during, and after treatment, biopsy specimens of all suspicious lesions were examined, and skin cancers were removed surgically. The patients had a total of 121 tumors in the two years before treatment. During two years of treatment with isotretinoin, there were twenty-five tumors, with an average reduction in skin cancers of 63 percent (p = 0.019). After use of the drug was discontinued, the tumor frequency increased a mean of 8.5 times over the frequency during treatment (p = 0.007). Although all patients experienced mucocutaneous toxic effects, and abnormalities in triglyceride levels, results of liver function tests, or skeletal findings occurred in some, high-dosage oral isotretinoin was effective in the chemoprophylaxis of skin cancers in patients with xeroderma pigmentosum.

Topics: Administration, Oral; Adolescent; Adult; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Child; Female; Follow-Up Studies; Humans; Male; Prospective Studies; Skin Neoplasms; Tretinoin; Xeroderma Pigmentosum

Although few actinic keratoses eventuate as squamous cell carcinomas, these precancerous lesions cannot be ignored. A medical regimen of topical tretinoin use and sun protection appears to be effective in treating and preventing these precancers, with the added cosmetic benefits of ameliorating the alterations which accompany sun damage on exposed skin.

Topics: Administration, Topical; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Neoplasms, Radiation-Induced; Precancerous Conditions; Skin Neoplasms; Sunlight; Tretinoin

A 55-year-old patient was treated with a combination of minoxidil and retinoic acid. After 1 month an explosive eruption of pyogenic granuloma appeared on the scalp. Despite redness and itchy reaction, caused only by the test containing both chemicals, histology did not give evidence of contact allergy.

Topics: Alopecia; Drug Combinations; Hemangioma; Humans; Male; Middle Aged; Minoxidil; Scalp; Skin Neoplasms; Tretinoin

A 59-year-old woman with a history of papillary carcinoma of the thyroid gland developed three reddish nodules on the scalp. A skin biopsy showed a dermal tumor composed of sheets of clearly differentiated thyroid vesicles. Cutaneous metastases of thyroid carcinoma are very rare and this case is the first case confirmed by immunoperoxidase studies using monoclonal antithyroglobulin antibody. Positive reactions were obtained in colloid and at apices of thyrocytes. Monoclonal antibodies to human thyroglobulin may offer a unique opportunity to confirm the tissue origin of cutaneous metastasis.

Topics: Acitretin; Antibodies, Monoclonal; Carcinoma, Papillary; Female; Humans; Immunoenzyme Techniques; Immunohistochemistry; Middle Aged; Skin Neoplasms; Thyroglobulin; Thyroid Neoplasms; Tretinoin

We report a new case of localized Darier's disease or keratosis follicularis with successful response to topical retinoic acid treatment. We comment the clinical histopathological features and differential diagnosis of these uncommon variant which has only been reported in 10% of the patients.

Topics: Administration, Topical; Adult; Darier Disease; Diagnosis, Differential; Female; Humans; Nevus; Skin Neoplasms; Tretinoin

The present study examined the effect of several prototypic inhibitors of phorbol ester skin tumor promotion on skin tumor promotion by chrysarobin, an anthrone tumor promoter. Retinoic acid (RA) inhibited skin tumor promotion by chrysarobin; however, the degree of inhibition was dependent on the treatment protocol. When RA (10 micrograms/mouse) was given 1 h after each twice-weekly application of chrysarobin (220 nmol/mouse), a marked inhibition of papilloma formation was observed (78%). In additional experiments, using a once-weekly application of chrysarobin, RA also inhibited skin tumor promotion but the magnitude of inhibition was less. Interestingly, RA (10 micrograms/mouse), given 1 or 6 h after the promoter, did not inhibit the induction of epidermal ornithine decarboxylase (ODC) activity induced by a single topical application of chrysarobin (220 nmol). Fluocinolone acetonide (1 microgram/mouse), given 5 min before each twice-weekly application of chrysarobin (220 nmol/mouse) effectively inhibited skin tumor promotion (88%). A 0.5 or 0.25% supplement of alpha-difluoromethylornithine (alpha-DFMO) in the drinking water inhibited the induction of epidermal ODC following chrysarobin (220 nmol/mouse) treatment by 85 or 70%, respectively. Supplements of both 0.25 and 0.5% of alpha-DFMO also led to a 50 and 61% inhibition, respectively, in the number of papillomas per mouse after 25 weeks of promotion with chrysarobin. Interestingly, 0.25% alpha-DFMO in the drinking water did not reduce the number of papillomas per mouse after 20 weeks of promotion with 1.7 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the number of papillomas per mouse that were greater than or equal to 4 mm in diameter was significantly reduced in both chrysarobin- and TPA-treated mice. The data indicate that RA, FA and alpha-DFMO may be general inhibitors of tumor promoter regardless of the chemical class of tumor promoter. The ability of these inhibitors of phorbol ester promotion to inhibit anthrone promotion indicates that some common biochemical pathways may exist for both classes of skin tumor promoters.

Topics: Animals; Anthracenes; Carcinogens; Cocarcinogenesis; Eflornithine; Female; Fluocinolone Acetonide; Mice; Ornithine Decarboxylase; Papilloma; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Twelve patients with multiple basal cell carcinomas resulting from varying causes were treated with high-dose oral isotretinoin (mean daily dosage: 3.1 mg/kg/day) for a mean of 8 months. Of the 270 tumors monitored in these patients, only 8% underwent complete clinical and histologic regression. All patients developed moderate to severe acute toxicities, leading five patients to withdraw from the study. Retinoid skeletal toxicity was identified in two patients who were examined after long-term therapy. Lower doses of isotretinoin (0.25 to 1.5 mg/kg/day) were ineffective for chemotherapy but demonstrated a chemopreventive effect in a subset of three patients who received these lower doses for 3 to 8 years. Two of these three patients have been observed after discontinuation of therapy. In one patient with a history of arsenic exposure, only one new tumor has appeared in a 27-month posttreatment observation period; in the other patient with the nevoid basal cell carcinoma syndrome, 29 new tumors have appeared within a 13-month period. This suggests that the need for long-term maintenance therapy with isotretinoin for chemoprevention of basal cell carcinoma may depend on the underlying cause of the skin cancers.

Topics: Administration, Oral; Adult; Aged; Carcinoma, Basal Cell; Female; Humans; Isomerism; Isotretinoin; Male; Middle Aged; Neoplasms, Multiple Primary; Remission Induction; Skin Neoplasms; Tretinoin

For study of the correlation between differentiation and organ colonization properties of tumor cells, F9 embryonal carcinoma (EC) cells were treated with retinoic acid, an inducer of differentiation; and their organ colonization pattern was assessed by the experimental metastasis assay. Untreated cells were found to colonize the liver, whereas treated cells colonized the lungs. This pattern held true when metastases were scored after spontaneous death or after a careful microscopic search for micrometastases. Histologic examination revealed that both the tumor nodules produced by the untreated and the treated cells had the characteristics of EC devoid of any evidence of differentiation. The immunohistochemical study of the expression of markers typical of embryonal carcinoma cells or of the extracellular matrix components laminin and collagen type IV, typical of differentiated cells, confirmed these results. However, the lack of expression of stage-specific embryonal antigen 1 (SSEA-1), a marker generally associated with the undifferentiated state, observed only in the tumors obtained after injection of treated cells, indicates that the lung nodules probably derive from cells that have responded to the induction in vitro but have dedifferentiated in vivo.

Topics: Animals; Antigens, Surface; Cell Differentiation; Cell Line; Collagen; Extracellular Matrix; Laminin; Liver Neoplasms; Lung Neoplasms; Neoplasm Metastasis; Phenotype; Skin Neoplasms; Teratoma; Tretinoin

Evidence is presented that inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC; EC 4.1.1.17) by retinoic acid may involve inhibition of protein kinase C-mediated synthesis of ODC mRNA. A single application of 10 nmol of TPA to intact mouse skin led to an increase in the steady state levels of epidermal ODC mRNA; a maximal level of ODC mRNA occurred at about 3.5 h after TPA treatment. TPA-induced increase in ODC mRNA preceded the increase in epidermal ODC activity. Application of 17 nmol of retinoic acid 1 h before application of TPA to mouse skin inhibited the induction of both ODC mRNA and ODC activity. Using the DNA-excess filter hybridization technique, we found that TPA-increased steady state levels of ODC mRNA in primary culture of newborn mouse epidermal cells were the result of enhanced accumulation of newly synthesized ODC mRNA. Furthermore, in a pulse-chase experiment, we could not detect any difference in the half-life of ODC mRNA in epidermal cells after TPA or the vehicle dimethyl sulfoxide treatments; the half-life of ODC mRNA was about 7 h in both cases. Exposure of primary cultures of newborn epidermal cells to retinoic acid, in conjunction with TPA, inhibited the synthesis of ODC mRNA and failed to alter the half-life of ODC mRNA. These results implicate the role of transcription activation in TPA-induced ODC gene expression and indicate that retinoic acid may inhibit TPA-induced ODC gene transcription. We also found that protein kinase C may play a role in the mechanism of inhibition by retinoic acid of ODC gene expression. Supporting evidence is the finding that L-alpha-dioctanoylglycerol, an activator of protein kinase C, is a Stage II mouse skin tumor promoter and the application of retinoic acid 1 h before application of L-alpha-dioctanoylglycerol to mouse skin inhibited the induction of ODC activity and ODC mRNA as well as tumor promotion by L-alpha-dioctanoylglycerol. Taken together, one may conclude that the mechanism of inhibition of TPA-induced ODC by retinoic acid may involve the inhibition of protein kinase C-mediated accumulation of newly synthesized ODC mRNA.

Topics: Animals; Diglycerides; Dimethyl Sulfoxide; Enzyme Activation; Female; Glycerides; Mice; Mice, Inbred BALB C; Ornithine Decarboxylase; Protein Kinase C; RNA, Messenger; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Thirty patients, 13 female and 17 male, have been followed from 3 months to 22 years (mean, 81 months; median, 63 months) and special studies have been performed on a proportion of these in order to try to predict malignant evolution. Age at onset was from 20 to 70 years (mean, 43 years; median, 42 years). Duration of disease was from 1 to 30 years (mean, 119 months; median 161 months). Seven patients also had parapsoriasis en plaque or plaque-stage mycosis fungoides at the time of diagnosis and one patient had erythroderma. None of the 22 uncomplicated lymphomatoid papulosis patients developed malignant cutaneous lymphoma during the period of observation, while the remaining 8 patients who had concurrent parapsoriasis en plaque, mycosis fungoides, or erythroderma did not deteriorate further. Single-cell deoxyribonucleic acid (DNA) measurements on the dermal infiltrate were done in 13 patients and were abnormal in 7 patients. Two of these had greatly abnormal DNA histograms and at the same time an abnormal clinical presentation with multiple nodules and tumors. The remaining five patients had DNA histograms that indicated a potential for malignancy. Monoclonal antibody studies were performed on skin biopsy specimens of 10 patients. The dermal infiltrate was dominated by T-helper lymphocytes and some Hodgkin and Reed-Sternberg cells could be detected by the antibodies Ki-1, Ki-24, and Ki-27. Human T-lymphotropic virus type I (HTLV-I) antibodies were found in 3 of 18 patients examined. Treatment with psoralens plus ultraviolet A (PUVA) was effective (partial or complete remission) in six patients but they relapsed at cessation of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Viral; Deltaretrovirus; Deltaretrovirus Antibodies; DNA; Female; Follow-Up Studies; Humans; Isotretinoin; Male; Methotrexate; Middle Aged; Precancerous Conditions; PUVA Therapy; Skin Diseases; Skin Neoplasms; Tretinoin

Retinoids, including isotretinoin, have demonstrated antiproliferative and antineoplastic activity in laboratory and clinical trials. In a phase II trial, 25 patients with extensive mycosis fungoides were evaluated for response to isotretinoin. There was a 44% (11 patients) objective clinical response rate with three clinical complete responses without concomitant evidence of pathologic clearing of the disease. An additional 24% (six patients) showed a minor degree of clinical improvement. The median time to response was two months (range, 0.5 to eight months) and the median response duration was eight months or longer (range, one to 25 months). Chronic toxic reactions consisted primarily of drying of the skin and mucous membranes and resulted in dose reduction in the majority of patients. It is concluded that isotretinoin produces significant clinical benefit to some patients with mycosis fungoides.

Topics: Adult; Aged; Aged, 80 and over; Drug Eruptions; Drug Evaluation; Female; Humans; Isotretinoin; Male; Middle Aged; Mycosis Fungoides; Sezary Syndrome; Skin Neoplasms; Tretinoin; Triglycerides

Topical tretinoin has been used for a number of years to treat patients with acne vulgaris. This paper reviews some of the newer uses of tretinoin, including treatment of patients with photoaging of the skin, premalignant lesions, dry-eye disorders, and its use after dermabrasion.

Topics: Acne Vulgaris; Administration, Topical; Dermabrasion; Humans; Photosensitivity Disorders; Precancerous Conditions; Skin Neoplasms; Tretinoin; Wound Healing; Xerophthalmia

The activity of dietary and topical administration of three retinoids, all-trans-retinoic acid, 13-cis-retinoic acid, and N-(4-hydroxyphenyl)retinamide (4-HPR), as promoters of skin tumor induction in SENCAR mice was studied. When administered as dietary supplements at their maximum tolerated dose levels, all three retinoids promoted tumorigenesis in mice initiated with a single topical dose of 5 micrograms 7,12-dimethylbenz(a)anthracene. Maximal promoting activity was observed with dietary 13-cis-retinoic acid; dietary 4-HPR was significantly less active than was either isomer of retinoic acid. When administered via topical application, all-trans- and 13-cis-retinoic acids both promoted skin tumor induction; 4-HPR did not. HPLC analysis of skin samples from mice receiving dietary 4-HPR showed the parent compound and six metabolites; these metabolites were not found in the skin of mice receiving topical 4-HPR exposure, although 4-HPR itself was present. These data indicate that skin tumor promotion can be induced by systemic administration as well as topical application of the all-trans- and 13-cis-retinoic acids. Substitution of a 4-hydroxyphenylamide terminal group results in a significant reduction in promoting activity. 4-HPR appears to require metabolic activation for tumor promoting activity; this metabolism does not occur in the skin following topical application, but is observed following systemic exposure.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Carcinogens; Diet; Female; Fenretinide; Isomerism; Mice; Mice, Inbred Strains; Skin Neoplasms; Structure-Activity Relationship; Tretinoin

Chronic treatment with the tumor-promoting phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA) and 12-O-retinoylphorbol-13-acetate (RPA) causes permanently increased levels of active collagenolytic enzymes in the dermis and leads to a stable reduction of dermal collagen content. Non-promoting skin mitogens like the Ca-ionophore A 23187 or the 4-O-methylether of TPA, while being active stimulators of collagenolytic enzymes, do not support chronic collagen degradation throughout the experimental period. On the other hand, TPA-induced collagen degradation is not necessarily influenced by inhibition of tumor promotion. Fluocinolone acetonid (FA), an inhibitor preventing not only tumor development but also chronic inflammation and the establishment of a stationary hyperplasia, has been compared with retinoic acid (RA) which has no influence on either the inflammatory reaction or hyperplasia. While FA inhibited the dermal effects of TPA almost completely, RA at a dose that prevented tumor development by 80% had no effect whatsoever in this respect. Therefore, we conclude that both epidermal proliferation and inflammation are accompanied by collagenolytic reactions in the dermis. During chronic treatment sustained collagenolysis correlates with inflammation and/or the establishment of a stationary hyperplasia. Like these it can be regarded as a necessary but insufficient condition of tumor promotion (second stage).

Topics: Animals; Calcimycin; Cell Division; Collagen; Female; Fluocinolone Acetonide; Mice; Phorbol Esters; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

The present study was designed to determine the effects of dietary 13-cis-retinoic acid and retinyl palmitate on mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). Female CD-1 mice were initiated with 150 nmol of 7,12-dimethylbenz(a)anthracene and promoted twice weekly with 8 nmol of TPA. Diets supplemented with retinyl palmitate to yield 60,000 or 200,000 IU or 700,000 for 5 wk followed by 350,000 IU per kg of diet (700,000/350,000) fed to mice during tumor promotion resulted in 9%, 37%, and 65% inhibition of the papilloma yield, respectively, at 21 wk of promotion. Although topical applications of 13-cis-retinoic acid have been almost as effective as retinoic acid in preventing the appearance of mouse skin tumors, dietary 13-cis-retinoic acid at 200,000 or 700,000 IU per kg of diet resulted in no reduction in papilloma yield but did result in a dose-dependent decrease in the tumor burden (weight of tumors per mouse). Therefore, dietary retinyl palmitate yielded a dose-dependent inhibition of the number and weight of tumors promoted by TPA, whereas dietary 13-cis-retinoic acid resulted in a decrease in weight but not in number of tumors promoted by TPA.

Topics: Administration, Cutaneous; Animals; Cell Transformation, Neoplastic; Diet; Diterpenes; Dose-Response Relationship, Drug; Female; Isotretinoin; Mice; Papilloma; Retinyl Esters; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin; Vitamin A

To determine the efficacy of oral isotretinoin in refractory advanced squamous cell carcinoma of the skin.. Case series trial.. Tertiary care center at a university hospital.. A consecutive collection of four patients with advanced squamous cell carcinoma of the skin who failed to respond to standard surgical or radiation therapy.. Isotretinoin in gelatin capsules was given at a total daily dose of 1 mg/kg body weight in two divided doses for at least 4 weeks.. Bidimensional tumor measurements at monthly intervals showed striking responses to isotretinoin in all four patients. Response durations ranged from 2 to more than 23 months. The drug produced reversible moderate mucocutaneous side effects and asymptomatic laboratory abnormalities.. Impressive responses to isotretinoin occurred in our four patients and in six of ten other reported patients. Retinoic acid's mechanisms of action in cutaneous squamous cell carcinoma is not precisely known, but may involve the modulation of epidermal growth factor receptors and certain protein kinases. These in-vitro findings and the clinical data suggest that retinoids may be an effective and well-tolerated therapy for refractory advanced squamous cell carcinoma of the skin. The absence of any other effective systemic therapy indicates the need for continuing trials with retinoids in this disease.

Topics: Aged; Carcinoma, Squamous Cell; Combined Modality Therapy; Humans; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Skin Neoplasms; Tretinoin

A group of 50 patients with basal cell carcinoma of the face was treated by 13-cis-retinoic acid. The treatment resulted in diminution of the tumors. Complete regression was observed in 4 cases. Histological examination revealed necrosis of cancer cells and mononuclear infiltration into the treated tumors. In the group with weak clinical and histological reaction to the treatment all basal cell carcinomas were of adenoid type. A better effect was observed in the group with lower serum retinol level. This treatment method seems to be supplementary to surgery in prevention of the tumor recurrence.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Basal Cell; Female; Humans; Isotretinoin; Male; Middle Aged; Skin Neoplasms; Tretinoin; Vitamin A

Two patients with multiple basal cell carcinomas, due either to the nevoid basal cell carcinoma syndrome (NBCCS) or arsenical insecticide exposure, were treated with oral isotretinoin for 7 or 8 years, respectively. Gradually decreasing dosage levels were employed. During the initial courses of therapy, high doses (2.0-3.0 mg/kg/day) were intended as chemotherapy. In these patients only 6 of 40 (15%) lesions underwent complete clinical regression. In subsequent courses aimed at chemoprevention, the dose was progressively reduced from 1.5 to 0.25 mg/kg/day. During therapy, no new lesions were observed in the patient with the arsenical exposure. The NBCCS patient developed 1 new lesion during therapy at 1.0 mg/kg/day, 1 new lesion at 0.5 mg/kg/day and 5 new lesions at 0.25 mg/kg/day. Treatment was discontinued and the patient with the arsenic exposure developed his first new tumor 17 months afterwards; in contrast, the NBCCS patient developed 29 tumors within 13 months. These findings suggest that long-term therapy with isotretinoin is needed for the continuation of the cancer chemopreventive effect. However, the need for continuous rather than intermittent maintenance therapy, and the determination of the optimal dose for this purpose may depend on the etiology of the multiple carcinomas and on the tolerability of the lowest effective dose by the individual patient. With these encouraging data, it now appears appropriate to expand this pilot study and perform larger trials to determine the usefulness of isotretinoin in the chemoprevention of basal cell carcinoma in patients with multiple tumors.

Topics: Basal Cell Nevus Syndrome; Carcinoma, Basal Cell; Humans; Isotretinoin; Male; Middle Aged; Neoplasms, Multiple Primary; Prognosis; Skin Neoplasms; Tretinoin

Oral retinoids are effective in the treatment of patients with a variety of malignant and nonmalignant skin disorders, including mycosis fungoides. We treated six patients with cutaneous T-cell lymphomas with isotretinoin 1 to 2 mg/kg/d. All patients experienced symptomatic relief (fading of skin lesions and disappearance of pruritus) within two to eight weeks of starting the drug therapy; pretreatment and posttreatment biopsy specimens were unchanged. Adverse effects were minor and primarily consisted of drying of the mucous membranes. We conclude that isotretinoin is a well-tolerated, easily administered drug that provides good palliation of symptoms and signs associated with cutaneous T-cell lymphoma in patients who are unable or unwilling to comply with standard therapy.

Topics: Aged; Female; Humans; Isotretinoin; Lymphoma, Non-Hodgkin; Male; Middle Aged; Skin Neoplasms; T-Lymphocytes; Tretinoin; Xerostomia

Sixteen patients - 12 with cutaneous T cell lymphoma (CTCL), 1 with Sézary syndrome, 1 with actinic reticuloid, and 2 with parapsoriasis variegata - were treated with either a new, potent arotinoid alone or with combined etretinate (Tigason) and PUVA therapy (Re-PUVA). 92% of all patients showed a minor up to a distinct response of their skin lesions within 12.6 +/- 7.4 weeks. More than 50% of the skin lesions cleared in 67% of the patients. After discontinuation of the retinoid therapy, relapses occurred in all cases within 3-10 weeks. There was no difference between the therapeutic efficacy of arotinoid alone and the Re-PUVA regimen, but the latter was less toxic.

Topics: Antineoplastic Agents; Benzoates; Combined Modality Therapy; Humans; Isotretinoin; Lymphoma; PUVA Therapy; Retinoids; Skin Neoplasms; T-Lymphocytes; Tretinoin

Retinoic acid is a potent inhibitor of mouse skin tumor promotion by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). We have further evaluated the effect of retinoic acid on the stages of tumor promotion and also analyzed the effect of duration of retinoic acid treatment on mouse skin tumor promotion by TPA. In a number of independent experiments, either with female CD-1 or SENCAR mice, we failed to observe a specificity of inhibition by retinoic acid of either Stage I or Stage II tumor promotion. In a typical experiment with SENCAR mice, application of 34 nmol of retinoic acid concurrently with each application of either TPA (3.2 nmol) or mezerein (3.2 nmol) to initiated (with 10 nmol 7,12-dimethylbenz(a)anthracene) skin equally inhibited promotion of skin papilloma formation. Furthermore, sustained inhibition of tumor promotion by retinoic acid required a continuous application of retinoic acid in conjunction with each promotional treatment with TPA; if retinoic acid treatment was discontinued, TPA treatment elicited tumor formation. These results indicate: (a) retinoic acid inhibits both Stage I and Stage II of tumor promotion; and (b) inhibition of tumor promotion exhibits retinoic acid dependency.

Topics: Animals; Female; Mice; Ornithine Decarboxylase; Proto-Oncogenes; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin

Topical application of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) to SENCAR mouse skin results within 48 h in a 3-fold elevation of xanthine oxidase (XO) activity, an enzyme capable of generating the reactive oxygen species superoxide and hydrogen peroxide. The antiinflammatory steroid fluocinolone acetonide, an inhibitor of TPA-induced hyperplasia, as well as the multiple stages of tumor promotion as defined in SENCAR mice (Stages I and II), inhibited the TPA-dependent elevation of epidermal XO activity. Neither tosylphenylalanyl chloromethyl ketone nor retinoic acid, inhibitors of promotion Stages I and II, respectively, had significant effects on TPA-induced hyperplasia or elevated XO activity. The nonpromoting but hyperplasiogenic agents ethyl phenylpropiolate and acetic acid significantly elevated XO activity within 48 h of topical application. The non-phorbol ester tumor promoter benzoyl peroxide also elevated XO activity consistent with the degree of induced hyperplasia. Multiple treatments with TPA or ethyl phenylpropiolate resulted in a sustained elevation of XO activity which peaked at five treatments and then declined. Sustained inhibition of XO activity by p.o. administration of allopurinol did not inhibit the TPA-induced hyperplasia as determined histologically. These results suggest that the TPA-dependent elevation of epidermal XO activity is associated with the hyperplasia induced by the agent, and is a consequence of the hyperplasia rather than the cause of it.

Topics: Animals; Carcinogens; Epidermis; Female; Fluocinolone Acetonide; Mice; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tosylphenylalanyl Chloromethyl Ketone; Tretinoin; Xanthine Oxidase

Cholera toxin (CT) at concentrations of 0.1-100 ng/ml induced anchorage-independent growth and DNA synthesis of JB6 cells derived from mouse epidermis. This induction was reversible. CT caused marked increase in the level of intracellular cAMP. Forskolin also increased the cAMP level and induced anchorage-independent growth. However, 12-O-tetradecanoylphorbol-13-acetate (TPA) and 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] induced irreversibly anchorage-independent growth of JB6 cells but did not increase the cAMP level. TPA-resistant clone-30 cells were also resistant to CT in terms of anchorage-independent growth and cAMP induction. Retinoic acid inhibited the induction of anchorage-independent growth of JB6 cells by CT, TPA and 1 alpha,25(OH)2D3. These results suggest that anchorage-independent growth of JB6 cells is induced by cAMP-dependent and cAMP-independent pathways, both of which may include a retinoic acid-sensitive step.

Topics: Animals; Cell Adhesion; Cell Division; Cell Line; Cholera Toxin; DNA Replication; Kinetics; Mice; Precancerous Conditions; Skin Neoplasms; Tetradecanoylphorbol Acetate; Thymidine; Tretinoin

One of the earliest events after treatment of mouse skin with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is the induction of ornithine decarboxylase (ODC). Using an immunoperoxidase technique with a rabbit antiserum specific for ODC, the localization of cells containing high levels of ODC following TPA treatment was determined. CD-1 female mice treated with multiple topical applications of TPA and killed 4.5 h after the last TPA treatment exhibited a heterogeneous localization of ODC in this hyperplastic epidermis. The cells which exhibited intense immunostaining were found predominantly in the suprabasal cells lining the hair follicles. This specific ODC staining in cells surrounding hair follicles was inhibited by pretreatment of mice with either retinoic acid or cycloheximide 1 h before TPA treatment. The induction of ODC-specific staining after TPA treatment in hyperplastic mouse skin was transient, since no staining was observed 16 or 24 h after TPA treatment. In contrast, benign papillomas produced by two-stage tumorigenesis contained some cells demonstrating high levels of ODC a week after the last TPA application. These results indicate that both normal mouse epidermal cells as well as tumor tissue display cellular heterogeneity of ODC expression.

Topics: Animals; Enzyme Induction; Epidermal Cells; Epidermis; Female; Keratins; Mice; Mice, Inbred Strains; Ornithine Decarboxylase; Papilloma; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

The effects of retinol, all-trans-retinoic acid, isotretinoin and etretinate on the activity of basement membrane collagen degrading enzyme was studied in melanoma cells. The results indicated that retinoids at concentrations of up to 10(-6) M did not significantly affect type IV collagenolytic activity in these cells in vitro. Since type IV collagenolytic enzyme may be involved in the metastatic potential of tumour cells, it appears that retinoids do not affect the metastatic potential of melanoma cells by affecting type IV collagenolytic activity.

Topics: Cells, Cultured; Etretinate; Humans; Isotretinoin; Melanoma; Microbial Collagenase; Neoplasm Metastasis; Retinoids; Skin Neoplasms; Tretinoin; Vitamin A

The activity of the synthetic retinoid, N-(4-hydroxyphenyl)retinamide (4-HPR), as a promoter and as an inhibitor of tumor promotion in mouse skin was investigated using CD-1 and SENCAR mice. Dietary administration of 4-HPR inhibited skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) in both mouse strains, although protective activity was observed only at high TPA doses. Dietary 4-HPR had no promoting activity in mice receiving initiation and no TPA promotion. These data suggest that retinoid promotion of skin tumorigenesis may be specific to retinoic acid, and is not necessarily characteristic of the entire chemical class.

Topics: Animals; Carcinogens; Cocarcinogenesis; Diet; Drug Antagonism; Female; Fenretinide; Mice; Mice, Inbred Strains; Neoplasms, Multiple Primary; Phorbols; Skin Neoplasms; Species Specificity; Tetradecanoylphorbol Acetate; Tretinoin

The effect of the time and duration of retinoid treatment on the inhibition of Stage II tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) was studied in CD-1 mice. All mice were initiated with 400 nmol of benzo(a)pyrene and received Stage I tumor promotion (3.2 nmol of TPA twice weekly for 2 wk). Animals were then randomized into groups which received 13-cis-retinoic acid during early, middle, or late Stage II promotion. 13-cis-Retinoic acid pretreatments starting on Day 1, Wk 8, or Wk 23 of Stage II promotion resulted in 47, 28, or 19% inhibition, respectively, of TPA-induced tumor formation. One-half of the mice receiving 13-cis-retinoic acid at Day 1 or Wk 8 were removed from the retinoid treatments at Wk 23, the time of cessation of TPA promotion. The inhibition of tumor formation remained constant during the 15-wk observation period after cessation of retinoid treatment, suggesting that retinoid inhibition of mouse skin tumor promotion is stable in the absence of further promotion and preceded the step of irreversible conversion of promoter dependence to promoter independence.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; DNA; Female; Isotretinoin; Mice; Mice, Inbred Strains; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin

The effects of dietary supplementation of 13-cis-retinoic acid (13-cis-RA) and alpha-difluoromethylornithine (DFMO) in the drinking water on 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation was determined. Administration of 13-cis-RA in the diet and DFMO in the drinking water was started 1 week and 2 days before the first TPA application to the dimethylbenz[a]anthracene-initiated skin of either female CD-1 or SENCAR mice, respectively. Dietary 13-cis-RA failed to inhibit both the tumor yield and the incidence; papillomas per mouse at 0, 5, 50, 100 and 200 mg/kg diet 13-cis-RA doses were 25, 30, 22, 28 and 25 respectively at 18 weeks of promotion treatment and at all doses 100% of the mice bore papillomas. However, dietary 13-cis-RA dramatically reduced the size of skin tumor promoted with TPA. 13-Cis-RA at doses of 5, 50, 100 and 200 mg/kg diet inhibited skin papillomas (greater than 4 mm diameter) per mouse by 28, 55, 76 and 93%, respectively. Retinoid treatment did not affect body weight gains and the survival was more than 80% in all groups. In accord with our previous findings, DFMO when given in drinking water, was a very effective inhibitor of mouse skin tumor promotion by TPA; DFMO at 0.25% concentration inhibited the number of papillomas by 50%. Inhibition of skin tumor promotion by combined treatments with dietary 13-cis-RA (100 mg/kg) and DFMO (0.25%) in the drinking water was possibly additive. The retinoid and DFMO preclude TPA-increased ornithine decarboxylase (ODC) activity and the accumulation of putrescine by differential effects on ODC, an enzyme associated with skin tumor promotion by TPA.

Topics: Animals; Diet; Eflornithine; Female; Isotretinoin; Mice; Mice, Inbred Strains; Ornithine; Ornithine Decarboxylase; Papilloma; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Retinoic acid has been reported to act as an inhibitor and as an enhancer of mouse skin carcinogenesis in vivo. However, no in vitro cell transformation model has been reported to be sensitive to both effects. In an attempt to provide such a model, the effect of retinoic acid on an early step in carcinogen-induced transformation of mouse epidermal cell line 271c was measured using a recently described assay. The step observed is altered response to extracellular Ca2+ as an epidermal terminal differentiation signal. In six out of twelve experiments retinoic acid increased the frequency of altered colonies resulting from treatment with three chemical carcinogens. The enhancement effect was stronger after DMBA treatment than MNNG or MCA, resulting in up to a 13.7-fold increase in the frequency of colonies exhibiting altered terminal differentiation (TF). On the other hand, up to a 10-fold decrease in TF was observed in other experiments. Both the enhancement and inhibitory effects were greater at the higher doses of retinoic acid tested in the range of 10(-10) - 10(-7) M. Variations in cloning efficiency or surviving colony density did not account for the effects on TF. Enhancement effects tended to be observed at lower doses of carcinogen, or in experiments in which TF resulting from treatment with carcinogen alone was in the lower range observed. However, the factors determining each effect have yet to be defined. The enhancement effect of retinoic acid was not merely suppression of the phenotypic endpoint of the in vitro assays, because treatment of carcinogen-altered cells with retinoic acid or TPA in vitro also enhanced their tumorigenicity in vivo compared to acetone controls. These findings suggest that studies of the determinants of retinoid activity should be a prerequisite to their use in chemoprevention.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Cell Line; Cell Transformation, Neoplastic; Cocarcinogenesis; Dose-Response Relationship, Drug; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

A 56-year-old man with a 7-year history of well-documented mycosis fungoides is reported. Because the patient was a treatment failure with topical nitrogen mustard due to severe allergic contact dermatitis, and because of recent reports of the efficacy of retinoid compounds, he was treated with a 6-month course of isotretinoin with total clearing of his skin lesions. Previous case reports and possible mechanisms of action are reviewed.

Topics: Humans; Immunity; Isotretinoin; Male; Middle Aged; Mycosis Fungoides; Nitrogen Mustard Compounds; Skin Neoplasms; Tretinoin

Terminal differentiation of normal and malignant keratinocytes is routinely determined by the ability of these cells to form cornified envelopes after incubation with a calcium ionophore. We have used the human squamous cell carcinoma, SqCC/Y1, to quantify cellular differentiation by the formation of detergent-insoluble protein. The methodology developed employs the metabolic labeling of detergent-insoluble cellular protein with [35S]methionine in the presence of a calcium ionophore. The ratio of filter-retainable radioactivity to that of total cellular protein was shown to be closely correlated to the results obtained by measuring the number of envelope-competent cells when cells were induced to enter a pathway of terminal differentiation in culture by serum deprivation or by treatment with hydrocortisone, and during the inhibition of maturation by either retinoic acid (RA) or epidermal growth factor (EGF). This way of measuring the degree of terminal differentiation of epidermal cells is a relatively simple one that readily allows the simultaneous measurement of multiple samples.

Topics: Blood; Carcinoma, Squamous Cell; Cell Differentiation; Cell Line; Culture Media; Epidermal Growth Factor; Epidermis; Humans; Hydrocortisone; Membrane Proteins; Skin Neoplasms; Solubility; Tretinoin

Ursolic acid (UA) and oleanolic acid (OA), which had been isolated from Glechoma hederacea as inhibitors of Epstein-Barr virus (EBV) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), were tested against inhibitory effect on tumor promotion by TPA in vivo. They inhibited effectively the tumor promotion in mouse skin and the activities were comparable to that of a known inhibitor of tumor promotion, retinoic acid (RA). Interestingly, UA was more effective on a single application before initial TPA-treatment than on a continuous application before each TPA-treatment, while OA and RA were ineffective in the same treatment. These data suggest that the role of UA for inhibitory action on tumor promotion differs slightly from those of RA and OA.

Topics: Animals; Antineoplastic Agents, Phytogenic; Female; Mice; Mice, Inbred ICR; Oleanolic Acid; Sapogenins; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin; Triterpenes; Ursolic Acid

A dermatitis occurring during the treatment of mycosis fungoides with A vitamin analogues (13-cis-retinoic acid and etretinate) and mimicking a progression of the disease is described. It is considered to be a skin reaction due to the treatment. Its benign nature is revealed by histology showing a lymphocytic infiltrate without any atypical sign.

Topics: Aged; Diagnosis, Differential; Drug Eruptions; Etretinate; Humans; Isotretinoin; Middle Aged; Mycosis Fungoides; Skin; Skin Neoplasms; Tretinoin

Retinoic acid has the ability to act as either a weak first stage promoter or a weak complete promoter in the initiation-promotion protocol for skin carcinogenesis in the SENCAR mouse. The retinoid analog RO-10-9359 lacks this tumor promoting activity. Both retinoids however inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion. Additional comparisons revealed that retinoic acid alone can induce dark keratinocytes, a characteristic of tumor promoters, while RO-10-9359 cannot. Retinoic acid but not RO-10-9359 can induce an immediate chemiluminescence response in human polymorphonuclear cells. Both retinoids, however, inhibit a TPA-induced response. Since the chemiluminescence response is believed to be due to oxygen free radical generation, the data suggest that the ability of retinoic acid but not RO-10-9359 to promote tumors and induce dark cells may be due to initial oxidative reactions at the cell membrane.

Topics: Animals; Etretinate; Female; Keratins; Luminescent Measurements; Mice; Neutrophils; Ornithine Decarboxylase; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

The effect of all-trans-retinoic acid (RA) on cellular transformation and on tumorigenicity of retrovirally transformed cells was investigated. RA treatment of NRK and NIH/3T3 cells transformed by BALB/c murine sarcoma virus (MuSV), Kirsten murine sarcoma virus (K-MuSV), and simian sarcoma virus resulted in a significant reduction in anchorage-dependent growth of only K-MuSV-transformed NRK cells. A 62% reduction in cell number was observed at 10(-5) M RA. In contrast, anchorage-independent growth induced by each of the viruses tested was suppressed by RA. Balb/cMSV3T3 cells showed the greatest level of sensitivity with a significant reduction in anchorage-independent growth occurring at 10(-9) M RA. The level of cytoplasmic retinoic acid-binding protein (CRABP) was determined in both parent and transformed cell lines. CRABP was present at a high level in all 3T3 cell types but was absent in all NRK cell lines. For testing the antineoplastic activity of RA in vivo, Balb/cMSV3T3 cells were injected intradermally into nude mice. Subsequent treatment of the tumor sites of these animals by topical application of RA resulted in a significant reduction in both tumor incidence and tumor size, confirming the in vitro results. Analysis of the level of v-onc mRNA revealed that inhibition of retroviral transformation by RA was not due to a decrease in transcription of the v-onc genes.

Topics: Animals; Carrier Proteins; Cell Division; Cell Line; Cell Transformation, Viral; Mice; Mice, Nude; Oncogenes; Receptors, Retinoic Acid; RNA, Messenger; RNA, Viral; Sarcoma Virus, Woolly Monkey; Sarcoma Viruses, Murine; Skin Neoplasms; Transcription, Genetic; Tretinoin; Tumor Virus Infections

A florid case of osteoma cutis was observed following isotretinoin treatment of severe cystic acne in which a few scattered osteomata of the skin were observed prior to the treatment with isotretinoin.

Topics: Acne Vulgaris; Adult; Facial Neoplasms; Female; Humans; Isomerism; Isotretinoin; Osteoma; Skin Neoplasms; Time Factors; Tretinoin

Topics: Animals; Mice; Papilloma; Retinoids; Skin Neoplasms; Tretinoin

Topics: Adult; Female; Humans; Isotretinoin; Skin Neoplasms; Tretinoin

Extensive animal data have suggested that, in some systems, the induction of ornithine decarboxylase (ODC) is an essential, although not sufficient, aspect of tumor promotion and that compounds that inhibit ODC can inhibit tumor formation. Using fasting human volunteers, we report that human epidermal and dermal ODC are consistently induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in a manner similar to that seen in mouse skin. There is a marked intersubject variation in TPA-induced epidermal ODC activity levels. Orally administered compounds significantly inhibited TPA-caused human epidermal ODC induction. These data may be useful in the further development of drugs, doses, and dose schedules for use in human cancer chemoprevention studies.

Topics: Adult; Cells, Cultured; Enzyme Induction; Female; Humans; Indomethacin; Isotretinoin; Male; Ornithine Decarboxylase Inhibitors; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

beta-All-trans-retinoic acid (RA) inhibited the anchorage-independent growth of JB6 cells induced by either mezerein or alpha-epidermal growth factor (alpha-EGF) (a purified fraction of epidermal growth factor). The inhibition was dose dependent for alpha-EGF as well as for RA. Mezerein-induced growth in soft agar was inhibited to a greater extent by RA than was alpha-EGF-induced growth in soft agar, at similar colony yields. The extent of inhibition of anchorage-dependent growth induced by RA was similar for nontransformed JB6 cells and for alpha-EGF-transformed cells, so that transformation was shown not to influence the sensitivity of cells to retinoid inhibition of anchorage-dependent growth. RA was as effective at inhibiting anchorage-independent growth when it was applied after promoter-induced transformation as when it was applied during promoter-induced transformation. Therefore, the antiproliferative effect of RA, without an additional antitransformation effect, was sufficient to account for the reduced colony yield. These results suggest that the antipromoting action of retinoids in JB6 cells may occur by limiting proliferation, the regulation of which may be coupled with the state of differentiation of cells.

Topics: Animals; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Diterpenes; Epidermal Growth Factor; Epidermis; Mice; Skin Neoplasms; Terpenes; Tretinoin

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Cocarcinogenesis; Croton Oil; Fluocinolone Acetonide; Mice; Mice, Inbred Strains; Papilloma; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tosylphenylalanyl Chloromethyl Ketone; Tretinoin

The effect of 1 alpha, 25-dihydroxyvitamin D3 (1 alpha, 25-(OH)2D3) and its 24,24-difluoro analog on the formation of skin tumors in mice was evaluated in a complete carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) as the carcinogen. Twice weekly topical application of 0.25-0.50 nmol of 1 alpha, 25-(OH)2D3 or 0.05-0.10 nmol of the difluoro analog of 1 alpha, 25-(OH)2D3 1 hour prior to treatment with 50 nmol DMBA stimulated tumor formation several fold compared to animals receiving DMBA alone. Topical application of 0.50 nmol of 1 alpha, 25-(OH)2D3 24 hours after treatment with DMBA, or half of this dose of the vitamin D3 metabolite, applied 1 hour before and 24 hours after treatment with DMBA, also stimulated tumor formation several fold. These results are in marked contrast to the potent inhibitory effect of 1 alpha, 25-(OH)2D3 and its difluoro analog on the formation of skin tumors in mice promoted by 12-O-tetradecanoylphorbol-13-acetate.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acetone; Animals; Body Weight; Calcitriol; Cocarcinogenesis; Female; Mice; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin

Benzoyl peroxide (BzPo), a free radical generator with tumor promoting activity on mouse skin, is shown to promote neoplastic transformation of JB6 mouse epidermal cells in vitro. Repeated exposures to BzPo are required to readily detect promotion of transformation of JB6 cells. Markedly reduced net synthesis of the major epidermal ganglioside, trisialoganglioside GT1b, (GT) occurs with BzPo treatment as with other tumor promoters active in this system. Addition of ganglioside GT prevents transformation by BzPo while retinoic acid does not.

Topics: Animals; Benzoyl Peroxide; Cell Line; Cell Transformation, Neoplastic; Cocarcinogenesis; Gangliosides; Mice; Peroxides; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Previous studies have demonstrated that retinoids possess antineoplastic properties against melanoma. The purpose of this study was to determine whether topically applied retinoic acid could prevent melanoma development in syngeneic mice after intracutaneous cell inoculation. Trans-retinoic acid in DMSO was applied daily for 28 days after melanoma implantation and tumor growth was quantitated by the uptake of [14C]thiouracil, a tracer compound specific for melanoma which is incorporated linearly according to the weight of the tumor. Marked reduction in tumor growth was noted at the highest concentration (0.1%) tested and lesser but significantly decreased tumor growth patterns were also realized at lower concentrations in a dose-dependent manner. Thus, topically applied retinoic acid is capable of inhibiting S91 melanoma growth in vivo.

Topics: Administration, Topical; Animals; Carbon Radioisotopes; Dimethyl Sulfoxide; Dose-Response Relationship, Drug; Male; Melanoma; Mice; Mice, Inbred DBA; Neoplasm Transplantation; Skin Neoplasms; Thiouracil; Tretinoin

Currently there is no well-defined biological parameter or marker to help define agents, doses, and dose schedules for human cancer chemoprevention trials. Induction of ornithine decarboxylase, the rate limiting enzyme in the polyamine biosynthetic pathway, has been shown to be an essential aspect of mouse skin tumor promotion. Supplementary information suggest that this enzyme is an important aspect of carcinogenesis in other organ systems and in other animals (including humans). We have developed an assay system which effectively measured tumor promoter (TPA)-induced ornithine decarboxylase activity on 3-4 mm skin samples from mice and humans. Using this system we evaluated the doses and dose schedules of retinoic acid and indomethacin needed to effectively inhibit ornithine decarboxylase activity. Our data suggest that the doses and schedules of these compounds needed to inhibit ornithine decarboxylase activity would be toxic in humans.

Topics: Administration, Oral; Animals; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Indomethacin; Male; Mice; Mice, Inbred Strains; Ornithine Decarboxylase Inhibitors; Phorbols; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Twenty patients with mycosis fungoides and four with Sézary's syndrome were treated with 13-cis-retinoic acid as single therapy in an initial dose of 1 to 2 mg per kg body weight in most cases. Complete remission in mycosis fungoides was obtained in six cases (33%) and partial remission in another ten cases (50%). No convincing response was observed in three cases, and progression of limited nodular lesions occurred in one case. In cases responding to treatment the first sign of remission was observed within two to four weeks. Our short-term experience is that the drug is effective in early as well as advanced stages of mycosis fungoides. Patients with Sézary's syndrome, however, did not respond to the same extent.

Topics: Adult; Aged; Female; Humans; Isomerism; Isotretinoin; Male; Middle Aged; Mycosis Fungoides; Sezary Syndrome; Skin Neoplasms; Time Factors; Tretinoin

Topics: Animals; Cell Transformation, Neoplastic; Etretinate; Female; Humans; Keratins; Male; Middle Aged; Neoplasm Recurrence, Local; Papilloma; Skin Neoplasms; Tretinoin; Urinary Bladder Neoplasms

Treatment with 13-cis-retinoic acid during 12 weeks of a patient with multiple trichoepitheliomas and acne cystica et comedonica did not affect the number of trichoepitheliomas. The cystic lesions, most of them trichoepitheliomas with only a few non-inflammatory cystic acne lesions, were not affected by this treatment.

Topics: Acne Vulgaris; Adult; Face; Humans; Isotretinoin; Male; Neck; Skin Neoplasms; Tretinoin

Tumor initiation in CD-1 mice by benzo[a]pyrene (BaP) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was unaffected by topical pretreatment with 13-cis-retinoic acid (13-cis-RA). Likewise, anthralin-induced tumor promotion in SENCAR mice was unaffected by pretreatment with 13-cis-RA. These results suggest that the action of retinoids in preventing either tumor initiation or promotion is very carcinogen or cocarcinogen specific.

Topics: Animals; Anthralin; Benzo(a)pyrene; Benzopyrenes; Female; Isotretinoin; Methylnitronitrosoguanidine; Mice; Papilloma; Skin Neoplasms; Time Factors; Tretinoin

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Dexamethasone; DNA Replication; Hyperplasia; Indomethacin; Mice; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

A previous paper reports that the potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), has a time-dependent effect on mouse epidermal gap junctions. A single topical application of 1.0 micrograms TPA results in the absence of gap junctions from mouse interfollicular epidermis between 18 and 30 h post-treatment. This paper describes the dose-dependent effect of TPA on mouse epidermis. Observations indicate that only promoting doses of TPA affect the gap junctions. Similarly, while a low dose of the hyperplasiogenic compound mezerein (1.0 microgram) is ineffective, a higher dose (4.0 micrograms) results in a significant reduction in the gap junction number. One and two applications of TPA had identical effects. The potent inhibitor of both stage I and stage II of tumor promotion, Fluocinolone acetonide, used in combination with TPA, completely suppressed the hyperplasiogenic and the gap junction modulating effects of TPA. Retinoic acid, which inhibits only stage II of tumor promotion, did not influence the gap junction eliminating property of TPA. Tosylphenylalanine chloromethyl ketone which is a mild but specific inhibitor of only stage I of tumor promotion counteracted the action of TPA on gap junctions to some extent, which remained present in smaller numbers than in normal tissue at 24 h after the treatment. These results suggest that gap junctions are essential and specifically relevant to stage I tumor promotion.

Topics: Animals; Cell Communication; Diterpenes; Dose-Response Relationship, Drug; Female; Fluocinolone Acetonide; Intercellular Junctions; Mice; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Tosylphenylalanyl Chloromethyl Ketone; Tretinoin

Two retinoids (13-cis-retinoic acid and retinyl palmitate ) have been shown to exert a good preventive effect in chemically induced papillomas and carcinomas of the skin in female Swiss mice; this effect was investigated over a period of 23 weeks. The tumors were induced by repeated topical application of 3-methylcholanthrene (0.3% MCA, dissolved in acetone; 14 applications). Retinyl palmitate (RP; 6 mg in 0.1 ml acetone/mouse; 10 applications) and 13-cis-retinoic acid (RA; 3 mg in 0.1 ml acetone/mouse; 10 applications) were also administered topically for the 3rd to 9th week from the start of the experiment. This investigation gave evidence for the fact that both the retinoids did not only inhibit the development of skin papillomas but had also a marked effect on skin carcinomas.

Topics: Animals; Diterpenes; Isotretinoin; Methylcholanthrene; Mice; Papilloma; Retinyl Esters; Skin Neoplasms; Tretinoin; Vitamin A

An 83-year-old woman with multiple squamous cell carcinomas and keratoacanthomas of the legs was treated with orally administered isotretinoin (13 cis-retinoic acid). Complete regression of the tumors was noted during the initial six-month treatment period. In the subsequent 36 months, four new cutaneous tumors were excised. There have been no recurrences of lesions that regressed while the patient was receiving retinoid therapy.

Topics: Administration, Oral; Aged; Carcinoma, Squamous Cell; Female; Humans; Isotretinoin; Keratoacanthoma; Leg; Skin Diseases; Skin Neoplasms; Tretinoin

Patients with basal cell carcinoma were treated locally with 13-cis-retinoic acid. Disappearance of the tumors was observed in two of fifteen patients. Thirteen patients whose tumors diminished after the treatment were finally managed surgically. Biopsy specimens were examined histopathologically and by autoradiography. Treated tumors showed reduction of labeling indices as compared with the nontreated group.

Topics: Adult; Aged; Carcinoma, Basal Cell; Female; Humans; Isotretinoin; Male; Middle Aged; Skin Neoplasms; Tretinoin

Four patients with refractory cutaneous T-cell lymphoma (mycosis fungoides) were treated with 13-cis-retinoic acid. Near complete clearing of extensive tumours and plaques was seen in one patient, who remains in partial remission with continued improvement after fifteen months. Two patients showed improvement in pruritus and 50% reduction in plaques by four and six weeks, respectively. The fourth patient had improvement in pruritus and clearing of plaques, but dryness and scaling necessitated reduction and eventually withdrawal of the treatment.

Topics: Adult; Aged; Female; Humans; Isotretinoin; Male; Middle Aged; Mycosis Fungoides; Skin Neoplasms; Time Factors; Tretinoin

Topics: Humans; Isotretinoin; Lymphoma; Skin Neoplasms; T-Lymphocytes; Tretinoin

The naturally occurring retinoids (vitamin A alcohol = retinol and all-trans-retinoic acid) have been largely replaced by synthetic retinoids in recent years as systemic drugs for use in dermatology. At the present time, two synthetic retinoids are commercially available: etretinate (Tigason) and isotretinoin (Accutane). These compounds-which have a more favourable therapeutic index than the naturally occurring retinoids-ushered in a new era of dermatological therapy by their potent antikeratinizing, antiseborrhoeic (only isotretinoin) and antineoplastic action. The broadest indications for the use of these retinoids are psoriasis (etretinate) and cystic acne (isotretinoin), whereas the most dramatic effects are encountered in a number of severe ichthyosiform disorders. Another important, although at present not clearly defined role of the retinoids is in the prophylaxis of skin tumours.

Topics: Acne Vulgaris; Etretinate; Humans; Ichthyosis; Isotretinoin; Psoriasis; Retinoids; Skin Diseases; Skin Neoplasms; Tretinoin

Retinoic acid, a potent inhibitor of mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate, fails to inhibit tumor formation by the complete carcinogen, 7, 12-dimethylbenz[a]anthracene (DMBA). To obtain further clues about the nature of the mechanism of the carcinogenic process as well as the mechanism of the effect of retinoic acid on tumor promotion, the effect of retinoic acid and two other modifiers (dexamethasone and 7,8-benzoflavone) of tumor formation on tumor promotion by 7-bromomethylbenz[a]anthracene (BrMBA) was determined. BrMBA, a structural analogue of DMBA, is a weak mouse skin tumor-initiating agent but is a good skin tumor promoter. Application of 10, 100, and 200 nmol of BrMBA twice weekly to DMBA-initiated skin resulted in 0, 1.6, and 2.5 papillomas per mouse, and 0, 44, and 60% of mice had papillomas at the 25th week of promotion treatment, respectively. Application of 17 nmol of retinoic acid or 76 nmol of dexamethasone 30 min prior to each twice weekly application of 100 nmol of BrMBA to DMBA-initiated skin inhibited the formation of skin papillomas by 73 and 100%, respectively. 7,8-Benzoflavone, at a 367-nmol dose, did not inhibit tumor promotion by BrMBA. Application of 200 nmol of BrMBA to mouse skin induced epidermal ornithine decarboxylase activity; a peak activity was observed between 8 and 18 hr following BrMBA treatment. Application of 17 nmol of retinoic acid or 76 nmol of dexamethasone inhibited the induction of ornithine decarboxylase activity by BrMBA. 7,8-Benzoflavone did not inhibit the induction of ornithine decarboxylase activity by BrMBA. Retinoic acid and dexamethasone, which inhibit tumor promotion by 12-O-tetradecanoylphorbol-13-acetate, also inhibited tumor promotion by BrMBA, but the nature of the mechanism of tumor promotion by BrMBA is unclear; BrMBA did not inhibit specific binding of 12-O-[3H]tetradecanoylphorbol-13-acetate to the cellular membrane fraction of mouse epidermis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benz(a)Anthracenes; Cocarcinogenesis; Dexamethasone; Drug Interactions; Enzyme Induction; Female; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Papilloma; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Benzoates; Cell Differentiation; Cell Division; Guinea Pigs; Humans; Hyperplasia; In Vitro Techniques; Isotretinoin; Neoplasms, Experimental; Rabbits; Retinoids; Skin; Skin Neoplasms; Tretinoin; Vitamin A

Topics: Animals; Avitaminosis; Female; Humans; Neoplasms; Neoplasms, Experimental; Nutritional Physiological Phenomena; Papilloma; Safety; Skin Neoplasms; Tretinoin; Vitamin A; Vitamins; World Health Organization; Xerophthalmia

Epidermal changes (mitosis, DNA synthesis, hyperplasia and acanthosis) were used to assay the effects of three different treatments on the dorsal skin of hairless mice: ultraviolet radiation (UVR), all-trans retinoic acid (RA) and/or 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Mice receiving 20 exposures to fluorescent sunlamps in 4 wk (200 Robertson-Berger counts, or about one erythema dose daily, 5 days/wk) and subsequent topical application of methanol (3 applications/wk, beginning 3 wk after the end of UVR treatment) still displayed hyperproliferative cellular activity at least 17 wk after the final UV irradiation. Alone, either RA or TPA (0.001% in methanol, applied topically 3 times/wk) had similar hyperproliferative effects on the epidermis initially, but the skin appeared to adapt to continued treatment with TPA after 14 wk while RA-treated skin remained hyperproliferative. To study the effects of each reagent on UVR-exposed skin, an initiation-promotion protocol was used: repeated applications of the test compound were started 3 wk after the end of 4 wk of UVR exposures. By this method, treatment with either TPA or RA resulted in additional epidermal activity initially. However, although TPA-treated epidermis returned to the control level of activity by wk 21, no significant adaptation to RA treatment was seen.

Topics: Animals; Carcinogens; Cocarcinogenesis; Epidermis; Male; Mice; Mice, Hairless; Mitosis; Neoplasms, Radiation-Induced; Phorbols; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin; Ultraviolet Rays

Papillomas and carcinomas were induced on the skin of mice by initiation with dimethylbenzanthracene, followed by promotion with 12-O-tetradecanoylphorbol-13-acetate. Retinoic acid was applied topically, either chronically, throughout the promotion period, or acutely, to the papillomas or carcinomas. All tumor types were verified histologically. Tumor tissue was incubated with labeled glucosamine and labeled glycoproteins released into media were fractionated on DEAE-Sephadex. For papillomas, one peak (eluted with 0.17 M NaCl) appeared and another (0.40 M) all but disappeared as a result of retinoic acid treatment. Carcinomas also showed the 0.40 M peak released by papillomas, which was also suppressed by retinoic acid. Carcinomas released a 0.26 M peak instead of the 0.17 M peak in response to the retinoid. All three peaks yielded single, symmetrical peaks on gel filtration columns. They were all resistant to mild alkaline hydrolysis. Labeling experiments revealed the presence also of mannose, galactose, and traces of fucose in all three glycoproteins. The 0.17 and 0.26 M peaks were bound by concanavalin A-Sepharose columns, the 0.40 M peak was not. Molecular weights, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, were approximately 80,000 and 105,000 (0.17 M peak), 67,000 (0.26 M peak), 70,000 and 80,000 (0.4 M peak).

Topics: Animals; Electrophoresis, Polyacrylamide Gel; Glycoproteins; Male; Mice; Molecular Weight; Neoplasm Proteins; Neoplasms, Experimental; Papilloma; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

There is a correlation between the ability to induce the polyamine-biosynthetic enzyme ornithine decarboxylase (ODC) and the tumor-promoting ability of various carcinogens in mouse epidermis. Some agents which inhibit skin carcinogenesis also inhibit ODC induction. In this study, all-trans-retinoic acid (RA) regimens that inhibited the induction of epidermal ODC by ultraviolet-B (UVB) were tested for their ability to inhibit UVB skin carcinogenesis. Hairless mice were irradiated once daily with UVB for 20 days, receiving a total dose of UVB (17.1 kJ/sq m). Topical RA was applied immediately (RA, one dose) or applied 0, 1, 2, 3, and 4 hr (RA, five doses) after each irradiance. The mice were maintained for 52 weeks and then sacrificed. Groups treated with RA tended to have fewer mice with tumors, fewer tumors per mouse, smaller tumor diameters, and slower growing tumors than did appropriate irradiated control groups. RA given five times was more effective than was RA given one time at inhibiting UVB skin carcinogenesis. These results show that RA treatments that inhibit epidermal ODC induction may be effective in reducing the carcinogenicity of UVB.

Topics: Animals; Carboxy-Lyases; Enzyme Induction; Female; Hyperplasia; Mice; Ornithine Decarboxylase; Skin; Skin Neoplasms; Time Factors; Tretinoin; Ultraviolet Rays

Topics: Administration, Oral; Adult; Etretinate; Humans; Mycosis Fungoides; Photochemotherapy; PUVA Therapy; Skin Neoplasms; Tretinoin

Twelve patients with various types of lymphoma were treated with etretinate. The diagnosis included parapsoriasis en plaque, epidermotropic lymphoma (diffuse chronic erythroderma with atypical mononuclear cells, Sézary syndrome or MF tumours) and non-epidermotropic lymphoma. The patients received etretinate in a dose of 0.8 to 1.0 mg/kg/day for 2 to 14 months. No additional therapy was given. Patients with epidermotropic lymphomas stage I and II had a favourable clinical and histological response whereas those with deeply infiltrating tumours remained unresponsive. Patients with parapsoriasis en plaque and poikiloderma showed little response. Of the four patients who discontinued the treatment, three had recurrences after 3 to 4 months but one remained clear. The results obtained with etretinate may equal those obtained with more aggressive treatments.

Topics: Aged; Etretinate; Female; Humans; Lymphoma; Male; Middle Aged; Parapsoriasis; Skin Neoplasms; Tretinoin

Topics: Bowen's Disease; Carcinoma, Squamous Cell; Etretinate; Genital Neoplasms, Male; Humans; Male; Recurrence; Skin Neoplasms; Tretinoin

Topics: Acne Vulgaris; Humans; Isotretinoin; Keratins; Psoriasis; Skin Diseases; Skin Neoplasms; Tretinoin; Vitamin A

Pathological and histochemical studies were made to clarify the response to an aromatic retinoids (Ro 10-1670, Ro 10-9359) of the papilloma and carcinoma in hamster cheek pouch and mouse dorsal skin. The sizes of papilloma and carcinoma were remarkably reduced or completely regressed following systemic and topical administration of the aromatic retinoids. The antitumor effects increased in proportion to the frequency of administration than doses and were showed no side effects. Tumor tissues responded remarkably to the aromatic retinoids indicated an irregular keratinization including loss of hornified cells, nuclear vacuolization and inflammatory infiltrates which located in the border layer between stromas and neoplastic epithelia. Histochemically, tumor tissues which intensely affected by drugs were characterized by the presence of abundant acid phosphatase active cells. Those acid phosphatase active cells may be consisted of tumor cells, histiocytes and fibroblasts. In the electrocytochemical study acid phosphatase (a lysosomal marker enzyme) activity was found in epithelial tumor cells and fibroblasts. These results were indicated that epithelial tumor regression by aromatic retinoids the might be due to the accelerated lysosomal activity in the tumor cells and fibroblasts.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acitretin; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cricetinae; Etretinate; Mesocricetus; Mice; Neoplasms, Experimental; Papilloma; Skin Neoplasms; Tretinoin

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benz(a)Anthracenes; Benzo(a)pyrene; Benzoflavones; Benzopyrenes; Dose-Response Relationship, Drug; Enzyme Induction; Female; Flavonoids; Injections, Intraperitoneal; Methylcholanthrene; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Papilloma; Phorbols; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Two distinct forms of intercellular communication have been found in animal tissues, one using the familiar, trans-membrane, extracellular route and the other using an entirely intracellular route. The intracellular route depends on specialized, permeable (gap) junctions which form at areas of contact between adjacent cells. The junctions contain aqueous channels which directly link the cytoplasms of the coupled cells. Small ions and molecules pass through these channels and move freely between all cells in coupled populations. The structural protein which forms the gap junctional channel has been isolated and characterized. It has an apparent M.Wt. of 16,000 and readily forms multimeric structures. In the membrane, six protein subunits surround the central aqueous pore. Addition of retinoic acid to cells appears to close the junctional channels. This effect of retinoic acid on the junctional pathway of intercellular communication may explain some of its biological activities.

Topics: Animals; Cell Communication; Humans; Intercellular Junctions; Ion Channels; Liver; Liver Regeneration; Membrane Proteins; Molecular Weight; Neoplasms; Permeability; Rats; Skin Neoplasms; Tretinoin

The biology of tumor formation by the initiation-promotion protocol differs from that of the complete carcinogenesis process. In the latter case, the latency period is longer and tumor yield is less, but carcinomas appear much earlier. Retinoic acid, a potent inhibitor of both the induction of ODC activity and tumor promotion by TPA, failed to inhibit both the induction of ODC activity and tumor formation by DMBA. 7,8-Benzoflavone, which did not inhibit the induction of ODC activity by TPA, inhibited the induction of ODC activity and tumor formation by DMBA. The results indicate that: (a) mechanism of the induction of ODC activity and tumor formation by a complete carcinogen appears to be different from that of the tumor promoter TPA; (b) DMBA-induced ODC activity may be an important component of the mechanism of DMBA carcinogenesis; and (c) although there is a wealth of data that indicate the efficacy of the retinoids in the prevention of a variety of cancers in experimental animals, including mammary carcinogenesis by DMBA (3,5), the present results and those reported by others (2) are not in agreement with a universal effect of retinoic acid in the prevention of carcinogenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benz(a)Anthracenes; Benzoflavones; Carcinogens; Cocarcinogenesis; Enzyme Induction; Flavonoids; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Chromatography, Affinity; Female; Fibronectins; Fucose; Leucine; Mice; Neoplasms, Experimental; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Both auricles of 21 domestic rabbits were painted with dimethylbenzanthracene (DMBA). Eleven animals of this group were additionally fed aromatic retinoid (AR) by an esophageal tube. Two control animals were not treated at all. Eight or 9 weeks after the beginning of the study six of the seven remaining animals, which had only been painted with DMBA, developed a total of 25 keratoacanthoma-like tumors (KA). On the other hand, none of the seven animals left, which were painted with DMBA and fed AR showed any tumor by this time. The systemic effect of AR was studied in biopsies from the snout and the back. The epidermis of the snout showed 'mucous mataplasia' by histochemical and electron-microscopic criteria, whereas the epidermis of the back was not significantly altered. The production of intra- and extracellular lamellated material indicated an additional effect of AR on epidermal lipid metabolism. The effect of AR in the prevention of DMBA-induced tumors was characterized by 'mucoid cytolysis' and karyolysis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benz(a)Anthracenes; Esophagus; Etretinate; Intubation; Keratoacanthoma; Microscopy, Electron; Neoplasms, Experimental; Rabbits; Skin; Skin Diseases; Skin Neoplasms; Tretinoin

Three patients with multiple basal cell carcinomas, due either to excessive sunlight exposure, the nevoid basal cell carcinoma syndrome, or arsenical insecticide exposure, were treated with oral isotretinoin for 2 1/2 to 4 years. Although higher doses were used initially, approximately 1.5 mg/kg/day was used for long-term therapy in all three patients. Therapeutic effects on existing tumors varied between each patient, and only nine of sixty-five lesions underwent complete clinical regression. No tumors enlarged in two patients; a few tumors enlarged slightly in the third patient, particularly during the later courses of therapy when isotretinoin was given at lower dosage. No new lesions have been observed in any of these three patients. With these encouraging preliminary data, it now may be appropriate to perform larger trials for longer periods of time to determine the usefulness of isotretinoin in the chemoprevention of basal cell carcinoma in patients with multiple tumors.

Topics: Aged; Carcinoma, Basal Cell; Humans; Isomerism; Isotretinoin; Male; Middle Aged; Neoplasms, Multiple Primary; Skin Neoplasms; Tretinoin

Investigation of retinoids for anticancer activity in humans, either in the chemopreventive or treatment mode, has been little studied. We summarize here our ongoing investigations in four different areas: (1) secondary prevention of cervical dysplasia with topical application of all-trans-retinoic acid; (2) adjuvant treatment of resected high-risk stage I and II malignant melanoma with bacille Calmette Guérin (BCG) plus or minus oral vitamin A; (3) topical vitamin A acid therapy for cutaneous metastatic melanoma; an (4) oral isotretinoin as an anticancer agent.

Topics: Diterpenes; Female; Humans; Isomerism; Isotretinoin; Melanoma; Neoplasms; Palmitates; Retinyl Esters; Skin Neoplasms; Tretinoin; Uterine Cervical Dysplasia; Vitamin A

A 77-year-old woman developed a diffuse nodular eruption with histologic, ultrastructural, and biologic evidence of cutaneous T-cell lymphoma (CTCL) limited to the skin. She was treated with a new aromatic retinoid Ro 10-9359 (1 mg/kg/day). After 34 days, the lesions flattened completely and the mononuclear cell infiltrate decreased significantly. No clinical recurrences occurred after a 4-month survey. Discontinuation of the aromatic retinoid led to a relapse with identical clinical and histologic features.

Topics: Aged; Etretinate; Female; Humans; Lymphoma; Skin Neoplasms; T-Lymphocytes; Tretinoin

Topics: Adolescent; Female; Humans; Keratolytic Agents; Middle Aged; Papilloma; Skin; Skin Neoplasms; Syndrome; Tretinoin

The tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) causes a dose-dependent induction (up to 300-fold) of ornithine decarboxylase activity in the epidermis of intact mice within 5 hours after the application to the skin of from 1 to 10 nmoles of the ester in 0.2 ml of acetone. Enzyme activity regresses with a half-life of 17 minutes, the shortest known for any enzyme. The induction is inhibited in a dose-dependent manner by a single application of from 0.034 to 3.4 nmoles of retinoic acid within an hour before to an hour after phorbol ester treatment. Of over thirty natural and synthetic retinoids that were tested for this property, all-trans-retinoic acid was most effective. The ability of retinoic acid and its congeners to inhibit tumor promotion by the phorbol ester correlated with the effect of dose, structure, and time of treatment on the induction of ornithine decarboxylase. It appears that a permanently increased level of the enzyme and its product, putrescine, may be one of the essential components of the mechanism of tumor promotion.

Topics: Animals; Carboxy-Lyases; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Topics: Etretinate; Female; Humans; Middle Aged; Mycosis Fungoides; Skin Neoplasms; Tretinoin; Vitamin A

Retinoids given in a high dosage are able to reduce or prevent the growth of experimental skin tumors in animals. Our study on the systemic effect of aromatic retinoid (Ro 10-9359) on DMBA-induced skin tumors in rabbits supported these findings. The antitumor effect seems to be independent of the type of tumor induction. Previous reports and the possibility of using this retinoid effect in the treatment of skin tumors in man are discussed.

Topics: Animals; Antineoplastic Agents; Etretinate; Humans; Neoplasms, Experimental; Rabbits; Skin Neoplasms; Tretinoin; Vitamin A

Several analogues (15a--e) of methyl (E,E,Z,E)-3,7-dimethyl-6-fluoro-9-(4-methoxy-2,3,6-trimethylphenyl)nonatetraenoate (15f), which had been found to cause a marked regression of chemically induced skin papillomas in mice, were prepared. Two synthetically versatile methods leading to these derivatives are described. The key intermediate, ethyl (Z)-2-fluoro-3-methyl-4,4-dimethoxy-2-butenoate (8), was elaborated to the C10 aldehyde ester, methyl (2E,4E,6Z)-3-methyl-6-fluoro-7-formyl-2,4,6-octatrienoate (14a), which upon Wittig condensation with the aryl-phosphonium salts 13a--e gave the (2E,4E,6Z,8E)-3,7-dimethyl-6-fluoro-9-aryl-2,4,6,8-nonatetraenoates 15a--e. Alternatively, Wittig reaction of 8 and [(4-methoxy-2,3,6-trimethylphenyl)methyl]triphenylphosphonium chloride (13f) gave a mixture of (E/Z,E)-2-fluoro-3-methyl-5-(2,3,6-trimethyl-4-methoxyphenyl)-2,4-pentadienoates 17 and 18, which was converted to 15f. The biological activity of these analogues and the 1H and 19F NMR spectral properties of the intermediates and final products are discussed.

Topics: Animals; Antineoplastic Agents; Mice; Papilloma; Skin Neoplasms; Tretinoin

Topics: Child; Etretinate; Female; Humans; Skin Neoplasms; Time Factors; Tretinoin; Xeroderma Pigmentosum

Aromatic retinoid Ro 10-9359 1 mg/kg body weight was given to an 11-year-old girl with xeroderma pigmentosum. Therapy resulted in disappearance of actinic keratoses and basal cell carcinomas. The occurrence of new tumors could be prevented in this patient while she participated in this preventive therapy for 7 months. The reduction of the aromatic retinoid to 0.4 mg/kg body weight every other day resulted in the reappearance of four basal cell carcinomas an one keratoacanthoma within 6 weeks.

Topics: Child; Etretinate; Female; Humans; Skin Neoplasms; Tretinoin; Xeroderma Pigmentosum

Analogues of retinoic acid that have their major modifications in the 5,6 double bond and 4-methylene group regions of the beta-cyclogeranylidene ring have been synthesized as potential agents for the treatment and prevention of epithelial cancer. These modifications were intended to reduce retinoid toxicity by lowering the effective treatment dose because the major metabolic deactivation pathway would be inhibited. Ethyl (E)-3,7-dimethyl-9-(exo-2-bicyclo[2.2.1]-heptyl)-2,4,6,8-nonatetraenoate (7), ethyl (E)-3,7-dimethyl-9-(2,2,6-trimethylbicyclo[4.1.0]hept-1-yl)-2,4,6,8-nonatetraen oate (18), (E)-1-(4-carbethoxyphenyl)-2-methyl-4-(2,2,6-trimethylbicyclo[4.1.0]hept-1-yl)- 1,3-butadiene (28), (E)-retinoic acid-4,4,18,18,18-d5 (39), and ethyl (E)-3,7-dimethyl-9-(3,3-ethano-2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoate (47) displayed moderate to excellent activity in an assay for the inhibition of tumor promoter-induced mouse epidermal ornithine decarboxylase.

Topics: Animals; Antineoplastic Agents; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Tretinoin

Topics: Adult; Bowen's Disease; Carcinoma, Squamous Cell; Etretinate; Female; Humans; Skin Neoplasms; Tretinoin; Vulvar Neoplasms

Topics: Animals; Humans; Neoplasms; Neoplasms, Experimental; Organ Culture Techniques; Papilloma; Rats; Skin Neoplasms; Stomach Neoplasms; Structure-Activity Relationship; Tretinoin; Vitamin A; Vitamin A Deficiency

Topics: Animals; Etretinate; Female; Folic Acid; Humans; Isomerism; Isotretinoin; Neoplasms; Neoplasms, Experimental; Skin Neoplasms; Tretinoin; Uterine Cervical Neoplasms; Vitamin A; Vitamin E

Cellular retinoic acid-binding protein (cRABP) was detected in the cytosol of virus-induced papilloma (Shope) of rabbit skin. The Shope papilloma cRABP showed the same ligand specificity and sedimentation value (2S) as was found in other animal species. The level of cRABP in the papillomatous tissue was significantly higher than that in the normal rabbit skin and increased in accordance with the growth and development of the tumor, reaching a peak about 40 days after the inoculation of the Shope papilloma virus. Although this binding capacity was about 15 times greater than in the normal skin, the level of cRABP in the transplantable carcinomas Vx2 and Vx7, both originating from the virus-induced papillomas over 20 years ago, was much the same as in normal rabbit skin.

Topics: Animals; Carrier Proteins; Cell Line; Centrifugation, Density Gradient; Chromatography, Gel; Rabbits; Skin Neoplasms; Time Factors; Tretinoin; Tumor Virus Infections

The effects of all-trans retinoic acid (RA) in 0.05%, 0.025% and 0.005% concentrations on ultraviolet (UV) induced carcinogenesis was investigated in the skin of Uscd strain hairless mice. A carcinogenic amount of UV energy was delivered over the 12-mo period of the study. The 0.025% and 0.005% RA solutions did not alter the development of cutaneous cancers. However, the 0.05% RA concentration significantly inhibited the tumor formation in this study.

Topics: Animals; Mice; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Ornithine Decarboxylase; Skin Neoplasms; Tretinoin; Ultraviolet Rays

The evidence for effects of the retinoids on UV-induced carcinogenesis is sparse. Clinical observations indicate that topical RA can cause significant regression of premalignant actinic keratoses. Also there is some evidence that this agent can cause dissolution of some basal cell epitheliomas. However this latter effect does not appear to be of therapeutic value. Systemic retinoids are of little value in the treatment of premalignant and malignant cutaneous lesions though 13-cis-retinoic acid might be of use in the basal cell nevus syndrome. Examination of the influence of the retinoids on photocarcinogenesis essentially has been confined to RA and animal experimentation. RA in nontoxic concentrations can both stimulate and inhibit photocarcinogenesis depending upon the circumstances of the study. The mechanisms of these responses are not clear. Influences on DNA synthesis directly and/or indirectly or on immune responses may be involved in both effects. Preliminary studies with oral 13-cis-retinoic acid have not demonstrated any effects to date on UV-induced skin cancer formation.

Topics: Animals; DNA; Mice; Neoplasms, Radiation-Induced; Skin Neoplasms; Tretinoin; Ultraviolet Rays

Topics: Animals; Dose-Response Relationship, Drug; Etretinate; Neoplasm Transplantation; Rabbits; Skin Neoplasms; Tretinoin; Tumor Virus Infections

Although much recent work suggests that retinoids can prevent the development of epithelial cancers, their mechanism of action remains unknown. Since malignancy has been associated with alterations in gap junctions, desmosomes, microfilaments, and hemidesmosomes, the authors examined freeze-fracture replicas and thin sections of cell membranes of: (1) 11 basal cell cancers (BCC) treated twice daily for two weeks with topical 1.0% retinoid acid (RA); (2) 21 BCC treated for 2 to 17 weeks with oral 13-cis retinoic acid (CRA) (1.0-8.0 mg/kg/day); and (3) 17 BCC prior to retinoid treatment and/or after applications of vehicle alone. Both thin sections and replicas were examined and photographed in a single-blind fashion, and the density and size distribution of gap junctions and desmosomes were computed planimetrically. Topical RA treatment induced a two-fold increase in gap junction density (P less than 0.025) over controls. In contrast, RA produced a concurrent = 35% decrease in desmosome density. Systemic CRA did not significantly alter either gap junction or desmosome density or size. Finally, neither RA nor CRA treatment appeared to influence hemidesmosome or microfilament populations. Structural changes in both treatment groups did not correlate with either tumor regression or inflammation. Topical and systemic retinoids may exert their antineoplastic activity by different cellular mechanisms.

Topics: Administration, Topical; Adult; Aged; Carcinoma, Basal Cell; Cell Membrane; Desmosomes; Freeze Fracturing; Humans; Intercellular Junctions; Male; Middle Aged; Skin Neoplasms; Tretinoin; Vitamin A

A controversy exists regarding the ability of retinoic acid to enhance photocarcinogenesis. Divergent results have been obtained with albino hairless mice. We examined this issue with the lightly pigmented variety. We followed two designs: 1. ultraviolet light and topical retinoic acid were given concomitantly while the retinoic acid was continued for many weeks after stopping irradiation; 2. tumors were first induced by ultraviolet light and then treated topically with retinoic acid. In both studies, retinoic acid did not enhance photocarcinogenesis with regard to latent period, tumor yield or tumor progression. It appears that different treatment schedules and different varieties of mice can produce widely disparate results.

Topics: Administration, Topical; Animals; Female; Mice; Mice, Hairless; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Skin Neoplasms; Tretinoin; Ultraviolet Rays

Topics: Adolescent; Adult; Aged; Darier Disease; Diagnosis, Differential; Female; Humans; Male; Middle Aged; Nevus; Skin; Skin Neoplasms; Tretinoin

Analogues of retinoic acid have been synthesized as potential chemopreventive agents against epithelial cancer. Ethyl (E)-9-(2-norbornenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate (9), (E)-3,7-dimethyl-9-(2-ethyl-6,6-dimethyl-1-cyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid (25), and 2-(2'-methoxyethoxy)ethyl retinoate (26) displayed good activity in the inhibition of tumor promoter-induced mouse epidermal ornithine decarboxylase assay. (E)-1-(3-Acetoxyphenyl)-4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)hexa1,3,5 -triene (34) had low activity. (E)-5-[2,6-Dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)octa-1,3,5,7-tetraen-1 -yl]tetrazole (40) was inactive.

Topics: Animals; Epidermis; Female; Mice; Neoplasms; Neoplasms, Experimental; Ornithine Decarboxylase Inhibitors; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Tretinoin

Two patients with cutaneous metastatic melanoma were treated with a topical retinoid, beta-all-trans-retinoic acid. Complete regression of the treated lesions was noted in one patient and a partial response was seen in the other patient. The mechanism of anti-tumour action of the retinoids is not completely known but binding to intracytoplasmic receptors with promotion of cellular differentiation, alteration of membranes, and immunological adjuvant effects may be involved.

Topics: Administration, Topical; Adult; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Skin Neoplasms; Tretinoin

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Carboxy-Lyases; Cyclooxygenase Inhibitors; Female; Indomethacin; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Phorbols; Prostaglandins; Prostaglandins E, Synthetic; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Topics: Administration, Oral; Adult; Animals; Carcinoma, Squamous Cell; Etretinate; Humans; Male; Papillomaviridae; Skin Diseases, Infectious; Skin Neoplasms; Tretinoin; Tumor Virus Infections

The effects of fluocinolone acetonide (FA), retinoic acid (RA), and tosylphenylalanine chloromethyl ketone (TPCK) on two-stage promotion after 7,12-dimethylbenz[a]-anthracene (DMBA) initiation in female Sencar mice were investigated. The two-stage promotion protocol was achieved by twice weekly applications of 2 microgram of 12-O-tetradecanoylphorbol 13-acetate (TPA) for 2 weeks (stage I) followed by twice weekly applications of mezerein for 18 weeks (stage II). Separately stage I and II do not cause any tumors to develop after DMBA initiation. FA was found to be a potent inhibitor of stages I and II but to a greater degree for stage I than for stage II. RA was ineffective in stage I but was a potent inhibitor of stage II; TPCK specifically inhibited stage I but not stage II. FA and TPCK effectively counteract the appearance of the dark basal keratinocytes, whereas RA has no effect. These results provide additional evidence for the importance of dark basal keratinocytes in stage I of promotion and indicate that most of the other biochemical and morphological responses normally associated with promotion (such as polyamines) are actually associated with stage II of promotion.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Diterpenes; Epidermal Cells; Female; Fluocinolone Acetonide; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Phorbol Esters; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Tosylphenylalanyl Chloromethyl Ketone; Tretinoin

Topics: Administration, Oral; Adult; Foot Dermatoses; Foot Diseases; Humans; Isotretinoin; Keratoacanthoma; Male; Neoplasms, Multiple Primary; Skin Neoplasms; Tretinoin

Topics: Animals; Carcinoma, Basal Cell; Cell Division; Humans; Mice; Ornithine Decarboxylase; Skin; Skin Neoplasms; T-Lymphocytes; Tretinoin; Ultraviolet Rays

A new rapid assay has been developed for measurement of the binding of [3H]retinoic acid to cellular retinoic acid-binding protein. The assay, which uses activated charcoal for the separation of bound from unbound retinoic acid, was used to determine the concentration required to inhibit the binding of [3H]retinoic acid to cellular retinoic acid-binding protein by 50% for 18 retinoids with free carboxylic acid groups. Partially purified cellular retinoic acid-binding proteins isolated from rat testes and carcinogen-induced rat mammary tumors were used for these determinations. The following parameters were also determined for some or all of the retinoids: hypervitaminosis A doses; activity against carcinogen-induced mouse skin papillomas; inhibition of growth of a rat chondrosarcoma; inhibition of growth of 3T6 cells; and differentiation of the embryonal carcinoma cell line PCC4.azaIR. While all retinoids that are potent in these biological test systems bind tightly to cellular retinoic acid-binding protein, the converse is not true. The lack of a consistent quantitative correlation between 50% inhibitory concentration and biological activity is probably due to insufficient concentrations of the retinoid in the target tissue or celll, which is a consequence of factors such as absorbability, metabolism, tissue distribution, and pharmacokinetics.

Topics: Animals; Binding, Competitive; Chondrosarcoma; Female; In Vitro Techniques; Male; Mammary Neoplasms, Experimental; Mice; Neoplasms, Experimental; Papilloma; Rats; Retinol-Binding Proteins; Skin Neoplasms; Testis; Tretinoin; Vitamin A

Studies of tumor induction on mouse skin have provided insight into the basis biology of chemical carcinogenesis, but molecular mechanisms have been more difficult to elucidate. Mouse epidermal cell cultures have proven to be a valuable model for performing mechanistic studies. Previous data have indicated that such cultures proliferate and differentiate in a manner highly analogous to epidermis in vivo. In addition, carcinogen metabolism, DNA repair, and responses to tumor promoters are quite similar in mouse skin in vivo and in vitro. Recent data have extended these observations toward defining the biological characteristics of initiated cells and elucidating the mechanism of action of promoters and antipromoters. When mouse epidermis is cultured under conditions of low extracellular Ca++, proliferation is enhanced and terminal differentiation is inhibited. Addition of Ca++ induces terminal differentiation. If cells are treated with carcinogens under low Ca++ conditions and subsequently switched to standard Ca++, cell colonies which do not terminally differentiate evolve. Such colonies continue to synthesize keratin, are subculturable, and may represent preneoplastic cells. In other experiments, epidermal cells derived from mouse skin treated with carcinogens in vivo also demonstrate prolonged in vitro survival and subculturability while controls have a limited lifespan. Such studies suggest that biological alterations can be detected in epidermal cells exposed to carcinogens well before and the phenotypic expression of neoplasia. Exposure of epidermal cells to phorbol-ester tumor promoters induces ornithine decarboxylase (ODC). This induction is enhanced by corticosteroids and markedly inhibited by retinoids. Ultraviolet light also induces ODC in epidermal cells, but kinetic studies suggest that the early pathway of induction (afferent to the nucleus) is different from that of phorbol esters. The later pathways (efferent from the nucleus-i.e., transcription and translation) appear to be similar. Retinoids have only a minor suppressive effect on ODC induction by UV while corticosteroids enhance UV induction to the same extent as seen with phorbol esters These results suggest that the site of retinoids is in the afferent pathway while steroids act on the efferent pathway.

Topics: Animals; Carcinogens; Cell Differentiation; Cell Transformation, Neoplastic; Cells, Cultured; Environmental Exposure; Enzyme Induction; Epidermal Cells; Epidermis; Methylnitronitrosoguanidine; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

The ability of 5,6-epoxyretinoic acid, a biologically active metabolites of retinoic acid, to inhibit both the induction of ornithine decarboxylase (ODC) activity and skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) was evaluated. Application of 5,6-epoxyretinoic acid either concurrently with or 1 hr after each application of TPA to the initiated mouse skin inhibited the formation of skin tumors as effectively as did retinoic acid. 5,6-Dihydroretinoic acid, which is a poor substrate for epoxidation, also inhibited skin tumor promotion. 5,6-Epoxyretinoic acid, 5,6-dihydroretinoic acid, and retinoic acid were equally effective in inhibiting the induction of ODC activity by TPA. Insect juvenile hormones inhibited neither the induction of ODC activity nor skin tumor promotion by TPA. These results indicate that (a) epoxidation of retinoic acid at the 5,6-position is not a rate-limiting modification for the anti-promoting activity of retinoic acid and that (b) inhibition of the induction by TPA of mouse epidermal ODC activity may be a simple test for screening the potential prophylactic activities of new retinoids.

Topics: Animals; Female; Juvenile Hormones; Mice; Ornithine Decarboxylase Inhibitors; Papilloma; Phorbol Esters; Phorbols; Skin Neoplasms; Time Factors; Tretinoin

Topics: Animals; Carboxy-Lyases; DNA; Enzyme Induction; Female; Indomethacin; Mice; Models, Biological; Neoplasms, Experimental; Organ Culture Techniques; Ornithine Decarboxylase; Phorbols; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Beneficial effects of oral retinoids in prophylaxis of epithelial neoplasias have been demonstrated by experimental works. In this study oral retinoid (RO 10-9359) was used in human dermatosis with high frequency of cutaneous malignancies: xeroderma pigmentosum with or without malignant neoplasias, Mibelli's porokeratosis with multifocal malignant degeneration, basal cell naevus syndrome with basal cell carcinomas, familial epithelioma of Ferguson-Smith and actinic keratosis. This work started in december 1977. Visible epitheliomas have been treated before trial. Initial dose of retinoid was 1 mg/kg daily, decreased depending on individual tolerance. Results were appreciated by comparising number of epitheliomas observed in years preceding retinoid therapy and number of them appearing during treatment; in two familial cases (basal cell naevus syndrom in twins and xeroderma pigmentosum in two brothers) comparison was made between treated and untreated patients. First results are very promising: an excellent response on solar keratosis is noted; epitheliomas occurrence seems actually to be prevented or delayed by oral retinoid therapy. Of course more numerous cases, a longer time, periods without treatment are necessary to confirm these interesting first results. On the other hand drug is not with this dose active on already constituted carcinomas.

Topics: Adolescent; Basal Cell Nevus Syndrome; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Child; Etretinate; Female; Humans; Keratosis; Male; Precancerous Conditions; Skin Diseases; Skin Neoplasms; Tretinoin; Xeroderma Pigmentosum

Topics: Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Epithelium; Etretinate; Humans; Skin Diseases; Skin Neoplasms; Tretinoin; Vitamin A

Application of a single large dose (3.6 micromol) or smaller weekly repeated doses (0.2 micromol) of 7,12-dimethylbenz[a]anthracene (DMBA) to the skin of CD-1 mice led to a 20 to 50-fold increase in epidermal ornithine decarboxylase (ODC) (EC 4.1.1.17) activity as well as tumor formation. Retinoic acid (0.17-68 nmol), a potent inhibitor of both the induction of ODC activity and tumor formation by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), failed to inhibit both the induction of ODC activity and tumor formation by DMBA. In contrast, 7,8-benzoflavone (367 nmol), which did not inhibit the induction of ODC activity by TPA, effectively inhibited the induction of ODC activity as well as the formation of skin tumors caused by DMBA. These results indicate that (a) the mechanism of the induction of ODC activity and tumor formation by a complete carcinogen appears to be different from that of the tumor promoter TPA, (b) DMBA-induced ODC activity may be an important component of the mechanism of DMBA carcinogenesis, and (c) the protective effect of retinoic acid on skin carcinogenesis is not universal; it inhibits skin tumor formation by some agents and not by others.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benzoflavones; Carcinogens; Drug Interactions; Enzyme Induction; Enzyme Inhibitors; Epidermis; Female; Mice; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Blepharoconjunctivitis developed as a side-effect of treatment of patients with basal cell carcinomas, keratinizing dermatoses, and cystic acne with oral 13-cis-retinoic acid. Forty-two of the 97 dermatologic patients had signs and symptoms of blepharoconjunctivitis that were dose related and abated one week after discontinuation of the medication. About half of the patients had a history of similar symptoms prior to treatment. Staphylococcus aureus was present in eye cultures of 73% to 79% of the patients, whether symptomatic or not. Patients whose clinical appearance was that of staphylococcal blepharoconjunctivitis and whose cultures grew S aureus were successfully treated with topical erythromycin ointment to the lids even while being treated with the 13-cis-retinoic acid.

Topics: Acne Vulgaris; Blepharitis; Carcinoma, Basal Cell; Conjunctivitis; Erythromycin; Eyelid Diseases; Humans; Keratosis; Skin Diseases; Skin Neoplasms; Staphylococcal Infections; Tretinoin

Topical application of retinoic acid (RA) solutions greatly enhanced the response of hairless mouse skin to a moderate dose of simulated sunlight. Tumors appeared much earlier, and in much greater numbers, in animals treated daily with 1 or 10 micrograms of RA in methanol immediately after 2 h exposure to a xenon arc filtered through 2 mm of Schott WG 320 glass (approximately equivalent in human erythema effectiveness to 5 min of mid-summer noon solar exposure in northern mid-latitudes), compared to mice treated with light and methanol only. The higher amount of RA, in combination with light, produced moderate epidermal hyperplasia and some scaling and transient erythema, but no gross ulceration or inflammation of skin. The lower amount of RA, though about equally effective in carcinogenesis, produced minimal epidermal hyperplasia compared to the ultraviolet radiation + methanol control.

Topics: Administration, Topical; Animals; Cocarcinogenesis; Female; Male; Mice; Mice, Nude; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Skin Neoplasms; Time Factors; Tretinoin; Ultraviolet Rays

(4-Methoyx-2,3,6-trimethylphenyl)nonatetraenoic acids, esters, and amides (analogues of retinoic acid) bearing a fluorine atom(s) or a trifluoromethyl group on the polyene side chain were synthesized. The biological activities of these compounds and of 10-, 12-, and 14-fluororetinoic acid esters were evaluated in vivo in a chemically induced mouse papilloma test; the toxicities were assessed in an in vivo mouse hypervitaminosis A test. Antipapilloma activity greater than the parent nonfluorinated ester was found for 1c (ethyl 12-fluororetinoate) and 23 and 39 (aromatic 4- and 6-fluororetinoid esters, respectively). A similar increase in antipapilloma activity was observed for 71 and 72, the aromatic 4- and 6-fluororetinoic acids, respectively, relative to 2 and for 73 (aromatic 4-fluororetinoid amide) relative to 4.

Topics: Animals; Mice; Neoplasms, Experimental; Papilloma; Skin Neoplasms; Structure-Activity Relationship; Tretinoin

Topics: Adult; Child; DNA Repair; Health Education; Humans; Skin Neoplasms; Tretinoin

Topics: Animals; Carboxy-Lyases; Enzyme Induction; Female; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Papilloma; Phorbols; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin; Vitamin A

Topics: Acne Vulgaris; Administration, Oral; Carcinoma, Basal Cell; Darier Disease; Drug Evaluation; Humans; Ichthyosis; Pityriasis Rubra Pilaris; Skin Neoplasms; Tretinoin; Vitamin A

15 patients with superficial basaliomas or premalignant epithelial neoplastic disorders (actinic keratosis, leukoplakia, Bowen's disease) were treated locally over three weeks with retinoic acid (RA) alone or in combination with 5-fluorouracil (5-FU). In 11 cases the lesions disappeared clinically, however, only 5 patients proved to be cured by histological examination. 4 of them were treated with RA combined with 5-FU. There was a decrease of the 3H-index after the first week and an increase after the third week of treatment. These findings suggest, that RA inhibits the proliferation of neoplastic keratinocytes and stimulates the proliferation of normal epidermal cells. Retinoic acid, therefore, has an inhibitory effect on epithelial neoplasias, particularly in combination with 5-FU. Since local therapy with RA and 5-FU is not sufficient for routine clinical purposes in all cases, their use should be restricted to selected patients.

Topics: Aged; Carcinoma, Basal Cell; Drug Therapy, Combination; Female; Fluorouracil; Humans; Keratosis; Leukoplakia; Light; Lip Neoplasms; Male; Middle Aged; Mouth Neoplasms; Neoplasms, Radiation-Induced; Precancerous Conditions; Scalp; Skin Neoplasms; Thorax; Tretinoin; Vitamin A

Topics: Adolescent; Adult; Carcinoma, Basal Cell; Humans; Middle Aged; Skin Diseases; Skin Neoplasms; Tretinoin; Vitamin A

Topics: Adenosylmethionine Decarboxylase; Alkaloids; Amines; Animals; Carboxy-Lyases; Enzyme Induction; Epidermis; Female; Indomethacin; Mice; Neoplasms, Experimental; Nucleotides, Cyclic; Ornithine Decarboxylase; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin; Ultraviolet Rays

The syntheses of the ring and four side-chain dihydroretinoic acids and/or their esters, 3-7, are described. The syntheses of several other retinoids containing a substituted aromatic ring are also included. The biological activity of the compounds was evaluated in vivo in a chemically induced mouse skin papilloma test and in vitro in two vitamin A deficient assays. The activity observed for 1a, 1c, and 2a in the former test was partially retained in the dihydro derivatives 4b, 4c, and 6b. Similar results were found in the in vitro assays.

Topics: Animals; Cells, Cultured; Cricetinae; Female; Mice; Neoplasms, Experimental; Organ Culture Techniques; Papilloma; RNA; Skin; Skin Neoplasms; Tretinoin; Vitamin A; Vitamin A Deficiency

The mode of action of an aromatic analogue of retinoic acid, ethyl all-trans-9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate (Ro 10-9359), a compound known to possess a considerable prophylactic and therapeutic effect on skin papillomas and carcinomas, was investigated with autoradiographic and histopathologic methods. The ip application of a single dose of 1,000 mg Ro 10-9359/kg to female Swiss mice with chemically induced skin papillomas caused a 29% regression of the mean tumor diameter after 3 days and a 51% regression after 7 days. In the tumors, the number of DNA-synthesizing cells [measured by the labeling index (LI)] and the length of the cell cycle were not affected by the retinoid; thus a mode of action at the level of cell proliferation can be excluded. In the normal skin, an increase in the LI of about 30% was observed. A small effect on the cell loss was observed; however, it was not sufficient to explain quantitatively the regression of the tumors. When measured histometrically, it appeared that the loss of the horn and the formation of necroses, 3-10 times larger than in the placebo groups, were mainly responsible for the tumor regressions caused by the retinoid. After 7 days, the proportion of stroma in the tumors was increased, and dilation of the vessels and edema in the stroma proximal to the necroses were frequent.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Cell Division; Croton Oil; DNA, Neoplasm; Female; Mice; Necrosis; Neoplasms, Experimental; Papilloma; Skin Neoplasms; Tretinoin; Vitamin A

Topics: Animals; Carcinoma, Basal Cell; Humans; Neoplasms, Experimental; Papilloma; Precancerous Conditions; Skin Diseases; Skin Neoplasms; Tretinoin; Vitamin A; Vitamin A Deficiency

Topics: Animals; Epithelium; Female; Humans; Lung Neoplasms; Mammary Neoplasms, Experimental; Neoplasms; Neoplasms, Experimental; Nutritional Requirements; Precancerous Conditions; Skin Neoplasms; Structure-Activity Relationship; Tretinoin; Urinary Bladder Neoplasms; Vitamin A; Vitamin A Deficiency

Topics: Adenosylmethionine Decarboxylase; Animals; Carboxy-Lyases; Drug Administration Schedule; Enzyme Induction; Female; In Vitro Techniques; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Papilloma; Phorbols; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin; Vitamin A

In a patient with systematized verrucous epidermal nevus, marked improvement was obtained with oral administration of a new aromatic retinoid (Ro 10-9359). Mild cheilitis and thinning of scalp hair were the only side effects obser Withved. continuous treatment the good result was maintained for 10 months. Further investigation is needed to determine, whether long-term oral administration of this new drug is feasible.

Topics: Administration, Oral; Adult; Drug Evaluation; Humans; Male; Nevus; Skin Neoplasms; Time Factors; Tretinoin; Vitamin A

Topics: Animals; Cell Membrane; Female; Mice; Microscopy, Electron; Papilloma; Skin Neoplasms; Time Factors; Tretinoin; Vitamin A

Topics: Administration, Oral; Adolescent; Adult; Aged; Child; Darier Disease; Female; Humans; Ichthyosis; Keratoderma, Palmoplantar; Keratosis; Leukoplakia; Male; Middle Aged; Pityriasis Rubra Pilaris; Psoriasis; Skin Neoplasms; Tretinoin; Vitamin A

Topics: Acne Vulgaris; Animals; Congresses as Topic; Humans; In Vitro Techniques; Neoplasms, Experimental; Skin Diseases; Skin Neoplasms; Switzerland; Tretinoin; Vitamin A

The properties of a new aromatic retinoic acid analog are described. The compound: all-trans-N-ethyl-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenamide = Ro 11-1430, exerts a therapeutic influence on chemically induced papillomas and carcinomas of the skin of mice. It leads to a marked regression of chemically induced epithelial tumors but does not inhibit the growth of transplantable tumors. The therapeutic use of retinoic acid and its analogs is limited by the appearance of the toxic side effects of the so-called hypervitaminosis A syndrome. The relationship between the anti-tumor activity and these toxic effects is considered a good inidicator for establishing the quality of a compound. The new retinoic acid analog posses a ten times more favorable therapeutic ratio than retinoic acid. The mechanism of action is discussed.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma; Mice; Neoplasms, Experimental; Papilloma; Skin Neoplasms; Tretinoin; Vitamin A

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma; Croton Oil; Female; Mice; Neoplasms, Experimental; Papilloma; Skin Neoplasms; Tretinoin; Vitamin A

Topics: Administration, Oral; Animals; Female; Injections, Intraperitoneal; Mice; Neoplasms, Experimental; Papilloma; Skin Neoplasms; Tretinoin; Vitamin A