tretinoin and Neoplasms

Retinoids are essential nutrients for human beings. Among them, all-trans retinoic acid (ATRA), considered one of the most active metabolites, plays important roles in multiple biological processes. ATRA regulates the transcription of target genes by interacting with nuclear receptors bonded to retinoic acid response elements (RAREs). Besides its differentiation-inducing effect in the treatment of acute promyelocytic leukemia and some solid tumor types, its immunoregulatory role in tumor microenvironment (TME) has attracted considerable attention. ATRA not only substantially abrogates the immunosuppressive effect of tumor-infiltrating myeloid-derived suppressor cells but also activates the anti-tumor effect of CD8 + T cells. Notably, the combination of ATRA with other therapeutic approaches, including immune checkpoint inhibitors (ICIs), tumor vaccines, and chemotherapy, has been extensively investigated in a variety of tumor models and clinical trials. In this review, we summarize the current understanding of the role of ATRA in cancer immunology and immunotherapy, dissect the underlying mechanisms of ATRA-mediated activation or differentiation of different types of immune cells, and explore the potential clinical significance of ATRA-based cancer therapy.

Topics: Cell Differentiation; Humans; Neoplasms; Receptors, Retinoic Acid; Retinoids; Tretinoin; Tumor Microenvironment

Cellular Retinol Binding Protein 1 (CRBP1) gene is a protein coding gene located on human chromosome 3q21, which codifies a protein named CRBP1. CRBP1 is widely expressed in many tissues as a chaperone protein to regulate the uptake, subsequent esterification and bioavailability of retinol. CRBP1 combines retinol and retinaldehyde with high affinity to protect retinoids from non-specific oxidation, and transports retinoids to specific enzymes to promote the biosynthesis of retinoic acid. The vital role of CRBP1 in retinoids metabolism has been gradually discovered, which has been implicated in tumorigenesis. However, the precise functions of CRBP1 in different diseases are still poorly understood. The purpose of this review is to provide an overview of the role of CRBP1 in various diseases, especially in both the promotion and inhibition of cancers, which may also offer a novel biomarker and potential therapeutic target for human diseases.

Topics: Biomarkers, Tumor; Humans; Neoplasms; Retinoids; Retinol-Binding Proteins, Cellular; Tretinoin; Vitamin A

Retinoic acid (RA) is an active metabolite of vitamin A, which is an essential signaling molecule involved in cell fate decisions, such as differentiation, proliferation, and apoptosis, in a wide variety of cell types. Accumulated data have demonstrated that expression of RA-metabolizing enzymes, CYP26A1, B1, and C1 (cytochrome P450, family 26A1, B1, and C1, respectively), protects cells and tissues from exposure to RA through restriction of RA access to transcriptional machinery by converting RA to rapidly excreted derivatives. CYP26 enzymes play similar but separate roles in limiting the consequences of fluctuations in nutritional vitamin A. Recently, we found that RA depletion caused by expression of CYP26A1 promotes malignant behaviors of tumor cells derived from various tissues, implicating CYP26A1 as a candidate oncogene. We also showed that the expression levels of CYP26 enzymes are elevated in various types of cancer. We have provided evidence for oncogenic and cell survival properties of CYP26 enzymes, indicating that these molecules are possible therapeutic targets for CYP26-expressing malignancies.

Topics: Cytochrome P450 Family 26; Feasibility Studies; Humans; Neoplasms; Retinoic Acid 4-Hydroxylase; Tretinoin; Vitamin A

The retinoic acid receptor-related orphan receptors (RORs) are ligand-mediated transcription factors with important biological roles in regulating circadian rhythms, metabolism, immunity, angiogenesis, inflammation, and development. They belong to the superfamily of nuclear receptors and include three family members: RORα, RORβ, and RORγ. Currently identified ROR ligands include cholesterol and cholesterol derivatives for RORα and RORγ, and stearic acid and all-trans retinoic acid for RORβ. Aberrant signaling of the RORs is involved in the pathogenesis of several human diseases including autoimmune diseases, metabolic disorders, and certain cancers. In the eye, RORs regulate normal development of the lens and the retina, and also contribute to potentially blinding eye diseases, especially retinal vascular diseases. Here, we review the role of RORs in eye development and disease to highlight their potential as druggable targets for therapeutic development in retinal vascular and degenerative diseases.

Topics: Humans; Neoplasms; Nuclear Receptor Subfamily 1, Group F, Member 3; Receptors, Retinoic Acid; Transcription Factors; Tretinoin

Retinoic acid-inducible gene-I (RIG-I) like receptor (RLR) pathway is one of the most significant pathways supervising aberrant RNA in cells. In predominant conditions, the RLR pathway initiates anti-infection function via activating inflammatory effects, while recently it is discovered to be involved in cancer development as well, acting as a virus-mimicry responder. On one hand, the product IFNs induces tumor elimination. On the other hand, the NF-κB pathway is activated which may lead to tumor progression. Emerging evidence demonstrates that a wide range of modifications are involved in regulating RLR pathways in cancer, which either boost tumor suppression effect or prompt tumor development. This review summarized current epigenetic modulations including DNA methylation, histone modification, and ncRNA interference, as well as post-transcriptional modification like m6A and A-to-I editing of the upstream ligand dsRNA in cancer cells. The post-translational modulations like phosphorylation and ubiquitylation of the pathway's key components were also discussed. Ultimately, we provided an overview of the current therapeutic strategies targeting the RLR pathway in cancers.

Topics: DNA Methylation; Humans; Neoplasms; Phosphorylation; RNA, Double-Stranded; Tretinoin

Recently, several chemotherapeutic drugs have been repositioned in neurological diseases, based on common biological backgrounds and the inverse comorbidity between cancer and neurodegenerative diseases. Fenretinide (all-trans-N-(4-hydroxyphenyl) retinamide, 4-HPR) is a synthetic derivative of all-trans-retinoic acid initially proposed in anticancer therapy for its antitumor effects combined with limited toxicity. Subsequently, fenretinide has been proposed for other diseases, for which it was not intentionally designed for, due to its ability to influence different biological pathways, providing a broad spectrum of pharmacological effects. Here, we review the most relevant preclinical and clinical findings from fenretinide and discuss its therapeutic role towards cancer and neurological diseases, highlighting the hormetic behavior of this pleiotropic molecule.

Topics: Antineoplastic Agents; Apoptosis; Fenretinide; Humans; Neoplasms; Tretinoin

Vitamin A is an important trace essential nutrient. Vitamin A is present as a retinyl ester in animal foods and as β-carotene (provitamin A), which is a precursor of vitamin A, in plant foods such as green and yellow vegetables. After ingestion and absorption in the body, these are converted into retinol and stored as retinyl esters in stellate cells in the liver. The stored retinyl esters are decomposed into retinol as needed, and converted into the aldehyde retinal, which plays an important role in vision. Retinoic acid (RA) has a variety of effects. In particular, RA is used as a therapeutic agent for acute promyelocytic leukemia. This review will cover (1) elucidation of anti-refractory cancer effects of retinol (vitamin A) not mediated by RA receptors, (2) elucidation of anti-cancer effects of RA not mediated by RA receptors and (3) the development of candidate new anti-cancer agents that combine the actions of RA and retinol. Lessons learned from these findings are that vitamin A has anti-cancer activity not mediated by RA receptors; that nutritional management of vitamin A leads to prevention and treatment of cancer, and that new compounds developed from RA derivatives represent good anti-cancer drug candidates that are in various stages of clinical trials.

Topics: Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Liver; Neoplasms; Receptors, Retinoic Acid; Retinyl Esters; Tretinoin; Vitamin A

The development of tumor therapeutic resistance is one of the important reasons for the failure of antitumor therapy. Starting with multiple targets and multiple signaling pathways is helpful in understanding the mechanism of tumor resistance. The overexpression of prolyl isomerase Pin1 is highly correlated with the malignancy of cancer, since Pin1 controls many oncogenes and tumor suppressors, as well as a variety of cancer-driving signaling pathways. Strikingly, numerous studies have shown that Pin1 is directly involved in therapeutic resistance. In this review, we mainly summarize the functions and mechanisms of Pin1 in therapeutic resistance of multifarious cancers, such as breast, liver, and pancreatic carcinomas. Furtherly, from the perspective of Pin1-driven cancer signaling pathways including Raf/MEK/ERK, PI3K/Akt, Wnt/β-catenin, NF-κB, as well as Pin1 inhibitors containing juglone, epigallocatechin-3-gallate (EGCG), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), it is better to demonstrate the important potential role and mechanism of Pin1 in resistance and sensitization to cancer therapies. It will provide new therapeutic approaches for clinical reversal and prevention of tumor resistance by employing synergistic administration of Pin1 inhibitors and chemotherapeutics, implementing combination therapy of Pin1-related cancer signaling pathway inhibitors and Pin1 inhibitors, and exploiting novel Pin1-specific inhibitors.

Topics: Antineoplastic Agents; Arsenic Trioxide; beta Catenin; Humans; Mitogen-Activated Protein Kinase Kinases; Neoplasms; NF-kappa B; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Tretinoin

HOX genes occupy a significant role in embryogenesis, hematopoiesis, and oncogenesis. HOXA5, a member of the A cluster of HOX genes, is essential for establishing the skeleton and normal organogenesis. As previously reported, aberrant HOXA5 expression contributes to anomalies and dysfunction of various organs, as well as affecting proliferation, differentiation, invasion, apoptosis, and other biological processes of tumor cells. Different cancers showed both downregulated and upregulated HOXA5 expression. The most common strategy for controlling HOXA5 downregulated expression may be CpG island hypermethylation. Additionally, current research demonstrated the regulatory network of HOXA5 and its connection with cancer stem cell progression and the immune microenvironment. Epigenetic modulators and upstream regulators, such as DNMTi and retinoic acid, may be beneficial for anti-tumor effects targeting HOXA5. Here, we summarize current knowledge about the HOXA5 gene, its role in various cancers, and its potential therapeutic value.

Topics: Cell Differentiation; CpG Islands; Genes, Homeobox; Homeodomain Proteins; Neoplasms; Transcription Factors; Tretinoin

Vitamin A is an important micro-essential nutrient, whose primary dietary source is retinyl esters. In addition, β-carotene (pro-vitamin A) is a precursor of vitamin A contained in green and yellow vegetables that is converted to retinol in the body after ingestion. Retinol is oxidized to produce visual retinal, which is further oxidized to retinoic acid (RA), which is used as a therapeutic agent for patients with promyelocytic leukemia. Thus, the effects of retinal and RA are well known. In this paper, we will introduce (1) vitamin A circulation in the body, (2) the actions and mechanisms of retinal and RA, (3) retinoylation: another RA mechanism not depending on RA receptors, (4) the relationship between cancer and actions of retinol or β-carotene, whose roles in vivo are still unknown, and (5) anti-cancer actions of vitamin A derivatives derived from fenretinide (4-HPR). We propose that vitamin A nutritional management is effective in the prevention of cancer.

Topics: Cell Differentiation; Delivery of Health Care; Humans; Neoplasms; Receptors, Retinoic Acid; Tretinoin; Vitamin A

In some types of human cancer, aldehyde dehydrogenases represent stemness markers and their expression is associated with advanced disease stages and poor prognosis. Although several biological functions are mediated by their product Retinoid acid, the molecular mechanism is tissue-dependent and only partially understood. In this review, we summarize the current knowledge about the role of ALDH in solid tumours, especially ALDH1A1 and ALDH1A3 isoforms, regarding the molecular mechanism of their transcription and regulation, and their crosstalk with main molecular pathways resulting in the excessive proliferation, chemoresistance, stem cells properties and invasiveness. The recent knowledge of the regulatory effect of lnRNA on ALDH1A1 and ALDH1A3 is discussed too.

Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Aldehyde Oxidoreductases; Humans; Neoplasms; Protein Isoforms; Retinal Dehydrogenase; Tretinoin

The retinoic acid (RA) signaling pathway is crucial for many biological processes. The RA transporter, Cellular Retinoic-Acid Binding Protein 2 (CRABP2), is abnormally expressed in various tumor types. CRABP2 presents significant effects on tumorous behaviors and functions, including cell proliferation, apoptosis, invasion, migration, metastasis, and angiogenesis. The tumorigenesis mechanism of CRABP2, as both suppressor and promotor, is complicated, therefore, there remains the need for further investigation. Elucidating the regulating mechanisms in a specific stage of the tumor could facilitate CRABP2 to be a biomarker in cancer diagnosis and prognosis. Besides, clarifying the pathways of CRABP2 in cancer development will contribute to the gene-targeted therapy. In this review, we summarized the expression, distribution, and mechanism of CRABP2 in solid tumors. Illuminating the CRABP2 signaling pathway may benefit understanding the retinoid signaling pathway, providing a useful biomarker for future clinical trials.

Topics: Apoptosis; Biological Transport; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Cell Proliferation; Fatty Acid-Binding Proteins; Gene Expression Regulation, Neoplastic; Humans; Lymphatic Metastasis; Neoplasm Staging; Neoplasms; Neovascularization, Pathologic; Receptors, Retinoic Acid; Signal Transduction; Tretinoin

The widely recognized problems of pharmacological strategies based on killing cancer cells demand a rethink of therapeutic approaches. Tumor reversion strategies that aim to shift cancer cells to a healthy differentiated state are a promising alternative. Although many studies have firmly demonstrated the possibility of reverting cancer to a normal differentiated state, we are still unable (with the exception of retinoic acid in a form of leukemia) to revert cancer cells to a stable differentiated healthy state. Here, we review the main biological bases of redifferentiation strategies and provide a description of the most promising research avenues.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Humans; Neoplasms; Tretinoin

NF-E2-related factor 2 (NRF2) is a master regulator of redox homeostasis and provides cellular protection against oxidants and electrophiles by inducing the expression of a wide array of phase II cytoprotective genes. Until now, a number of NRF2 activators have been developed for treatment of chronic diseases and some are under evaluation in the clinical studies. On the other hand, accumulating evidence indicates that NRF2 confers chemoresistance and radioresistance, and its expression is correlated with poor prognosis in cancer patients. Studies in the last decade demonstrate that diverse mechanisms such as somatic mutations, accumulation of KEAP1 binding proteins, transcriptional dysregulation, oncogene activation, and accumulation of reactive metabolites contribute to NRF2 activation in cancer. In the present review, we illustrate the molecular mechanisms governing the function of NRF2 and explain how they are hijacked in cancer. We also provide some examples of NRF2 inhibitors together with a brief explanation of their mechanisms of action.

Topics: Animals; Antineoplastic Agents; Gene Expression Regulation, Neoplastic; Humans; Kelch-Like ECH-Associated Protein 1; Lung Neoplasms; Molecular Targeted Therapy; Mutation; Neoplasms; NF-E2-Related Factor 2; Quassins; Tretinoin

All-trans retinoic acid (ATRA), an active metabolite of vitamin A, plays important roles in cell proliferation, cell differentiation, apoptosis, and embryonic development. The effects of ATRA are mediated by nuclear retinoid receptors as well as non-genomic signal pathway, such as MAPK and PKA. The great success of differentiation therapy with ATRA in acute promyelocytic leukemia (APL) not only improved the prognosis of APL but also spurred the studies of ATRA in the treatment of other tumors. Since the genetic and physiopathological simplicity of APL is not common in human malignancies, the combination of ATRA with other agents (chemotherapy, epigenetic modifiers, and arsenic trioxide, etc) had been extensively investigated in a variety of tumors. In this review, we will discuss in details about ATRA and its role in cancer treatment.

Topics: Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Cell Differentiation; Cell Proliferation; Drug Therapy; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Receptors, Retinoic Acid; Signal Transduction; Tretinoin

Cancer is considered a fetal disease caused by uncontrolled proliferation and progression of abnormal cells. The most efficient cancer therapies suppress tumor growth, prevent progression and metastasis, and are minimally toxic to normal cells. Natural compounds have shown a variety of chemo-protective effects alone or in combination with standard cancer therapies. Along with better understanding of the dynamic interactions between our immune system and cancer development, nutritional immunology-the use of natural compounds as immunomodulators in cancer patients-has begun to emerge. Cancer cells evolve strategies that target many aspects of the immune system to escape or even edit immune surveillance. Therefore, the immunesuppressive tumor microenvironment is a major obstacle in the development of cancer therapies. Because interaction between the tumor microenvironment and the immune system is a complex topic, this review focuses mainly on human clinical trials and animal studies, and it highlights specific immune cells and their cytokines that have been modulated by natural compounds, including carotenoids, curcumin, resveratrol, EGCG, and β-glucans. These natural compounds have shown promising immune-modulating effects, such as inhibiting myeloid-derived suppressor cells and enhancing natural killer and cytolytic T cells, in tumor-bearing animal models, but their efficacy in cancer patients remains to be determined.

Topics: Animals; beta-Glucans; Carotenoids; Catechin; Curcumin; Humans; Immune System; Immunologic Factors; Killer Cells, Natural; Mice; Neoplasms; Resveratrol; T-Lymphocytes; Tretinoin; Tumor Microenvironment

All-trans retinoic acid (ATRA), a derivative of vitamin A, has been shown to potentiate cancer chemotherapy due to its ability to induce signals for cell differentiation or death, and inhibit cell proliferation. The combination of ATRA with taxoids, kinase inhibitors, natural compounds, retinoids, ER or HER2 inhibitors, chemotherapeutic drugs, proteasome inhibitors and nanoformulations of tretinoin have demonstrated additive or synergistic effects in anti-cancer activities. The mechanisms by which the compounds exert their synergistic effects depend on the tumor and the cell type. However, several experiments demonstrated similar mechanisms such as reduction of PCK, c-myc, E2F and Bcl-2, as well as increase of p21 and TGF-β. When the apoptotic synergistic effect was observed, the predominant effect of ATRA was in differentiation induction. The results indicate that future combinations of ATRA and anti-tumor agents hold promise to enhance and improve anti-carcinogenic therapies.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Cell Proliferation; Cell Survival; Drug Synergism; Humans; Neoplasms; Tretinoin

Retinoic acid receptor-related orphan receptors (RORs) include RORα (NR1F1), RORβ (NR1F2), and RORγ (NR1F3). These receptors are reported to activate transcription through ligand-dependent interactions with co-regulators and are involved in the development of secondary lymphoid tissues, autoimmune diseases, inflammatory diseases, the circadian rhythm, and metabolism homeostasis. Researches on RORs contributing to cancer-related processes have been growing, and they provide evidence that RORs are likely to be considered as potential therapeutic targets in many cancers. RORα has been identified as a potential therapeutic target for breast cancer and has been investigated in melanoma, colorectal colon cancer, and gastric cancer. RORβ is mainly expressed in the central nervous system, but it has also been studied in pharyngeal cancer, uterine leiomyosarcoma, and colorectal cancer, in addition to neuroblastoma, and recent studies suggest that RORγ is involved in various cancers, including lymphoma, melanoma, and lung cancer. Some studies found RORγ to be upregulated in cancer tissues compared with normal tissues, while others indicated the opposite results. With respect to the mechanisms of RORs in cancer, previous studies on the regulatory mechanisms of RORs in cancer were mostly focused on immune cells and cytokines, but lately there have been investigations concentrating on RORs themselves. Thus, this review summarizes reports on the regulation of RORs in cancer and highlights potential therapeutic targets in cancer.

Topics: Animals; Carcinogenesis; Cell Transformation, Neoplastic; Circadian Rhythm; Gene Expression Regulation, Neoplastic; Homeostasis; Humans; Neoplasms; Orphan Nuclear Receptors; Receptors, Retinoic Acid; Tretinoin; Vitamin A

Cellular binding-proteins (BP), including CRBP1, CRBP2, CRABP1, CRABP2, and FABP5, shepherd the poorly aqueous soluble retinoids during uptake, metabolism and function. Holo-BP promote efficient use of retinol, a scarce but essential nutrient throughout evolution, by sheltering it and its major metabolite all-trans-retinoic acid from adventitious interactions with the cellular milieu, and by imposing specificity of delivery to enzymes, nuclear receptors and other partners. Apo-BP reflect cellular retinoid status and modify activities of retinoid metabolon enzymes, or exert non-canonical actions. High ligand binding affinities and the nature of ligand sequestration necessitate external factors to prompt retinoid release from holo-BP. One or more of cross-linking, kinetics, and colocalization have identified these factors as RDH, RALDH, CYP26, LRAT, RAR and PPARβ/δ. Michaelis-Menten and other kinetic approaches verify that BP channel retinoids to select enzymes and receptors by protein-protein interactions. Function of the BP and enzymes that constitute the retinoid metabolon depends in part on retinoid exchanges unique to specific pairings. The complexity of these exchanges configure retinol metabolism to meet the diverse functions of all-trans-retinoic acid and its ability to foster contrary outcomes in different cell types, such as inducing apoptosis, differentiation or proliferation. Altered BP expression affects retinoid function, for example, by impairing pancreas development resulting in abnormal glucose and energy metabolism, promoting predisposition to breast cancer, and fostering more severe outcomes in prostate cancer, ovarian adenocarcinoma, and glioblastoma. Yet, the extent of BP interactions with retinoid metabolon enzymes and their impact on retinoid physiology remains incompletely understood.

Topics: Animals; Fatty Acid-Binding Proteins; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Neoplasms; Receptors, Retinoic Acid; Retinoids; Retinol-Binding Proteins, Cellular; 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; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Metabolism reprogramming has been linked with the initiation, metastasis, and recurrence of cancer. The aldehyde dehydrogenase (ALDH) family is the most important enzyme system for aldehyde metabolism. The human ALDH family is composed of 19 members. ALDH1A3 participates in various physiological processes in human cells by oxidizing all-trans-retinal to retinoic acid. ALDH1A3 expression is regulated by many factors, and it is associated with the development, progression, and prognosis of cancers. In addition, ALDH1A3 influences a diverse range of biological characteristics within cancer stem cells and can act as a marker for these cells. Thus, growing evidence indicates that ALDH1A3 has the potential to be used as a target for cancer diagnosis and therapy.

Topics: Aldehyde Oxidoreductases; Animals; Biomarkers, Tumor; Energy Metabolism; Gene Expression Regulation; Humans; Molecular Targeted Therapy; Neoplasms; Neoplastic Stem Cells; Prognosis; Signal Transduction; Tretinoin

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

The identification of neurological symptoms caused by vitamin A deficiency pointed to a critical, early developmental role of vitamin A and its metabolite, retinoic acid (RA). The ability of RA to induce post-mitotic, neural phenotypes in various stem cells, in vitro, served as early evidence that RA is involved in the switch between proliferation and differentiation. In vivo studies have expanded this "opposing signal" model, and the number of primary neurons an embryo develops is now known to depend critically on the levels and spatial distribution of RA. The proneural and neurogenic transcription factors that control the exit of neural progenitors from the cell cycle and allow primary neurons to develop are partly elucidated, but the downstream effectors of RA receptor (RAR) signaling (many of which are putative cell cycle regulators) remain largely unidentified. The molecular mechanisms underlying RA-induced primary neurogenesis in anamniote embryos are starting to be revealed; however, these data have been not been extended to amniote embryos. There is growing evidence that bona fide RARs are found in some mollusks and other invertebrates, but little is known about their necessity or functions in neurogenesis. One normal function of RA is to regulate the cell cycle to halt proliferation, and loss of RA signaling is associated with dedifferentiation and the development of cancer. Identifying the genes and pathways that mediate cell cycle exit downstream of RA will be critical for our understanding of how to target tumor differentiation. Overall, elucidating the molecular details of RAR-regulated neurogenesis will be decisive for developing and understanding neural proliferation-differentiation switches throughout development.

Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Cell Cycle Proteins; Humans; Neoplasms; Neurogenesis; Neurons; Receptors, Retinoic Acid; Signal Transduction; Tretinoin

Vitamin A (retinol) and its active metabolite, all-trans-retinoic acid (atRA), play critical roles in regulating the differentiation, growth, and migration of immune cells. Similarly, as critical signaling molecules in the regulation of the cell cycle, retinoids are important in cancers. Concentrations of atRA are tightly regulated in tissues, predominantly by the availability of retinol, synthesis of atRA by ALDH1A enzymes and metabolism and clearance of atRA by CYP26 enzymes. The ALDH1A and CYP26 enzymes are expressed in several cell types in the immune system and in cancer cells. In the immune system, the ALDH1A and CYP26 enzymes appear to modulate RA concentrations. Consequently, alterations in the activity of ALDH1A and CYP26 enzymes are expected to change disease outcomes in inflammation. There is increasing evidence from various disease models of intestinal and skin inflammation that treatment with atRA has a positive effect on disease markers. However, whether aberrant atRA concentrations or atRA synthesis and metabolism play a role in inflammatory disease development and progression is not well understood. In cancers, especially in acute promyelocytic leukemia and neuroblastoma, increasing intracellular concentrations of atRA appears to provide clinical benefit. Inhibition of the CYP26 enzymes to increase atRA concentrations and combat therapy resistance has been pursued as a drug target in these cancers. This chapter covers the current knowledge of how atRA and retinol regulate the immune system and inflammation, how retinol and atRA metabolism is altered in inflammation and cancer, and what roles atRA-metabolizing enzymes have in immune responses and cancers.

Topics: Animals; Cytochrome P-450 Enzyme System; Humans; Immune System; Inflammation; Neoplasms; Tretinoin; Vitamin A

Topics: Alzheimer Disease; Animals; Antioxidants; Apoptosis; beta Carotene; Carotenoids; Humans; Metabolic Diseases; Neoplasms; Reactive Oxygen Species; Receptors, Cytoplasmic and Nuclear; Retinoids; Tretinoin; Vitamin A

Topics: Animals; DNA; Metabolic Diseases; Neoplasms; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Signal Transduction; Skin Diseases; Tretinoin

Retinoids comprise a group of compounds each composed of three basic parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that functions as a linker unit, and a polar carbon-oxygen functional group. Biochemical conversion of carotenoid or other retinoids to retinoic acid (RA) is essential for normal regulation of a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids regulate various physiological outputs by binding to nuclear receptors called retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which themselves are DNA-binding transcriptional regulators. The functional response of RA and their receptors are modulated by a host of coactivators and corepressors. Retinoids are essential in the development and function of several organ systems; however, deregulated retinoid signaling can contribute to serious diseases. Several natural and synthetic retinoids are in clinical use or undergoing trials for treating specific diseases including cancer. In this review, we provide a broad overview on the importance of retinoids in development and various diseases, highlighting various retinoids in the drug discovery process, ranging all the way from retinoid chemistry to clinical uses and imaging.

Topics: Aging; Animals; Drug Discovery; Eye; Humans; Kidney; Metabolic Diseases; Molecular Structure; Neoplasms; Signal Transduction; Tretinoin

Epigenetics is "the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being" as defined by Conrad Waddington in 1942 in a discussion of the mechanisms of cell differentiation. More than seven decades later we know that these mechanisms include histone tail post-translational modifications, DNA methylation, ATP-dependent chromatin remodeling, and non-coding RNA pathways. Epigenetic modifications are powerful drugs targets, and combined targeting of multiple pathways is expected to significantly advance cancer therapy.

Topics: Chromatin; Chromatin Assembly and Disassembly; DNA Methylation; Epigenesis, Genetic; Histones; Humans; Neoplasms; Protein Binding; Protein Multimerization; Protein Processing, Post-Translational; Receptors, Retinoic Acid; Retinoid X Receptors; RNA, Untranslated; Signal Transduction; Tretinoin

Retinoids and their naturally metabolized and synthetic products (e.g., all-trans retinoic acid, 13-cis retinoic acid, bexarotene) induce differentiation in various cell types. Retinoids exert their actions mainly through binding to the nuclear retinoic acid receptors (α, β, γ), which are transcriptional and homeostatic regulators with functions that are often compromised early in neoplastic transformation. The retinoids have been investigated extensively for their use in cancer prevention and treatment. Success has been achieved with their use in the treatment of subtypes of leukemia harboring chromosomal translocations. Promising results have been observed in the breast cancer prevention setting, where fenretinide prevention trials have provided a strong rationale for further investigation in young women at high risk for breast cancer. Ongoing phase III randomized trials investigating retinoids in combination with chemotherapy in non-small cell lung cancer aim to definitively characterize the role of retinoids in this tumor type. The limited treatment success observed to date in the prevention and treatment of solid tumors may relate to the frequent epigenetic silencing of RARβ. Robust evaluation of RARβ and downstream genes may permit optimized use of retinoids in the solid tumor arena.

Topics: Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Neoplasms; Receptors, Retinoic Acid; Retinoids; Signal Transduction; Translational Research, Biomedical; Tretinoin

Somatic stem cells can be found in many rapidly regenerating tissues, e.g., the skin, gastrointestinal mucosa, and hematopoietic system, but are also present at low numbers in non-regenerative organs such as the heart and brain. In these organs, somatic stem cells aid in normal tissue homeostasis and repair after injury as well as self-renewal and the generation of specific progenitor cells during differentiation. Cancer stem-like cells are a small subpopulation of self-renewing cells that are able to proliferate upon appropriate stimulation and differentiate into heterogeneous lineages in tumors. Modulation of the behavior of normal tissue stem cells and cancer stem-like cells is an emerging and thriving new field of research. The present review gives an overview of the state-of-the-art findings and highlights perspectives for future scientific developments and clinical application.

Topics: Antineoplastic Agents, Phytogenic; Biological Products; Cell Cycle Checkpoints; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell Survival; Embryonic Stem Cells; Humans; Neoplasms; Neoplastic Stem Cells; Pluripotent Stem Cells; Signal Transduction; Tretinoin

Expression of the sodium iodide symporter (NIS) is required for efficient iodide uptake in thyroid and lactating breast. Since most differentiated thyroid cancer expresses NIS, β-emitting radioactive iodide is routinely utilized to target remnant thyroid cancer and metastasis after total thyroidectomy. Stimulation of NIS expression by high levels of thyroid-stimulating hormone is necessary to achieve radioiodide uptake into thyroid cancer that is sufficient for therapy. The majority of breast cancer also expresses NIS, but at a low level insufficient for radioiodine therapy. Retinoic acid is a potent NIS inducer in some breast cancer cells. NIS is also modestly expressed in some non-thyroidal tissues, including salivary glands, lacrimal glands and stomach. Selective induction of iodide uptake is required to target tumors with radioiodide. Iodide uptake in mammalian cells is dependent on the level of NIS gene expression, but also successful translocation of NIS to the cell membrane and correct insertion. The regulatory mechanisms of NIS expression and membrane insertion are regulated by signal transduction pathways that differ by tissue. Differential regulation of NIS confers selective induction of functional NIS in thyroid cancer cells, as well as some breast cancer cells, leading to more efficient radioiodide therapy for thyroid cancer and a new strategy for breast cancer therapy. The potential for systemic radioiodide treatment of a range of other cancers, that do not express endogenous NIS, has been demonstrated in models with tumor-selective introduction of exogenous NIS.

Topics: Animals; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Humans; Iodine Radioisotopes; Models, Biological; Molecular Targeted Therapy; Neoplasms; Protein Transport; Radionuclide Imaging; Signal Transduction; Symporters; Tretinoin

Transforming growth factor-β (TGF-β) isoforms are profibrotic cytokines, par excellence, and have complex multifunctional effects on many systems, depending on the biologic setting. Retinoids are vitamin A derivatives that also have diverse effects in development, physiology, and disease. The interactions between these classes of molecules are, not surprisingly, highly complex and are dependent on the tissue, cellular, and molecular settings.

Topics: Embryonic Development; Fetal Development; Humans; Neoplasms; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Signal Transduction; Transforming Growth Factor beta; Tretinoin; Vitamin A; Wound Healing

All-trans retinoic acid (ATRA) is an active metabolite of vitamin A under the family retinoid. Retinoids, through their cognate nuclear receptors, exert potent effects on cell growth, differentiation and apoptosis, and have significant promise for cancer therapy and chemoprevention. Differentiation therapy with ATRA has marked a major advance and become the first choice drug in the treatment of acute promyelocytic leukemia (APL). Conversions of 13-cis-retinoic acid and 9-cis-retinoic acid to all-trans-retinoic acid is very rapid. Currently, two distinct families of retinoid responsive nuclear receptors have been identified and characterized: retinoic acid receptors (RARs) and retinoid receptors (RXRs), each of which include three isoforms, α,β,and γ. ATRA is being increasingly included in anti-tumour therapeutical schemes for the treatment of various tumoral diseases such as Kaposi's sarcoma, head and neck squamous cell carcinoma, ovarian carcinoma, bladder cancer, neuroblastoma and has shown antiangiogenic effects in several systems, inhibiting proliferation in vascular smooth muscle cells (VSMCs) and anti-inflammatory in rheumatoid arthritis. This review helps to understand in details about the ATRA and its role on cancer and it is predicted that modulating the activity of ATRA will soon provide novel prevention and treatment approaches for the cancer patients.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Neoplasms; Receptors, Retinoic Acid; Tretinoin

Modern adjuvants should induce strong and balanced immune responses, and it is often desirable to induce specific types of immunity. As an example, efficient Th1-immunity-inducing adjuvants are highly in demand. Such adjuvants promote good cell-mediated immunity against subunit vaccines that have low immunogenicity themselves. The development of such adjuvants may take advantage of the increased knowledge of the molecular mechanisms and factors controlling these responses. However, knowledge of such molecular details of immune mechanisms is relatively scarce for species other than humans and laboratory rodents, and in addition, there are special considerations pertaining to the use of adjuvants in veterinary animals, such as production and companion animals. With a focus on veterinary animals, this review highlights a number of approaches being pursued, including cytokines, CpG oligonucleotides, microparticles and liposomes.

Topics: Adaptive Immunity; Adjuvants, Immunologic; Animals; Animals, Domestic; Drug Delivery Systems; Immunity, Innate; Immunity, Mucosal; Interferons; Liposomes; Microspheres; Neoplasms; Oligodeoxyribonucleotides; Toll-Like Receptors; Tretinoin; Vaccination; Vaccines

Myeloid derived suppressor cells (MDSC) have been described as a heterogeneous cell population with potent immune suppressor function in mice. Limited data are available on MDSC in human diseases. Interpretation of these data is complicated by the fact that different markers have been used to analyze human MDSC subtypes in various clinical settings. Human MDSC are CD11b+, CD33+, HLA-DR(neg/low) and can be divided into granulocytic CD14⁻ and monocytic CD14+ subtypes. Interleukin 4Rα, VEGFR, CD15 and CD66b have been suggested to be more specific markers for human MDSC, however these markers can only be found on some MDSC subsets. Until today the best marker for human MDSC remains their suppressor function, which can be either direct or indirect through the induction of regulatory T cells. Immune suppressor activity has been associated with high arginase 1 and iNOS activity as well as ROS production by MDSC. Not only in murine models, but even more importantly in patients with cancer, different drugs have been shown to either reverse the immune suppressor function of MDSC or directly target these cells. Systemic treatment with all-trans-retinoic acid has been shown to mature human MDSC and reverse their immune suppressor function. Alternatively, MDSC can be targeted by treatment with the multi-targeted receptor tyrosine kinase inhibitor sunitinib. This review will provide a comprehensive summary of the recent literature on human MDSC.

Topics: Animals; Biomarkers; Humans; Immunosuppression Therapy; Indoles; Inflammatory Bowel Diseases; Mice; Molecular Targeted Therapy; Myeloid Cells; Myelopoiesis; Neoplasms; Pyrroles; Sunitinib; Tretinoin

Agents used for systemic chemotherapy can alter normal bone homeostasis through mechanisms that affect both osteoblast and osteoclast function. The identification of those agents that influence maintenance of the bone-remodeling compartment is an important component of the drug development and testing process. This brief review focuses on preclinical and clinical data illustrating the effect of several classes of chemotherapeutic agents on skeletal development and bone remodeling.. New preclinical data demonstrate that several classes of chemotherapeutic agents, including histone deacetylase inhibitors and proteasome inhibitors, alter osteoblast and osteoclast function. Preclinical data on retinoic acid analogues demonstrate that these agents inhibit osteoclastogenesis. In addition, a dose-dependent effect of methotrexate treatment on growth plate thickness and primary spongiosa height in rats has been demonstrated. Two recently published analyses of clinical data from trials of bortezomib in myeloma patients found increased biochemical markers of bone formation and evidence of increased bone deposition after bortezomib treatment.. Several classes of chemotherapeutic agents alter bone metabolism and negatively impact bone homeostasis. Bone mineral density (BMD) monitoring guidelines for patients receiving systemic chemotherapy are not established. Limited guidelines exist for BMD monitoring in patients receiving long-term hormonal modulation; however, the negative effect of other chemotherapeutic agents on the skeleton is underappreciated.

Topics: Antineoplastic Agents; Aromatase Inhibitors; Bone and Bones; Bone Density; Bone Remodeling; Glucocorticoids; Humans; Neoplasms; Osteoblasts; Osteoclasts; Selective Estrogen Receptor Modulators; Tretinoin

Topics: Antineoplastic Agents; Blood Coagulation; Cysteine Endopeptidases; Cytokines; Disseminated Intravascular Coagulation; Fibrinolytic Agents; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplasms; Thromboplastin; Tretinoin

Retinoids are useful pharmacological agents in therapy and prevention of cancer. All-trans retinoic acid (ATRA) is applied in chemoprevention and differentiation therapy of some cancers with particularly impressive results in the management of acute promyelocytic leukemia (APL). ATRA plays a major role in regulating growth and differentiation of a wide variety of normal and malignant cell types. ATRA mediates these effects by regulating gene transcription. Nuclear retinoic acid receptors (RARs) are considered to be the mediators of most of the effects of ATRA on gene expression. We present a current state of knowledge on the effects of ATRA on cell growth and differentiation as well as describe RARs and their role in the cellular mechanism of ATRA action. A particular attention was paid to the effects of ATRA on proliferation and differentiation of cancer cells.

Topics: Antineoplastic Agents; Humans; Neoplasms; Tretinoin

The retinoids are a class of compounds that are structurally related to vitamin A. Retinoic acid, which is the active metabolite of retinol, regulates a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids exert their effects through a variety of binding proteins including cellular retinol-binding protein (CRBP), retinol-binding proteins (RBP), cellular retinoic acid-binding protein (CRABP), and nuclear receptors i.e. retinoic acid receptor (RAR) and retinoid x receptor (RXR). Because of the pleiotropic effects of retinoids, understanding the function of these binding proteins and nuclear receptors assists us in developing compounds that have specific effects. This review summarizes our current understanding of how retinoids are processed and act with an emphasis on the application of retinoids in cancer treatment and prevention.

Topics: Animals; Cell Differentiation; Humans; Neoplasms; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Tretinoin; Vitamin A

Histone deacetylase inhibitors comprise a variety of natural and synthetic compounds, which have in common that they inhibit enzymes that mediate the removal of acetyl groups from a range of proteins, including nucleosomal histones. Histone deacetylase inhibitors have anti-cancer activities in vitro and in vivo and are used in the clinic for the treatment of advanced cutaneous T cell lymphoma. The molecular pathways targeted by these compounds are discussed with an emphasis on the effects of these compounds on retinoic acid signaling.

Topics: Animals; Antineoplastic Agents; DNA Methylation; Enzyme Inhibitors; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Lymphoma, T-Cell, Cutaneous; Models, Biological; Neoplasms; Tretinoin

Adaptive Foxp3(+)CD4(+) regulatory T (iTreg) cells develop outside the thymus under subimmunogenic antigen presentation, during chronic inflammation, and during normal homeostasis of the gut. iTreg cells are essential in mucosal immune tolerance and in the control of severe chronic allergic inflammation, and most likely are one of the main barriers to the eradication of tumors. The Foxp3(+) iTreg cell repertoire is drawn from naive conventional CD4(+) T cells, whereas natural Treg (nTreg) cells are selected by high-avidity interactions in the thymus. The full extent of differences and similarities between iTreg and nTreg cells is yet to be defined. We speculate that iTreg cell development is driven by the need to maintain a noninflammatory environment in the gut, to suppress immune responses to environmental and food allergens, and to decrease chronic inflammation, whereas nTreg cells prevent autoimmunity and raise the activation threshold for all immune responses.

Topics: Animals; Cell Differentiation; Dendritic Cells; Forkhead Transcription Factors; Humans; Immune Tolerance; Infections; Inflammation; Interleukin-15; Interleukin-2; Neoplasms; STAT Transcription Factors; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Thymus Gland; Transforming Growth Factor beta; Tretinoin

MicroRNAs (miRNAs) are an abundant class of short noncoding RNAs that are widely expressed in mammalian cells and are important in post-translational gene regulation, including regulation of cell proliferation, apoptosis, and differentiation processes. miRNAs are involved in cancer initiation and progression and their expression patterns serve as phenotypic signatures of different cancers. Recent evidence suggests that dietary components as diverse as folate, retinoids, and curcumin exert cancer-protective effects through modulation of miRNA expression. miRNAs may be useful as biomarkers of cancer prevention or nutritional status, as well as serve as potential molecular targets that are influenced by dietary interventions.

Topics: Curcumin; Diet; Folic Acid; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; Tretinoin

The properties of arsenic trioxide (arsenic) have been known for centuries. This compound has been used, among others, in the industrial production of paints and glass and also for the conservation of leather and wood. Although arsenic trioxide is highly toxic, this compound was shown to have a therapeutic potential as early as the fifteenth century. The period between the seventeenth and nineteenth centuries resulted in the development of new arsenic-based drugs which were applied for the treatment of skin diseases and acute promyelocytic leukemia. The mechanism of action of arsenic trioxide is mainly related to the induction of apoptosis (programmed cell death) in cancer cells. In particular it involves effects on the activities of JNK kinases, NF-kB transcription factor, glutathione, caspases, as well as pro- and anti-apoptotic proteins. Experiments investigating the effect of arsenic trioxide on cell lines such as glioma and prostate, breast, stomach, liver, and ovarian cancer are in progress. There are also clinical trials underway aimed at the use of arsenic trioxide with ascorbic acid, retinoid acid, and growth factors in combined therapy.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Caspases; Drug Therapy, Combination; Glutathione; Humans; Intercellular Signaling Peptides and Proteins; MAP Kinase Kinase 4; Neoplasms; NF-kappa B; Oxides; Tretinoin

The utility of recombinant Sendai virus (rSeV) has been considerably examined over the last decade as a potent gene transfer candidate in a cytoplasmic gene expression system. Such risks as excessive immune responses associated with this virus administration in vivo however have limited its applicability in clinical settings as is the case with other viral vectors including adenoviruses. In consequence of extensive assessment on the mechanisms of immune responses against SeV, we found that ex vivo infection of immature dendritic cells (DCs) with SeV demonstrates their spontaneous maturation and activation. We applied this result to create a unique, representative, and powerful agent to activate DCs, namely rSeV-modified DCs (rSeV/DCs), for use in cancer immunotherapy. Use of this system in vivo resulted in the induction of efficient antitumor immunity against vascularized rodent tumors, including melanoma, hepatocellular carcinoma, neuroblastoma, squamous cell carcinoma, and prostatic cancer, and it even frequently associated with elimination of those tumors. These results indicate that rSeV could be a powerful immune booster for DC-based cancer immunotherapy that is worth investigating further. We propose a conceptual term "immunostimulatory virotherapy" to describe this new method of cancer therapy using the rSeV/DCs system.

Topics: Animals; Dendritic Cells; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Immunotherapy; Models, Genetic; Mutation; Neoplasms; Sendai virus; Tretinoin

Evidence that membrane-bound and extracellular heat shock proteins (HSPs) with molecular weights of 70 and 90 kDa are potent stimulators of the immune responses has accumulated over the last decade. In this review, we discuss the modulation of Hsp70 expression, a major stress-inducible member of the HSP70 family, in the cytoplasm and on the plasma membrane of tumor cells by clinically applied interventions such as radio- and chemotherapy.

Topics: Amino Acid Sequence; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cell Differentiation; Gene Expression Regulation, Neoplastic; HSP70 Heat-Shock Proteins; Humans; Membrane Proteins; Mice; Mice, Mutant Strains; Mice, SCID; Molecular Sequence Data; Multigene Family; Neoplasm Proteins; Neoplasms; Peptide Fragments; Stress, Physiological; Tretinoin; Xenograft Model Antitumor Assays

Retinoic acid (RA) and derivatives are promising antineoplastic agents endowed with both therapeutic and chemopreventive potential. Although the treatment of acute promyelocytic leukemia with all-trans retinoic acid is an outstanding example, the full potential of retinoids in oncology has not yet been explored and a more generalized use of these compounds is not yet a reality. One way to enhance the therapeutic and chemopreventive activity of RA and derivatives is to identify rational combinations between these compounds and other pharmacological agents. This is now possible given the information available on the biochemical and molecular mechanisms underlying the biological activity of retinoids. At the cellular level, the antileukemia and anticancer activity of retinoids is the result of three main actions, cytodifferentiation, growth inhibition, and apoptosis. Cytodifferentiation is a particularly attractive modality of treatment and differentiating agents promise to be less toxic and more specific than conventional chemotherapy. This is the result of the fact that cytotoxicity is not the primary aim of differentiation therapy. At the molecular level, retinoids act through the activation of nuclear retinoic acid receptor-dependent and -independent pathways. The cellular pathways and molecular networks relevant for retinoid activity are modulated by a panoply of other intracellular and extracellular pathways that may be targeted by known drugs and other experimental therapeutics. This chapter aims to summarize and critically discuss the available knowledge in the field.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Differentiation; Chemoprevention; Chemotherapy, Adjuvant; Humans; Neoplasms; Receptors, Retinoic Acid; Retinoids; Signal Transduction; Tretinoin

The naturally occurring retinoids and their synthetic analogs play a key role in differentiation, proliferation, and apoptosis, and their use/potential in oncology, dermatology and a variety of diseases are well documented. This review focuses on the role of all-trans-retinoic acid (ATRA), the principal endogenous metabolite of vitamin A (retinol) and its metabolism in oncology and dermatology. ATRA has been used successfully in differentiated therapy of acute promyelocytic leukemia, skin cancer, Kaposi's sarcoma, and cutaneous T-cell lymphoma, and also in the treatment of acne and psoriasis. However, its usefulness is limited by the rapid emergence of acquired ATRA resistance involving multifactoral mechanisms. A key mechanism of resistance involves ATRA-induced catabolism of ATRA. Thus, a novel strategy to overcome the limitation associated with exogenous ATRA therapy has been to modulate and/or increase the levels of endogenous ATRA by inhibiting the cytochrome P450-dependent ATRA-4-hydroxylase enzymes (particularly CYP26s) responsible for ATRA metabolism. These inhibitors are also referred to as retinoic acid metabolism blocking agents (RAMBAs). This review highlights development in the design, synthesis, and evaluation of RAMBAs. Major emphasis is given to liarozole, the most studied and only RAMBA in clinical use and also the new RAMBAs in development and with clinical potential.

Topics: Animals; Antineoplastic Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dermatologic Agents; Enzyme Inhibitors; Humans; Neoplasms; Retinoic Acid 4-Hydroxylase; Skin Diseases; Tretinoin

Fenretinide, a synthetic retinoid, has emerged as a promising anticancer agent based on numerous in vitro and animal studies, as well as chemoprevention clinical trials. In vitro observations suggest that the anticancer activity of fenretinide may arise from its ability to induce apoptosis in tumor cells. Diverse signaling molecules including reactive oxygen species, ceramide, and ganglioside GD3 can mediate apoptosis induction by fenretinide in transformed, premalignant, and malignant cells. In many cell types, these signaling intermediates appear to be induced by mechanisms that are independent of retinoic acid receptor activation, and ultimately initiate the intrinsic or mitochondrial-mediated pathway of cell elimination. Numerous investigations conducted during the past 10 years have discovered a great deal about the apoptogenic activity of fenretinide. In this review we explore the mechanisms associated with fenretinide-induced apoptosis and highlight certain mechanistic underpinnings of fenretinide-induced cell death that remain poorly understood and thus warrant further characterization.

Topics: Animals; Antineoplastic Agents; Apoptosis; Fenretinide; Humans; Matrix Metalloproteinases; Models, Biological; Neoplasms; Preventive Medicine; Protective Agents; Protein Denaturation; Reactive Oxygen Species; Signal Transduction; Tretinoin

Anthracyclines are a well-known cause of cardiotoxicity, but a number of other drugs used to treat cancer can also result in cardiac and cardiovascular adverse effects. Cardiotoxicity can result in the alteration of cardiac rhythm, changes in blood pressure and ischemia, and can also alter the ability of the heart to contract and/or relax. The clinical spectrum of these toxicities can range from subclinical abnormalities to catastrophic life-threatening, and sometimes fatal, sequelae. These events may occur acutely or may only become apparent months or years following completion of oncological treatment. Ischemia and rhythm abnormalities are treated symptomatically in most cases. Knowledge of these toxicities can aid clinicians to choose the optimal and least toxic regimen suitable for an individual patient.

Topics: Anthracyclines; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Cardiovascular Diseases; Heart Diseases; Humans; Interferons; Interleukin-2; Neoplasms; Oxides; Stilbenes; Tretinoin

Retinoic acid (RA), the most potent natural retinoid, is essential for normal cell growth and differentiation. The RA signaling pathway is multistep, involving the precise regulation of retinoid levels and the control of RA-dependent gene expression in target cells. Within this complex scheme, there are many different aberrations in the RA signaling pathway of tumor cells that have been found to be associated with abnormal cell growth and tumorigenesis. This article reviews the normal pathways of RA signaling, followed by a discussion of the various sites that have been implicated in tumorigenesis and targeted for drug development. Currently, there are several retinoids and one rexinoid approved for the treatment of specific cancers. Future experimentation in drug discovery will continue to explore the efficacy of retinoids/rexinoids, either alone or in combination with other chemotherapeutic agents and/or chromatin remodeling agents, and the development of agents to modulate RA metabolism within cells. It is likely that different drug treatments will be developed that are specifically tailored to the unique point(s) in the RA signaling pathways that are aberrant in specific types of tumor cells.

Topics: Animals; Antineoplastic Agents; Forecasting; Humans; Molecular Structure; Neoplasms; Retinoids; Tretinoin

To be maximally effective, therapy of cancer must be directed against both the resting stem cells and the proliferating cells of the cancer. The cell populations of both normal and cancer tissues consist of resting stem cells, proliferating transit-amplifying cells, terminally differentiating cells and dying (apoptotic) cells. The difference between normal tissue renewal and growth of cancers is that some of the transit-amplifying cells in the cancer population do not mature into terminally differentiating cells, but instead continue to proliferate and do not die (maturation arrest). Because of this the number of cancer cells increase, whereas the cell population of normal tissues remains a relatively constant. Conventional radiation treatment and chemotherapy kill the actively proliferating transit- amplifying cells of the cancer. Differentiation therapy, using specific targeted inhibitors of activation, effectively induces differentiation of the proliferating transit-amplifying cancer cells. However, even if the proliferating cancer cells are completely inhibited or eliminated, the cancer stem cells may restore the transit-amplifying population, so that clinical remission is usually temporary. The hypothesis presented in this paper is that successful cancer therapy must be directed against both the resting stem cells and the proliferating cells of the cancer. This may be possible if specific stem cell signals are inhibited using gene therapy, while at the same time attacking proliferating cells by conventional radiation treatment or chemotherapy. With advances in approaches using specific inhibitory RNA, such combination therapy may now be possible, but critical problems in delivering the inhibitory effect specifically to the cancer stem cells have yet to be worked out.

Topics: Animals; Breast Neoplasms; Cell Differentiation; Cell Lineage; Cell Proliferation; Embryonal Carcinoma Stem Cells; Female; Genetic Therapy; Humans; Leukemia; Models, Biological; Neoplasms; Neoplastic Stem Cells; RNA Interference; Stem Cells; Teratocarcinoma; Tretinoin

Retinoid is a term for compounds that bind to and activate retinoic acid receptors (RARalpha, RARbeta, and RARgamma), members of the nuclear hormone receptor superfamily. The most important endogenous retinoid is all-trans-retinoic acid. Retinoids regulate a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation and apoptosis, and homeostasis, as well as their disorders. This review summarizes the considerable amount of knowledge generated on these receptors.

Topics: Animals; Binding, Competitive; Gene Expression; Humans; Mutation; Neoplasms; Receptors, Retinoic Acid; Retinoids; Skin Diseases; Tretinoin

Retinoids play important roles in cell differentiation and apoptosis, notably in epithelial tissues. Their utility in cancer therapy has been demonstrated in specific cancer types. Use of retinoic acid (RA) in the treatment of acute promyelocytic leukemia was the first successful example of retinoid-based differentiation therapy. RA has since been evaluated for treatment of other cancers, revealing variable effectiveness. The observation that expression of enzymes involved in RA biosynthesis is suppressed during tumorigenesis suggests that intra-tumor depletion in RA levels may contribute to tumor development and argues for the use of retinoids in cancer treatment. However, the induction of RA-inactivating enzymes is one of the mechanisms that may limit the efficacy of retinoid therapy and contribute to acquired resistance to RA treatment, suggesting that retinoic acid metabolism blocking agents may be effective agents in differentiation therapy.

Topics: Anticarcinogenic Agents; Humans; Intestinal Absorption; Neoplasms; Receptors, Retinoic Acid; Retinoids; Tretinoin; Vitamin A

Histone deacetylases (HDACs) are nuclear and cytoplasmic enzymes that deacetylate a number of substrates, of which histones are the best known and described in the literature. HDACs are present in eukaryotic and bacteria cells, and are fundamental for a number of cellular functions, including correct gene expression. Surprisingly, only up to 20% of the whole genome is controlled by HDACs, but key processes for survival, proliferation, and differentiation have been strictly linked to HDAC enzyme functioning. The use of HDAC inhibitors (HDACi) has been proposed for the treatment of neoplastic diseases. Their effectiveness has been suggested for a number of liquid and solid tumors, particularly acute promyelocytic leukemia (APL). The role of HDACs in embryo development is currently under investigation. Published data indicate knockout phenotype analysis to be of particular interest, in which a number of HDACs play a key role during development. Little data have been published on the effects of HDACi on embryonic development, although for valproic acid (VPA), literature from the 1980s described its teratogenic effects in experimental animals and humans. To date, all tested HDACi have shown teratogenic effects similar to those described for VPA when tested in zebrafish, Xenopus laevis, and mice. HDACs were also able to alter embryo development in invertebrates and plants. A model, similar to that proposed in APL, involving retinoic acid receptors (RAR) and tissue specific Hox gene expression, is suggested to explain the HDAC effects on embryo development.

Topics: Abnormalities, Drug-Induced; Animals; Embryonic Development; Enzyme Inhibitors; Female; Genes, Homeobox; Histone Deacetylase Inhibitors; Humans; Models, Biological; Neoplasms; Pregnancy; Receptors, Retinoic Acid; Teratogens; Tretinoin

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Benzamides; Clinical Trials as Topic; ErbB Receptors; Fusion Proteins, bcr-abl; Gefitinib; Hematologic Neoplasms; Humans; Imatinib Mesylate; Intracellular Signaling Peptides and Proteins; Neoplasms; Piperazines; Protein-Tyrosine Kinases; Pyrimidines; Quinazolines; Rituximab; Signal Transduction; Trastuzumab; Tretinoin

Topics: Alitretinoin; Animals; Antineoplastic Agents; Bexarotene; Humans; Ligands; Neoplasms; Retinoid X Receptors; Retinoids; Structure-Activity Relationship; Tetrahydronaphthalenes; Tretinoin

In eukaryotic organisms cellular fate and tissue specific gene expression are regulated by the activity of proteins known as transcription factors that by interacting with specific DNA sequences direct the activation or repression of target genes. The post genomic era has shown that transcription factors are not the unique key regulators of gene expression. Epigenetic mechanisms such as DNA methylation, post-translational modifications of histone proteins, remodeling of nucleosomes and expression of small regulatory RNAs also contribute to regulation of gene expression, determination of cell and tissue specificity and assurance of inheritance of gene expression levels. The relevant contribution of epigenetic mechanisms to a proper cellular function is highlighted by the effects of their deregulation that cooperate with genetic alterations to the development of various diseases and to the establishment and progression of tumors.

Topics: Chromatin; DNA; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Gene Silencing; Genetic Diseases, Inborn; Heterochromatin; Histones; Humans; Leukemia, Myeloid, Acute; Models, Biological; Neoplasms; Nucleosomes; Oligodeoxyribonucleotides; Protein Processing, Post-Translational; Protein Structure, Tertiary; RNA; RNA Interference; Sequence Analysis, DNA; Transcription, Genetic; Tretinoin

Beta-carotene and other carotenoids have been thought to have anti-cancer activity, either because of antioxidant activity or because of their ability to be converted to vitamin A. Nevertheless, two large scale intervention studies in humans using high doses of beta-carotene found that beta-carotene supplementation resulted in more lung cancer rather than less lung cancer among smoking and asbestos exposed populations. Studies conducted in the ferret have elucidated molecular mechanisms behind this observation, in that high-dose beta-carotene and smoke exposure in these animals leads to squamous metaplasia, a pre-cancerous lesion in the lung. High dose beta-carotene in the smoke exposed animals was found to give rise to a number of transient oxidative metabolites, which include P450 enzymes that result in the destruction of retinoic acid, and diminished retinoid signaling, and enhanced cell proliferation. In addition, eccentric cleavage beta-carotene metabolites facilitate the binding of smoke derived carcinogens to DNA. In other ferret studies low dose beta-carotene smoke exposure provided mild protection against squamous metaplasia. Thus, it appears that the explanation of the apparent paradoxical effects of beta-carotene on lung cancer is related to dose. The metabolism and breakdown of natural products should be thoroughly investigated in animal models before embarking on large scale intervention trials, particularly when using unusually high doses that greatly exceed normal dietary levels.

Topics: Animals; Asbestos; beta Carotene; Cytochrome P-450 Enzyme System; Dietary Supplements; Dose-Response Relationship, Drug; Ferrets; Humans; Lung; Lung Neoplasms; Neoplasms; Smoking; Tretinoin

Studies utilizing experimental animals, epidemiological approaches, cellular models, and clinical trials all provide evidence that retinoic acid and some of its synthetic derivatives (retinoids) are useful pharmacological agents in cancer therapy and prevention. In this chapter, we first review the current knowledge of retinoic acid receptors (RARs) and their role in mediating the actions of retinoic acid. We then focus on a discussion of RARalpha and acute promyelocytic leukemia followed by a discussion of the role of RARs, in particular RARbeta expression, in other cancer types. Loss of normal RAR function in the presence of physiological levels of RA (either due to alterations in the protein structure or level of expression) is associated with a variety of different cancers. In some cases treatment with pharmacological doses of RA can be effective.

Topics: Animals; Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Receptors, Retinoic Acid; Tretinoin

Considerable and intense progress has been made in the understanding of the chemistry, molecular biology and cell biology of transglutaminases (TGases: EC 2.3.2.13). The knowledge that very different processes such as cell growth, reproduction and death are dependent on the presence of adequate levels of these enzymes and that the amount of both free and protein-conjugated polyamines, formed by the enzyme, are capable of modulating the differentiation and proliferative capability of several cell types, has prompted a multitude of researchers to study the role of these fascinating molecules in cancer cell differentiation.

Topics: Animals; Cell Differentiation; Humans; Neoplasms; Polyamines; Proteins; Theophylline; Transglutaminases; Tretinoin; Xanthines

Chemoprevention is the use of noncytotoxic therapeutic intervention at the early stages of carcinogenesis against the development and progression of mutant clones to invasive cancer. Retinoids are the most extensively studied and one of the most prominent groups of chemopreventive agents to reach clinical trials. Acute promyelocytic leukemia is the first human malignancy that is successfully treated with all-trans retinoic acid. The t(15;17)(q22;q21) gene rearrangement and PML/RARalpha fusion product in acute promyelocytic leukemia played the key role to leukemogenesis and to sensitivity to differentiation-inducing therapy of all-trans retinoic acid. This review focuses on retinoid-based chemoprevention and therapy of cancer, and use acute promyelocytic leukemia as a model to illustrate the molecular mechanisms of retinoid signaling pathway.

Topics: Animals; Anticarcinogenic Agents; Cell Nucleus; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Signal Transduction; Translocation, Genetic; Tretinoin; Vitamin A

Topics: Antineoplastic Agents; Genes, Tumor Suppressor; Humans; Neoplasms; Tretinoin

The high mobility group A (HMGA) proteins are thought to work as ancillary transcription factors and to regulate the expression of a growing number of genes through direct binding to DNA or via protein-protein interactions. Both HMGA1 and HMGA2 are important regulators of basic biological processes, including cell growth, differentiation and transformation. Their qualitatively or quantitatively altered expression has been described in a number of human tumors. We studied and review here their expression in neuroblastic tumors. HMGA2 is expressed only in a subset of ex vivo neuroblastoma (NB) tumors and in the embryonic adrenal gland, but it is undetectable in the adult adrenal gland, suggesting that its anomalous expression might be associated with NB tumorigenesis and/or tumor progression. In vitro, its expression is easily detectable in retinoic acid (RA)-resistant cell lines. The exogenous expression of HMGA2 is sufficient to convert RA-sensitive SY5Y NB cells into RA-resistant cells, thus suggesting that HMGA2 might be a relevant player in determining NB cell responses to endogenous or therapeutically important growth inhibitory substances. In contrast, HMGA1 expression is readily detectable in all NB cell lines and tumors, but its expression is consistently higher in less differentiated NBs compared with ganglioneuromas and ganglioneuroblastomas. Interestingly, RA increases HMGA1 expression in RA-resistant NB cells but inhibits it in cells undergoing RA-induced growth inhibition and neuronal differentiation. Our studies indicate that HMGA molecules might be biologically and pathologically relevant factors in neuroblastic tumor development and progression.

Topics: Amino Acid Sequence; Blotting, Northern; Cell Differentiation; Cell Line, Tumor; Disease Progression; DNA; Gene Deletion; HMGA1a Protein; HMGA1b Protein; HMGA2 Protein; Humans; Models, Biological; Molecular Sequence Data; Neoplasms; Neuroblastoma; Phenotype; Protein Structure, Tertiary; Reverse Transcriptase Polymerase Chain Reaction; Sequence Homology, Amino Acid; Transcription, Genetic; Tretinoin

Topics: Cell Differentiation; Cell Division; DNA Methylation; Enzyme Activation; Enzyme Inhibitors; Female; Histone Deacetylases; Humans; Ligands; Male; Models, Biological; Neoplasms; Protein Kinase C; Tretinoin

The concept behind cancer treatment has evolved over the past decade from systemic, nonspecific, high-dose chemotherapy to targeted therapy and the introduction of cancer vaccines. Advanced technology and a better understanding of the cellular mechanisms that control cancer biology have helped in the development of such targeted treatment.. The aim of this article was to review some of the new and commonly used targeted treatments in cancer, emphasizing their mechanisms of action, safety profiles, and clinical applications.. The terms cancer, chemotherapy, monoclonal antibodies, targeted treatment, tyrosine kinase, epidermal growth factors, epidermal growth factor receptor, and cancer vaccines were used to search MEDLINE for English-language studies in humans, published between 1966 and March 2003. Identified publications addressing the objectives of this article were selected for review.. All-trans-retinoic acid, imatinib, gemtuzumab ozogamicin, rituximab, alemtuzumab, trastuzumab, cetuximab, and gefitinib are recently developed cancer therapies that target specific types of cells and receptors. They have been used in a variety of hematologic and solid tumors, and their tolerability makes them attractive for use even in elderly and extensively pretreated patients. Vaccines using dendritic cells, tumor cells, and fusions of tumor cells and antigen-presenting cells have also shown some promise in research, but further study is needed to obtain better, sustained results.. Targeted treatment and cancer vaccines are novel approaches in the treatment of cancer. Both fields are expanding rapidly, with new technology and ongoing medical research. The clinical implications of such agents, administered either solely or in combination with established chemotherapeutic agents, may ultimately lead to better regimens and improved clinical responses.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Benzamides; Cancer Vaccines; Drug Delivery Systems; Humans; Imatinib Mesylate; Neoplasms; Piperazines; Pyrimidines; Tretinoin

Chemoprevention of cancer is reviewed from the viewpoints of action mechanisms and methodology of clinical trials in order to introduce promising agents discovered by in vitro and/or in vivo studies to applications in humans. The clinical trial procedure essentially follows the phase study which has been employed for chemotherapeutic drugs. Chemoprevention of bladder cancer, prostate cancer, gastric cancer, hepatocellular carcinoma, breast cancer, head and neck cancer, colorectal cancer and lung cancer is reviewed, mainly focusing on clinical trials. Previous clinical trials have shown the effectiveness of the following: polyprenoic acid (acyclic retinoid) for hepatocellular carcinoma; tamoxifen for breast cancer; retinoic acids for head and neck tumor; and aspirin, a COX-2 inhibitor, for colorectal cancer. Despite the advantageous effects of some of these agents, their toxic effects must also be of concern at the same time. For example, in a chemoprevention trial of lung cancer, beta-carotene was unexpectedly found to increase the risk of lung cancer among high-risk groups. It is also noted that large-scale clinical trials demand large research grants, which may not be affordable in Japan. Chemoprevention is still an emerging field of oncology where researchers in both basic and clinical sciences face great challenges.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; beta Carotene; Breast Neoplasms; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Neoplasms; Prostatic Neoplasms; Tamoxifen; Tretinoin; Urinary Bladder Neoplasms

Cell differentiation is essential for normal growth and homeostasis, and drug-induced differentiation of tumor cells into benign or normal cells is an important approach for anticancer chemotherapy. Studies of induction mechanisms for cell differentiation and discovery of differentiation-inducing factors are thus critical components of drug development. The Screening of differentiation-inducing factors, such as purified aldehyde reductase, a xenobiotic metabolite enzyme, that induces differentiation of human acute myeloid leukemia HL60 cells into monocyte/macrophage cells is described. Mechanisms of all-trans-retinoic acid (RA)-induced differentiation are also covered. RA is a potent inducer of HL60 cell differentiation and when used as a sole agent it can induce complete remission in patients with acute promyelocytic leukemia (APL). While one mechanism of the effect of RA involves RA nuclear receptors, retinoylation (a posttranslational modification of proteins by RA) may be a new nongenomic mechanism by which RA acts on cells. An early event in RA-induced differentiation may be retinoylation of RII alpha (regulatory subunits of cAMP-dependent protein kinase), in which RII alpha units are retinoylated and the retinoylated RII alpha is then translocated to the nucleus. Drugs can also be combined with RA in RA-differentiation therapy. Cytodifferation therapy by RA in APL patients exhibits limitations due to the resistance of relapsed patients to further RA treatment. This may occur through the induction of expression of various genes that reduce RA blood concentrations. Treatment with combinations of RA and other agents may be one way to reduce induction of those genes. Good candidates for such agents include cAMP-elevating agents, retinoids, steroids, and fatty acids that synergistically induce differentiation of HL60 cells. Two derivatives of falconensone A, falconensone A p-bromophenylhydrazone, which has a bromophenyl residue, and falconensone A dioxime, which possesses a hydroxy residue, were synthesized to incorporate features of RA and N-[4-hydroxyphenyl] retinamide. Both derivatives have exhibited more potent biological activity than the parent falconensone A in vitro and in vivo.

Topics: Acylation; Animals; Antineoplastic Agents; Cell Differentiation; Drug Design; Humans; Ketosteroids; Neoplasm Proteins; Neoplasms; Retinoids; Signal Transduction; Tretinoin; Triglycerides

For the majority of patients with advance malignancies, current therapies are noncurative. Developing therapeutic agents that enhance the apoptotic effects and hence antitumor potential of currently available chemotherapy agents represents a rationale investigative strategy. Several chemotherapeutic agents including antimicrotubule agents and all-trans-retinoic acid utilize these pathways to mediate tumor cell killing. With specific agents such as oblimersan sodium in randomized "pivotal" studies, and agents targeting the TRAIL receptor-family recently entering early clinical study, cautious optimism is warranted.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Clinical Trials as Topic; Drug Design; Genes, bcl-2; Humans; Membrane Glycoproteins; Models, Biological; Neoplasm Proteins; Neoplasms; Oligodeoxyribonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Recombinant Proteins; Thionucleotides; TNF-Related Apoptosis-Inducing Ligand; Tretinoin; Tumor Necrosis Factor-alpha

In the post genome era it will soon be possible to associate a specific tumor type with a specific gene expression profile and to define each molecular lesion characteristic of any given cancer. It is intuitive that a successful therapeutic strategy for cancer should aim at blocking the aberrant biochemical activity triggered by the oncogene or the lack of tumor suppressor gene activity that ultimately leads to full-blown neoplastic transformation. However, an attractive alternative approach entails the blockade of the transcriptional consequences of such oncogenic activities irrespective of their original biochemical nature, thus antagonizing the key transcriptional events underlying cancer pathogenesis in any specific neoplastic cellular population. This approach is now rendered possible by major advances along several lines of investigation: (i) the possibility of analysing gene expression through high throughput methods; (ii) a more detailed knowledge of the regulatory regions and of the transcription factors that control gene expression also facilitated in the future by a comprehensive whole genome comparative analysis of these regulatory sequences; (iii) the ability of modulating gene expression at the single gene level through various approaches both pharmacological and biochemical; (iv) the opportunity of directly antagonizing the aberrant activities of oncogenic transcription factors through a detailed knowledge of their abnormal transcriptional function; (v) the possibility of validating, in vivo, in animal models the relevance for neoplastic transformation of specific transcriptional events as well as of testing the efficacy of 'transcription therapy' in faithful animal models of human cancer. Here, we will review the facts, the existing applications and the hypothesis underlying such therapeutic modality for cancer therapy.

Topics: Animals; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Transcription, Genetic; Tretinoin

The tissue distribution of retinoic acid (RA) throughout development is highly restricted, defined by the expression patterns of enzymes involved in RA synthesis and catabolism. Presented is a summary of recent research that examines the role of some of the enzymes involved in RA distribution, particularly those involved in RA catabolism (P450RAI). These latter enzymes protect against premature exposure to RA, and the implications of these findings are discussed.

Topics: Catalysis; Cytochrome P-450 Enzyme System; Humans; Keratolytic Agents; Mixed Function Oxygenases; Neoplasms; Retinoic Acid 4-Hydroxylase; Signal Transduction; Tretinoin; Vitamin A Deficiency

In vitro studies that showed RA could cause growth arrest and differentiation of myelogenous leukemia and neuroblastoma led to clinical trials of retinoids in APL and neuroblastoma that increased survival for both of those diseases. In the case of APL, ATRA has been the drug of choice, and preclinical and clinical data support direct combinations of ATRA with cytotoxic chemotherapy. For neuroblastoma, a phase I study defined a dose of 13-cis-RA, which was tolerable in patients after myeloablative therapy, and a phase III trial that showed postconsolidation therapy with 13-cis-RA improved EFS for patients with high-risk neuroblastoma. Preclinical studies in neuroblastoma indicate that ATRA or 13-cis-RA can antagonize cytotoxic chemotherapy and radiation, so use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. A limitation on the antitumor benefit of ATRA in APL is the marked decrease in drug levels that occurs during therapy as a result of induction of drug metabolism, resulting in a shorter drug half-life and decreased plasma levels. Although early studies sought to overcome the pharmacologic limitations of ATRA therapy in APL, the demonstration that ATO is active against APL in RA-refractory patients has led to a focus on studies employing ATO. Use of 13-cis-RA in neuroblastoma has avoided the decreased plasma levels seen with ATRA. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cis-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase I trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development.

Topics: Antineoplastic Agents; Child; Clinical Trials as Topic; Fenretinide; Humans; Isotretinoin; Leukemia, Myeloid, Acute; Neoplasms; Neuroblastoma; Randomized Controlled Trials as Topic; Receptors, Retinoic Acid; Retinoids; Tretinoin

The retinoids, natural and synthetic derivatives of vitamin A, are active in cancer therapy and prevention. Their biological effects are mediated through ligand-dependent interactions with retinoid receptors that associate with specific co-regulators. A better understanding of retinoid chemopreventive mechanisms is needed. Our prior work revealed that all-trans-retinoic acid (RA) prevented tobacco-specific carcinogenic transformation of cultured human bronchial epithelial cells. RA signaled G1 arrest that permitted repair of genomic DNA damage caused by these carcinogens. RA triggered G1 arrest at least partly through proteasome-dependent degradation of cyclin D1. Proteasomal inhibitors blocked RA-mediated cyclin D1 degradation. To confirm that a specific proteolysis pathway was induced by RA-treatment, a degradation assay was established using in vitro translated cyclin D1 and cellular extracts from RA-treated or untreated human bronchial epithelial cells. Incubation of RA-treated but not the control cellular extracts with in vitro translated cyclin D1 led to cyclin degradation. This degradation depended on the PEST domain of cyclin D1, implicating ubiquitination in this retinoid degradation. Retinoid receptor selective agonists demonstrated that retinoic acid receptor (RAR)beta and retinoid X receptor (RXR) but not RARalpha- or RARgamma-dependent pathways signaled this cyclin degradation. Findings were extended to the NT2/D1 human embryonal carcinoma differentiation model where a similar pathway was activated by RA-treatment. To determine whether G1 cyclins were involved directly in bronchial preneoplasia, immunohistochemical expression profiles for cyclins D1 and E were examined. Aberrant expression of these cyclins was frequent in bronchial preneoplasia. Taken together, these findings indicate that ubiquitin-dependent proteolysis of G1 cyclins is a retinoid chemoprevention mechanism. Whether the retinoids represent the optimal agents to activate this pathway is the subject of ongoing work. These findings provide a rationale for combining the retinoids in chemoprevention trials with other agents that do not activate this proteolysis pathway. What is now known about the retinoids as cancer prevention agents will be reviewed. Emphasis is placed on retinoid effects on cell cycle progression at G1.

Topics: Animals; Anticarcinogenic Agents; Bronchi; Bronchial Diseases; Carcinoma, Embryonal; Cell Differentiation; Cell Transformation, Neoplastic; Cyclins; Cysteine Endopeptidases; Endopeptidases; Epithelial Cells; G1 Phase; Gene Expression Profiling; Gene Expression Regulation; Humans; Metaplasia; Mice; Models, Biological; Multienzyme Complexes; Neoplasms; Precancerous Conditions; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Protein Structure, Tertiary; Receptors, Retinoic Acid; Retinoids; Tretinoin; Tumor Cells, Cultured; Ubiquitin; Vitamin A Deficiency

In vertebrates, the glucuronidation of small lipophilic agents is catalyzed by the endoplasmic reticulum UDP-glucuronosyltransferases (UGTs). This metabolic pathway leads to the formation of water-soluble metabolites originating from normal dietary processes, cellular catabolism, or exposure to drugs and xenobiotics. This classic detoxification process, which led to the discovery nearly 50 years ago of the cosubstrate UDP-glucuronic acid (19), is now known to be carried out by 15 human UGTs. Characterization of the individual gene products using cDNA expression experiments has led to the identification of over 350 individual compounds that serve as substrates for this superfamily of proteins. This data, coupled with the introduction of sophisticated RNA detection techniques designed to elucidate patterns of gene expression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism. In addition, characterization of the UGT1A locus and genetic studies directed at understanding the role of bilirubin glucuronidation and the biochemical basis of the clinical symptoms found in unconjugated hyperbilirubinemia have uncovered the structural gene polymorphisms associated with Crigler-Najjar's and Gilbert's syndrome. The role of the UGTs in metabolism and different disease states in humans is the topic of this review.

Topics: Autoimmunity; Chromosome Mapping; Glucuronides; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Neoplasms; Steroids; Terminology as Topic

Midkine is a heparin-binding growth factor, implicated in various biological phenomena such as neuronal survival and differentiation, tissue remodeling and carcinogenesis. Together with pleiotrophin, midkine constitutes a family that is distinct from other heparin-binding growth factors. In this review, I will briefly describe biochemical and biological characteristics of midkine and then focus on its biological significance in cancer. The most intriguing feature of midkine in cancer is its augmented expression in advanced tumors at very high frequency in non-tissue specific manner. In addition, its high expression is also detected in precancerous lesions. Midkine exerts carcinogenesis-related activities, including transforming, anti-apoptotic, angiogenic and fibrinolytic ones. These data provide a possibility of clinical application of midkine. Serum midkine level can be a useful tumor marker. Gene therapy using its promoter region and therapeutic strategy choosing midkine as a molecular target are worth challenging.

Topics: Amino Acid Sequence; Animals; Biomarkers, Tumor; Carrier Proteins; Cytokines; DNA-Binding Proteins; Genetic Therapy; Heparin; Humans; Midkine; Molecular Sequence Data; Neoplasms; Nerve Growth Factors; Precancerous Conditions; Promoter Regions, Genetic; Transcription Factors; Tretinoin; WT1 Proteins

Proteasomes are the main non lysosomal proteolytic structures of the cells. They correspond to the major system eliminating abnormal proteins, short half-life proteins and proteins controlling the cell cycle. They are essential for the production of peptides subsequently presented by the MHC-I. They are formed by a proteolytic core (the 20S proteasome) made of 4 rings of 7 proteic subunits associated with regulatory complexes (namely the 19S complex forming the 26S proteasome). Using classical cell biology techniques (cytometry, immunofluorescence microscopy, Western blot) our group has particularly studied the proteasome expression of leukaemic cell lines (U937 and CCRF-CEM) during in vitro differentiation induced by PMA and Vitamin D plus retinoïc acid. During differentiation, the level of proteasome expression and its localization vary. The various monoclonal antibodies used provided different patterns according to the different subunits. There was a general trend to a disappearance of nuclear proteasome and to a decrease in their cytoplasmic expression. In contrast, proteosomal antigens were increased on the cell membrane and in culture supernatants. We derived an ELISA test to measure plasma proteasome concentrations. Preliminary results showed differences between patients with haemopoietic malignancies or solid tumors and normal donors. Proteasome levels varied under treatment. They were correlated with LDH levels. Taken together, these results argue in favor of a role for cellular proteasomes in malignant differentiation process, and emphasize the qualitative changes in proteasome expression. Plasma proteasomes do not only reflect tumor cell mass and could play a role in addition to their proteolytic activity. They seem to be a relevant tool for diagnosis, prognosis and therapeutic monitoring.

Topics: Biomarkers, Tumor; Cell Differentiation; Cell Membrane; Cell Nucleus; Cell Transformation, Neoplastic; Cysteine Endopeptidases; Cytoplasm; Enzyme-Linked Immunosorbent Assay; Hematologic Neoplasms; Humans; L-Lactate Dehydrogenase; Leukemia-Lymphoma, Adult T-Cell; Multienzyme Complexes; Neoplasm Proteins; Neoplasms; Proteasome Endopeptidase Complex; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured; U937 Cells; Vitamin D

Topics: Animals; Gene Expression Regulation; Humans; Neoplasms; Polymorphism, Genetic; Receptors, Retinoic Acid; Signal Transduction; Transcription, Genetic; Transcriptional Activation; Tretinoin

Protein kinase C (PKC) isoforms are serine/threonine kinases involved in signal transduction pathways that govern a wide range of physiological processes including differentiation, proliferation, gene expression, brain function, membrane transport and the organization of cytoskeletal and extracellular matrix proteins. PKC isoforms are often overexpressed in disease states such as cancer. In this review, PKC in a variety of cancers is discussed along with some specific cell biological mechanisms by which PKC exerts its function(s). The PKC family consists of several isoforms comprising three groups: classical, novel and atypical. Although PKC has been investigated for around 2 decades, only recently has the specific function of each isoform started to be elucidated and the isoforms evaluated for use as targets of drug action. Phorbol esters such as the tumor-promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) or diacylglycerol (DAG) activate classical and novel PKC isoforms. Naturally occurring retinoids, antisense oligonucleotides against specific PKC isoforms and specific PKC inhibitors can block this activation. Beta carotene and retinoid derivatives act as anticarcinogenic agents and can antagonize some of the biological actions of phorbol esters and oxidants. Another important area of investigation is the use of antisense oligonucleotides to inhibit specific PKC isoforms. These compounds have proven effective in reducing specific types of cancer in rodents and humans and are currently used in clinical trials. This review examines PKC isoforms as a target of drug action with special emphasis on their use in cancer therapy.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Drug Delivery Systems; Enzyme Inhibitors; Gastrointestinal Neoplasms; Humans; Isoenzymes; Lung Neoplasms; Neoplasm Proteins; Neoplasms; Oligonucleotides, Antisense; Protein Kinase C; Retinoids; Staurosporine; Tretinoin

The past several years have seen demonstrable progress in the therapy of Kaposi's sarcoma (KS). Liposomal anthracyclines and paclitaxel have been found to be highly effective chemotherapeutic agents for this disease. Recent advances in our understanding of the pathogenesis of KS have led to the consideration of various new experimental agents. Two antiangiogenesis agents, TNP-470 and thalidomide, have been determined to induce some responses in KS, and others are now in early clinical trials or in preclinical development. Oral 9-cis retinoic acid has been shown to have anti-KS activity, and preliminary studies suggest that a urinary protein found in preparations of human chorionic gonadotropin also has activity. Effective anti-HIV treatment has been shown to affect the growth of KS, and the discovery of a new herpesvirus as a causative agent for KS has offered new potential targets for attack.

Topics: Administration, Oral; Alitretinoin; Anthracyclines; Antineoplastic Agents; Cyclohexanes; Humans; Immunosuppressive Agents; Liposomes; Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Paclitaxel; Sarcoma, Kaposi; Sesquiterpenes; Thalidomide; Tretinoin

Retinoids mediate a number of physiological pathways through their effects on cellular growth and differentiation. Upon binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), retinoids regulate cellular processes by directly modulating the expression of responsive genes. The wide-ranging effects of retinoid action are attributable to two main factors-the ubiquitous distribution of several subtypes and isoforms of RARs and RXRs, and the ability of these receptors to regulate numerous genes upon ligand activation. The broad range of effects mediated by retinoids means not only that they have many potential therapeutic applications but also that non-selective retinoids are associated with a high incidence of adverse effects. The design of retinoids that are receptor-selective and function-selective is a strategy that is proving successful in developing novel retinoids that offer not only good efficacy but also good tolerability. Tazarotene, a receptor-selective retinoid indicated for the topical treatment of psoriasis, is at the forefront of this new generation of retinoids. In the near future, other receptor-selective retinoids may prove useful for the treatment of other dermatological diseases, cancer, and diabetes.

Topics: Antineoplastic Agents; Diabetes Mellitus; Humans; Keratolytic Agents; Neoplasms; Psoriasis; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors; Tretinoin

Topics: Acetylation; Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Child; China; Chromatin; Drug Evaluation; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gastrointestinal Diseases; Histone Deacetylase Inhibitors; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Melarsoprol; Neoplasm Proteins; Neoplasms; Nervous System Diseases; Oxides; Phenylbutyrates; Protein Processing, Post-Translational; Salvage Therapy; Tretinoin

The concept that cancer can be prevented, or its onset postponed, by certain diet-derived substances is currently eliciting considerable interest. Agents which interfere with tumour development at the stage of promotion and progression in particular are of potential clinical value. As chemopreventive agents have to be administered over a long period of time in order to establish whether they possess efficacy in humans, it is of paramount importance to establish their lack of toxicity. The desire to select the best chemopreventive drug candidates for clinical trial, and the necessity to monitor efficacy in the short and intermediate term, render the identification of specific mechanism-based in vivo markers of biological activity a high priority. Antioxidation, inhibition of arachidonic acid metabolism, modulation of cellular signal transduction pathways, inhibition of hormone and growth factor activity and inhibition of oncogene activity are discussed as mechanisms by which the soya constituent genistein, the curry ingredient curcumin and the vitamin A analogue 13-cis retinoic acid exert tumour suppression. A better understanding of these mechanisms will help the establishment of screens for the discovery of new and better chemopreventive agents and the identification of surrogate markers to assess the outcome of clinical chemoprevention trials.

Topics: Anticarcinogenic Agents; Antioxidants; Chemoprevention; Clinical Trials as Topic; Curcumin; Diet; Genistein; Humans; Neoplasms; Tretinoin

Although significant advances have been made in the treatment of some malignancies, the prognosis of patients with metastatic tumors remains poor. Differentiating agents redirect cells toward their normal phenotype and therefore may reverse or suppress evolving malignant lesions or prevent cancer invasion. In addition, they offer a potential alternative to the classic cytostatic drugs.. The purpose of this review was to examine the current and potential future roles of differentiating agents in the treatment of cancer.. Initial studies with differentiating agents focused on retinoid therapy. Although retinoids have shown some clinical success, their widespread use has been limited by resistance and, in the chemopreventive setting, toxicity. This has led to the synthesis of a number of new retinoids that currently are undergoing clinical investigation. A further approach to overcoming the drawbacks associated with exogenous retinoids has been to increase the levels of endogenous retinoic acid (RA) by inhibiting the cytochrome P450-mediated catabolism of RA using a novel class of agents known as retinoic acid metabolism blocking agents (RAMBAs). Liarozole, the first RAMBA to undergo clinical investigation, preferentially increases intratumor levels of endogenous RA resulting in antitumor activity.. Although studies using exogenous retinoids in this setting have not yet fulfilled their initial promise, studies with a growing set of synthetic retinoids are ongoing. Furthermore, modulation of endogenous retinoids may offer a significant new potential treatment for cancer.

Topics: Antineoplastic Agents; Cell Differentiation; Chemoprevention; Cytochrome P-450 Enzyme Inhibitors; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Imidazoles; Neoplasms; Phenotype; Receptors, Retinoic Acid; Retinoids; Tretinoin

Vitamin A derived retinoids, including all-trans retinoic acid (RA), play an important role in regulating cellular growth and differentiation. Biological activities of retinoids are mediated through interactions with two classes of nuclear receptors, RA receptors (RARs) and retinoid X receptors (RXRs). In addition, cellular retinoid-binding proteins (CRBPs and CRABPs) and RA-metabolizing enzymes may explain the pleiotropic effects of retinoids. Recently, a novel cytochrome P450 enzyme (CYP26) with specific RA 4-hydroxylase activity, which is rapidly induced by RA, has been cloned from man, mouse and zebra fish, fullfilling all requirements of an enzyme which could be of crucial importance in controlling steady-state levels of active retinoids in cells and target tissues, thus protecting against excessive exposure. Besides the putative role of this newly identified CYP26 in contributing to susceptibility of cancer cells to retinoids, the possible function of this gene in early embryonic development is discussed.

Topics: Animals; Cytochrome P-450 Enzyme System; Embryonic and Fetal Development; Humans; Neoplasms; Receptors, Retinoic Acid; Retinoic Acid 4-Hydroxylase; Tretinoin

Vitamin A and its derivatives (collectively referred to as retinoids) are required for many fundamental life processes, including vision, reproduction, metabolism, cellular differentiation, hematopoesis, bone development, and pattern formation during embryogenesis. There is also considerable evidence to suggest that natural and synthetic retinoids have therapeutical effects due to their antiproliferative and apoptosis-inducing effects in human diseases such as cancer. Therefore it is not surprising that a significant amount of research was dedicated to probe the molecular and cellular mechanisms of retinoid action during the past decade. One of the cellular mechanisms retinoids have been implicated in is the initiation and modulation of apoptosis in normal development and disease. This review provides a brief overview of the molecular basis of retinoid signaling, and focuses on the retinoid-regulation of apoptotic cell death and gene expression during normal development and in pathological conditions in vivo and in various tumor cell lines in vitro.

Topics: Apoptosis; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Receptors, Retinoic Acid; Tretinoin

Topics: Carcinoma, Non-Small-Cell Lung; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mutation; Neoplasms; Receptors, Retinoic Acid; RNA, Messenger; RNA, Neoplasm; Tretinoin

Retinoic acids (RAs) exert a broad range of physiologic actions during embryonic development and adult life. Two families of RA receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR), have been identified. The therapeutic effect of all-trans-RA (ATRA) in induction of remission for acute promyelocytic leukemia (APL) has largely been proved, and this has, over the past 10 years, greatly stimulated research on oncogenesis and RA-regulated differentiation pathways. In APL, one of the RAR genes, RARA, is fused to PML in the great majority of patients as a result of the chromosomal translocation t(15; 17). However, a small subset of APL patients have a different fusion gene, PLZF-RARA, resulting from the variant translocation t(11;17). A third translocation, t(5;17), in which the NPM gene is fused to RARA, has been described. Current data suggest that PML-RAR alpha and PLZF-RAR alpha fusion receptors may play an important role in the development of APL and that PML-RAR alpha could be the target of ATRA differentiation therapy. Characterization of the genes regulated by retinoic acid may open up new prospects for an understanding of the mechanisms of ATRA differentiation therapy for APL and may help to extend the concept of cancer-targeting treatment to other types of leukemias or solid tumors.

Topics: Adult; Antineoplastic Agents; Base Sequence; Chimera; Chromosome Mapping; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cloning, Molecular; Consensus Sequence; Embryonic and Fetal Development; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplasms; Nuclear Proteins; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

9-cis retinoic acid (9-cis RA) is a retinoid receptor pan-agonist that binds with high affinity to both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Using a variety of in vivo and in vitro cancer models, we present experimental data that 9-cis RA has activity as a potential chemotherapeutic agent. Treatment of the human promyelocytic leukemia cell line HL-60 with 9-cis RA decreases cell proliferation, increases cell differentiation, and increases apoptosis. Induction of apoptosis correlates with an increase in tissue transglutaminase (type II) activity. In vivo, 9-cis RA induces complete tumor regression of an early passage human lip squamous cell carcinoma xenograft. Finally, 9-cis RA inhibits the anchorage-independent growth of the human breast cancer cell lines MCF-7 and LY2 (an antiestrogen-resistant MCF-7 variant). Transient co-transfection assays indicate that 9-cis RA inhibits estrogen receptor transcription of an ERE-tk-LUC reporter through RAR or RXR receptors. These data suggest that retinoid receptors can antagonize estrogen-dependent transcription and provides one possible mechanism for the inhibition of cell growth by 9-cis RA in breast cancer cell lines. In summary, these findings present evidence that 9-cis RA has a wide range of activities in human cancer models.

Topics: Animals; Apoptosis; Breast Neoplasms; Carcinoma, Squamous Cell; Cell Division; HL-60 Cells; Humans; Neoplasms; Tretinoin

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Design; Humans; Interferon-alpha; Medical Oncology; Neoplasms; Tretinoin

Topics: Cell Differentiation; Cell Division; Cytokines; Gene Expression Regulation, Neoplastic; Genes, fos; Genes, jun; Humans; Ligands; Neoplasms; Nuclear Proteins; Phosphorylation; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured

Acute promyelocytic leukemia (APL) is the first example among the human malignancies that responds to differentiation therapy, in that complete remission (CR) can be achieved in up to 90% of patients by using a differentiation inducer, all-trans retinoic acid (ATRA). The specific chromosomal translocation t(15;17) in APL has been shown to fuse the gene for the retinoic acid receptor alpha (RAR alpha) with a chromosome 15q locus, PML. Alterations to the RAR alpha and the PML gene structures in the t(15;17) have been characterized and used as specific molecular marker for diagnosis of the disease. PML/RAR alpha antagonizes wild-type PML and RXR and could block the differentiation pathways mediated by these two regulators. A variant translocation t(11;17) has also been discovered in a subset of APL which fuses RAR alpha to a new gene, PLZF on chromosome 11q23. Both PML/RAR alpha and PLZF/RAR alpha display the "dominant negative" effect on the wild-type RAR/RXR. However, t(11;17) APL patients differ from t(15;17) APL in that they respond poorly to ATRA. Morphologically defined APL cases which however do not have PML/RAR alpha generally show no response to ATRA. Recently it has been shown that PML/RAR alpha can be modulated directly by ATRA. All these data support the idea that PML/RAR alpha is a specific target of ATRA which can overcome the differentiation block imposed by PML/RAR alpha. The ATRA treatment of APL thus further reinforces the concept of differentiation therapy.

Topics: Gene Targeting; Humans; Leukemia, Promyelocytic, Acute; Models, Genetic; Neoplasms; Receptors, Retinoic Acid; Translocation, Genetic; Tretinoin

Preclinical data indicate that the combination of retinoids and interferons have synergistic antiproliferative and differentiating effects in some hematologic and solid tumor models. These observations have led to clinical trials in which 13-cis-retinoic acid (13cRA) 1 mg/kg/day was combined with interferon alpha-2a (IFN alpha) 3 or 6 x 10(6) U/day. The first two such trials produced exciting results: 50% response rate in patients with previously untreated stages IB-IVA cervix cancer and 68% in patients with advanced squamous cell skin cancer. These data led to a number of additional trials of the combination, but the high response rates seen in the initial cervix and skin trials have not been duplicated in the other squamous tumors tested (head and neck, lung, pretreated cervix). In addition, trials in two nonsquamous histologies were negative (lung and melanoma). However, the regimen was not always studied in an optimal population of previously untreated patients and the negative results in pretreated cervix patients point to the relevance of this consideration. Nevertheless, the observation that the combination of 13cRA and IFN alpha (both of which bind to specific receptors and change gene expression) is able to induce regression in advanced tumors, must be regarded as highly important. Key questions to be addressed include an understanding of the biologic mechanism of specific tumor sensitivity (why some squamous tumors and not others?), and mechanisms of resistance in sensitive tumor types (e.g. cervix). Such data may lead to trials targeted to tumor types with defined biologic features having a high liklihood of clinical benefit. In the meantime, studies integrating this combination with other active treatment modalities such as radiation is warranted in cervix and skin carcinomas.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Clinical Trials as Topic; Female; Humans; Interferon alpha-2; Interferon-alpha; Neoplasms; Recombinant Proteins; Tretinoin

This review will summarize the rationale for pursuing investigations into the use of retinoids for pediatric patients with cancer, describe the phase I results of all-trans-retinoic acid (ATRA) in children, and discuss the results of a series of preclinical and clinical pharmacokinetic studies of ATRA. The prognosis for children with advanced stage neuroblastoma, the most common extracranial solid tumor of childhood, has remained poor despite significant increases in the intensity of multi-modality therapy. Observations that neuroblastoma has the potential in vivo to differentiate into the more mature neuronal phenotype of a ganglioneuroma or to spontaneously regress, combined with the ability of ATRA to induce differentiation of neuroblastoma cell lines in vitro, suggests that neuroblastoma may be a prime candidate for a retinoid-based approach to differentiation therapy. We previously performed a standard pediatric phase I trial of ATRA and defined the maximum tolerated dose (MTD) in children to be 60 mg/m2/day, significantly lower than the MTD in adult patients. Pharmacokinetic results revealed that the plasma half-life of ATRA was short (45 min) relative to 13-cis-RA (12-24 h), and that plasma drug exposure decreased significantly by day 28 of daily drug administration. Preclinical studies using an i.v. formulation of ATRA in a Rhesus monkey pharmacokinetic model then demonstrated that ATRA is eliminated by a capacity-limited (saturable) process. This elimination process was rapidly induced within the first week of daily i.v. ATRA administration, and suggested that an intermittent schedule of drug administration might allow for down-regulation of the elimination process. These pre-clinical studies formed the basis for investigating whether an intermittent schedule of ATRA administration would allow for repeated periods of relatively higher plasma drug concentrations. Preliminary results of two clinical trials using intermittent schedules of administration suggest that this approach may result in significantly higher plasma drug exposure over time. Plans to study the role of intermittent schedules of ATRA administration in pediatric phase II trials in patients with neuroblastoma are underway.

Topics: Adolescent; Child; Humans; Metabolic Clearance Rate; Neoplasms; Tretinoin

The antitumor effect of different retinoids focused attention in the treatment of malignant disorders on different pathways. The therapeutic effect was proved in acute promyelocytic leukaemia, but was limited in juvenile form of chronic myeloid leukaemia and in acute myelomonocytic and monoblastic leukaemia. Combined with different leukostatics, long remission could be achieved. The most important therapeutic pathway is direct growth inhibition with and without cell differentiation. Clinically, retinoids are effective in tumours, like: cutan T-cell lymphoma, mycosis fungoides, Sézary syndrome, oral leukoplakia (prevention of head and neck cancer metastases), variant form of small lung cell carcinoma, oestrogen dependent breast-carcinoma and cervix-carcinoma. The most serious complication of the retinoids' administration is the retinoic acid syndrome which is followed sometimes with thromboembolic events. Retinoids are teratogenic and hepatotoxic.

Topics: Blood Coagulation Disorders; Hematologic Diseases; Hematopoietic System; Humans; Leukemia; Neoplasms; Retinoids; Thromboembolism; Tretinoin

Topics: Animals; Humans; Isotretinoin; Neoplasms; Neoplasms, Experimental; Receptors, Retinoic Acid; Retinoids; Tretinoin; Vitamin A

Differentiation therapy focuses on the development and use of specific agents designed to selectively engage the process of terminal differentiation, leading to the eventual elimination of tumorigenic cells and rebalance of normal cellular homeostasis. Extensive in vitro study of the molecular mechanism involved during drug-induced maturation has allowed the realization and application of a differentiation-based therapy to the clinic. Rationalization of this mode of therapy has included the combined use of differentiation agents with low-dose chemotherapy to lessen adverse cytotoxicity and to enhance the efficacy of differentiation agents, allowing some success in their application to conditions resistant to conventional therapy. This review discusses some biological principles that underlie the concept of a differentiation therapy and compares the in vitro and in vivo effectiveness of the two differentiation agents, in particular retinoic acid (RA) and hexamethylene bisacetamide (HMBA). It also evaluates the prospects for differentiation therapy as an effective strategy in the treatment and management of malignancy.

Topics: Acetamides; Animals; Antineoplastic Agents; Cell Differentiation; Drug Therapy, Combination; Gene Expression; Humans; Neoplasms; Receptors, Retinoic Acid; Tretinoin

Topics: Carrier Proteins; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Myelodysplastic Syndromes; Neoplasms; Receptors, Retinoic Acid; Retinoids; Teratogens; Tretinoin

The ability of vitamin A and its derivatives to induce differentiation in certain target tissues has been appreciated for nearly a century. Recently, oral all-trans retinoic acid (ATRA), a vitamin A metabolite, has been shown to induce terminal differentiation of leukemic cells in patients with acute promyelocytic leukemia (APL). Complete remissions are obtained and normal hematopoiesis is established in an outpatient setting with minimal side effects in the majority of cases. Although remissions are not durable, disseminated intravascular coagulation, a frequent complication of remission induction in APL, is avoided by oral ATRA prior to definitive chemotherapy. The molecular basis for the efficacy of ATRA in APL appears to be the involvement of the retinoic acid receptor alpha locus in the t(15;17) translocation breakpoint characteristic of APL.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Base Sequence; Binding Sites; Carrier Proteins; Cell Differentiation; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; DNA; Humans; Leukemia, Promyelocytic, Acute; Molecular Sequence Data; Neoplasms; Receptors, Cell Surface; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Transcription Factors; Translocation, Genetic; Tretinoin

Although cisplatin is applied with success in clinical oncology, this success is limited because some cancers are initially unresponsive to cisplatin or become so during treatment. In this review, some strategies to overcome this problem are discussed. Among these are combination with the differentiation inducing agent, retinoic acid, combination with radiotherapy, and the use of hyperthermia.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Humans; Hyperthermia, Induced; Neoplasms; Radiotherapy; Tretinoin

Interest in retinoids as therapeutic agents has developed as a result of the observations of remission induction with all-trans retinoic acid (tRA) in patients with acute promyelocytic leukemia (APL), and of high objective response rates noted with the combination of cis-retinoic acid (cRA) with interferon-alpha in squamous cell carcinomas of skin and cervix. The therapeutic experience with RA in APL is discussed in this article from the perspectives of new information concerning retinoid biology, observations related to the development of the retinoid syndrome, complex pharmacology of this agent, and possible explanations for development of retinoid resistance. The current National Cancer Institute-supported drug development strategy for RA used alone or in combination with other differentiating agents, and the potential therapeutic uses in cancer for other retinoids are also discussed.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drugs, Investigational; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Retinoids; Tretinoin

All-trans and 13-cis-retinoic acids are normal constituents of human blood. Blood levels of both compounds increase upon oral ingestion of all-trans-retinyl palmitate, to a greater extent with higher amounts of ingested retinyl palmitate. These data suggest a mechanism whereby levels of dietary vitamin A could influence blood levels of the known cancer chemopreventive retinoic acids.

Topics: Diterpenes; Humans; Neoplasms; Retinyl Esters; Tretinoin; Vitamin A

Topics: Animals; Antineoplastic Agents; Dehydroepiandrosterone; Drug Evaluation; Eflornithine; Fenretinide; Humans; Molybdenum; Neoplasms; Piroxicam; Tretinoin

Topics: Animals; Carrier Proteins; Cell Differentiation; Cell Division; Gene Expression Regulation; Humans; Neoplasms; Receptors, Retinoic Acid; Tretinoin

Topics: Animals; Cell Differentiation; Cell Division; Humans; Neoplasms; Tretinoin

A concept of neoplasms, based upon developmental and oncological principles, states that carcinomas are caricatures of tissue renewal, in that they are composed of a mixture of malignant stem cells, which have a marked capacity for proliferation and a limited capacity for differentiation under normal homeostatic conditions, and of the differentiated, possibly benign, progeny of these malignant cells. The concept brings order to the facts about carcinoma, has predictive value for embryogenesis, and indicates possibilities for differentiation therapy. One such possibility assumes on the basis of experimentation in vitro that malignant stem cells can be induced to differentiate into postmitotic cells by application of chemicals. Another suggests study of naturally occurring substances which regulate cell proliferation and differentiation in adult tissues. The other possibility, based upon experiments in vivo and in vitro, indicates that embryonic fields are capable of converting their closely corresponding malignant lineages into apparently normal lineages responsive to homeostatic control. Induced differentiation of embryonal carcinoma has been achieved in vivo with improvement in longevity of the host and in some cases with apparent cure. However, ultimate success of treatment based upon turning malignant cells into benign cells will depend upon the nature of the benign cells. Will they remain benign?

Topics: Azacitidine; Cell Differentiation; Colony-Stimulating Factors; Embryonic Induction; Humans; Neoplasms; Peptides; Transforming Growth Factors; 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

As described in this review, both partially purified and recombinant interferons are potent modulators of differentiation in diverse cell culture systems (Table 2). Depending on the target cell, interferon exerts either an inhibitory or an inductive effect on cell differentiation. In certain myeloid leukemic cells, such as HL-60, interferon by itself is growth suppressive but does not induce cell maturation, whereas in combination with inducers of differentiation, such as DMSO, TPA or retinoic acid, interferon potentiates their ability to stimulate differentiation in both sensitive and resistant cell populations (Grant et al., 1982, 1983; Tomida et al., 1982). Interferon also interacts synergistically with phorbol ester tumor promoters in inhibiting melanogenesis in murine B-16 cells (Fisher et al., 1981a, 1984a) and adipocyte formation in 3T3 cells (Cioe et al., 1980), whereas the combination is synergistic in inducing differentiation in human melanoma cells (Fisher et al., 1984b,c). In contrast, interferon and TPA display antagonistic effects on differentiation in human skeletal muscle cultures, i.e. interferon induces and TPA inhibits myogenesis (Fisher et al., 1982, 1983). Recent studies have demonstrated the presence of high affinity saturable cell membrane receptors for mouse and human interferons (Aguet, 1980; Branca and Baglioni, 1981, 1982; Mogensen et al., 1981; Branca et al., 1982; Anderson et al., 1982; Joshi et al., 1982; Faltynek et al., 1983; Yonehara et al., 1983; Langer and Pestka, in preparation). Similarly, specific membrane receptors have been identified for phorbol esters and mezerein (Driedger and Blumberg, 1980; Shoyab and Todaro, 1980; Horowitz et al., 1981; Fisher et al., 1981b). These findings suggest that the plasma membrane may be a primary target for mediating the biochemical effects induced by both interferon and phorbol esters. Although the mechanism by which interferon and phorbol esters transmit the necessary membrane signal(s) required for altering differentiation are not known, a possible component of this transmembrane signaling process may involve changes in the physical dynamics of the plasma membrane. It is therefore of interest that both interferon and TPA induce early changes in the fluidity of the plasma membrane (Fisher et al., 1979, 1981b, 1984d; Castagna et al., 1979; Kuhry et al., 1983).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adipose Tissue; Animals; Cell Differentiation; Cells, Cultured; Dimethyl Sulfoxide; Hematopoiesis; Humans; Interferons; Leukemia; Leukemia, Erythroblastic, Acute; Melanins; Melanoma; Mice; Muscles; Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin

Retinoids, particularly 13-cis-retinoic acid, have shown great promise against a number of benign, but serious dermatological conditions. In animal models, 13-cis-retinoic acid functions is a potent antipromoter whether a cancer has been initiated by chemical, physical, or viral agents. Additionally, substantial antiproliferative activity of this compound has been demonstrated in vitro in many culture systems. Clinical activity noted against several types of skin malignancies has led to several investigations to determine the anticancer activity of 13-cis-retinoic acid. Response of a variety of preneoplastic and neoplastic lesions of epithelial histology has been demonstrated. The toxicity of 13-cis-retinoic acid largely reflects its tissue distribution with skin and subcutaneous side-effects limiting dose escalation. The pharmacology and pharmacokinetics of 13-cis-retinoic acid has been explored in a number of patients and a long terminal half-life demonstrated. This review will discuss 13-cis-retinoic acid as a good model for a biological response modifier.

Topics: Animals; Humans; Isomerism; Isotretinoin; Kinetics; Metabolic Clearance Rate; Mice; Neoplasms; Retinoids; Retinol-Binding Proteins; Tretinoin

Topics: Animals; Cell Differentiation; Humans; Liver; Male; Neoplasms; Nutritional Requirements; Retinoids; Retinol-Binding Proteins; Skin Diseases; Tretinoin; Vitamin A; Vitamin A Deficiency

Topics: Animals; Cell Differentiation; Chemical Phenomena; Chemistry; Growth; Humans; Kinetics; Neoplasms; Skin Diseases; Tretinoin

Vitamin A, an unsaturated 20 carbon cyclic alcohol, subserves a number of important physiological functions. However, the biochemical basis of these roles is not well understood. The main sources of retinol are liver, egg yolk and milk fat. Several carotenoids show vitamin A activity. The conversion of beta-carotene to retinol is affected by copper-containing dioxygenase and zinc-containing retinene reductase. The efficiency of conversion varies in different species. The latter is defined in units as the daily dose required to produce a weight gain of 3 g/week in young rats between the 4th and 8th week. Retinol is unstable on exposure to light or heat, particularly in the presence of heavy metal ions and water. Much recent work has focused on the absorption, metabolism and excretion of vitamin A. It is now recognized that plasma vitamin A levels do not reflect the nutritional status except in severe hypo- and hypervitaminosis A. Also, many dietary factors may influence vitamin A metabolism. These basic and applied aspects of vitamin A are reviewed.

Topics: Absorption; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Artiodactyla; beta Carotene; Biological Availability; Biological Transport; Bone Development; Carotenoids; Chemical Phenomena; Chemistry; Drug Stability; Epithelium; Female; Fish Oils; Growth; Humans; Infections; Intestinal Absorption; Intracranial Pressure; Liver; Male; Neoplasms; Nutritional Requirements; Oxidation-Reduction; Reproduction; Silage; Structure-Activity Relationship; Tretinoin; Vision, Ocular; Vitamin A

Topics: Animals; Antineoplastic Agents; beta Carotene; Butylhydroxybutylnitrosamine; Carcinoma in Situ; Carcinoma, Papillary; Carotenoids; Cell Differentiation; Dose-Response Relationship, Drug; Epithelium; Fenretinide; Humans; Isotretinoin; Neoplasms; Neoplasms, Experimental; Tretinoin; Urinary Bladder Neoplasms; Vitamin A

Topics: Animals; Carrier Proteins; Cell Differentiation; Chemical Phenomena; Chemistry; Epithelium; Female; Growth; Humans; Isomerism; Male; Neoplasms; Pregnancy; Receptors, Retinoic Acid; Reproduction; Retinal Pigments; Retinaldehyde; Retinol-Binding Proteins; Skin Diseases; Structure-Activity Relationship; Tretinoin; Vitamin A; Vitamin A Deficiency

Topics: Adjuvants, Immunologic; Animals; Breast Neoplasms; Carcinogens; Cricetinae; Diterpenes; Female; Humans; Keratoacanthoma; Lung Neoplasms; Male; Mice; Neoplasms; Prostatic Neoplasms; Rats; Retinoids; Retinyl Esters; Tretinoin; Vitamin A

Topics: Animals; Antineoplastic Agents; Cell Division; Chemical Phenomena; Chemistry; Humans; Neoplasms; Ornithine Decarboxylase Inhibitors; Phenotype; Skin; Skin Diseases; Tretinoin; Vitamin A

Topics: Anthraquinones; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Cisplatin; Dose-Response Relationship, Drug; Female; Genetic Techniques; Hodgkin Disease; Hormones; Humans; Immunotherapy; Interferons; Male; Mechlorethamine; Methotrexate; Mitoxantrone; Neoplasm Metastasis; Neoplasms; Neoplasms, Germ Cell and Embryonal; Nitrosourea Compounds; Osteosarcoma; Prednisone; Procarbazine; Prognosis; Receptors, Cell Surface; Tretinoin; Vincristine

Topics: Acne Vulgaris; Administration, Oral; Adolescent; Dermatitis, Exfoliative; Half-Life; Humans; Ichthyosis; Isotretinoin; Neoplasms; Pityriasis Rubra Pilaris; Psoriasis; Tretinoin

The Vitamin A. derivatives known as Retinoids, are among the most exciting pharmacological agents used in the last few years. They strongly influence the keratinizing epithelia, have an antipromoting effect upon experimentally induced tumors and have immunomodulatory activities. Teratogenicity seems to be the most worrisome effect of the retinoids. However, it is reasonable to assume their release for physicians prescription in the near future. This review is intended to provide a general background for their correct use by dermatologists.

Topics: Animals; Carcinogens; Darier Disease; Humans; Ichthyosis; Mice; Neoplasms; Psoriasis; Rats; Skin Diseases; T-Lymphocytes; Tretinoin; Vitamin A; Vitamin A Deficiency

Topics: Animals; Antioxidants; Butylated Hydroxytoluene; Carcinogens; Disulfiram; Drug Therapy; Female; Humans; Inactivation, Metabolic; Male; Neoplasm Recurrence, Local; Neoplasms; Neoplasms, Experimental; Nutritional Requirements; Rats; Selenium; Tretinoin; Urinary Bladder Neoplasms; Vitamin A

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

The early and recent investigations in the field of retinoids and cancer are reviewed. The retinoids, including natural vitamin A compounds and their synthetic analogs, present a new class of substances exerting a prophylactic and a therapeutic effect both in certain experimental tumor models and in certain clinical conditions of preneoplastic and neoplastic lesions. Because of a particular physiological mechanism of action, the retinoids offer a new approach to the cancer problem, which is different from those of surgery, X-ray therapy, conventional chemotherapy, and immunotherapy.

Topics: Animals; Cell Division; Cell Transformation, Neoplastic; Clinical Trials as Topic; Humans; Neoplasms; Neoplasms, Experimental; Tretinoin; Vitamin A

Topics: Biological Evolution; Carcinogens; Chronic Disease; DNA Repair; Environmental Pollutants; Genetic Diseases, Inborn; Humans; Mutation; Neoplasms; Tretinoin; Xeroderma Pigmentosum

We evaluated MK-4621, an oligonucleotide that binds and activates retinoic acid-inducible gene I (RIG-I), as monotherapy (NCT03065023) and in combination with the anti-programmed death 1 antibody pembrolizumab (NCT03739138).. Patients were ≥ 18 years with histologically/cytologically confirmed advanced/metastatic solid tumors with injectable lesions. MK-4621 (0.2‒0.8 mg) was administered intratumorally as a stable formulation with jetPEI™ twice weekly over a 4-week cycle as monotherapy and weekly in 3-week cycles for up to 6 cycles in combination with 200 mg pembrolizumab every 3 weeks for up to 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), treatment-related adverse events (AEs), and treatment discontinuation due to AEs.. Fifteen patients received MK-4621 monotherapy and 30 received MK-4621 plus pembrolizumab. The only DLT, grade 3 pleural effusion that subsequently resolved, occurred in a patient who received MK-4621/jetPEI™ 0.8 mg plus pembrolizumab. 93% of patients experienced ≥ 1 treatment-related AE with both monotherapy and combination therapy. No patients experienced an objective response per RECIST v1.1 with MK-4621 monotherapy; 4 (27%) had stable disease. Three (10%) patients who received combination therapy had a partial response. Serum and tumor biomarker analyses provided evidence that MK-4621 treatment induced an increase in gene expression of interferon signaling pathway members and associated chemokines and cytokines.. Patients treated with MK-4621 monotherapy or in combination with pembrolizumab experienced tolerable safety and modest antitumor activity, and there was evidence that MK-4621 activated the RIG-I pathway. At the doses tested, MK-4621 did not confer meaningful clinical benefit.. ClinicalTrials.gov, NCT03065023 and NCT03739138.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cytokines; Humans; Interferons; Neoplasms; Oligonucleotides; 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; 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Retinoic acid derivatives have shown their greatest benefit in acute promyelocytic leukemia, but have also demonstrated pre-clinical anti-cancer effects in some solid tumors. Histone deacetylase inhibitors, by upregulating gene expression, are able to limit cancer cell proliferation and induce apoptosis. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid has been previously studied in hematologic malignancies. We conducted a phase I two-step dose escalation trial of the liposomal ATRA analog ATRA-IV and divalproex sodium (Depakote) in nine patients with advanced solid tumors refractory to prior therapy. Side effects attributed to therapy had a severity

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Enzyme Inhibitors; Histone Deacetylases; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Salvage Therapy; Survival Rate; Tissue Distribution; Treatment Outcome; Tretinoin; Valproic Acid

The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children.. Vorinostat was administered orally daily starting at 180 mg/m(2)/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC).. Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m(2)/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m(2)/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m(2)/d 4 times per week and 13cRA 80 mg/m(2)/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m(2)/d for the capsule (range, 1,415 to 9,291 ng/mL x hr) and oral suspension (range, 1,186 to 4,780 ng/mL x hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination.. In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m(2)/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.

Topics: Administration, Oral; Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Hydroxamic Acids; Hypokalemia; Male; Maximum Tolerated Dose; Neoplasms; Neutropenia; Thrombocytopenia; Tretinoin; Vorinostat

To outline an outpatient-based treatment for children with relapsed solid tumors, who already have been extensively pretreated, we defined a 4-drug protocol named COMBAT (combined oral maintenance biodifferentiating and antiangiogenic therapy). Using this protocol, we performed a pilot study to determine its feasibility in children with relapsed and/or high-risk pediatric solid tumors.. 22 children received the COMBAT protocol. Treatment consisted of daily celecoxib administration along with daily 13-cisretinoic acid (2 weeks on / 2 weeks off) and cycles of metronomic temozolomide (90 mg/m2 for 42 days) and low-dose etoposide (21 days). The treatment was scheduled for a period of 1 year.. 9 of the 14 patients assessable for response demonstrated evidence of treatment benefit manifested as prolonged disease stabilization or response. The protocol medication was well tolerated with very good compliance. Only minimal side effects where observed which responded to dose modification or local therapy.. The COMBAT regimen is well tolerated by patients with intensive prior therapy including myeloablative regimens. Favorable responses observed in this cohort of patients support the further exploration of this and/or similar strategies in the treatment of pediatric solid tumors.

Topics: Administration, Oral; Adolescent; Adult; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Celecoxib; Child; Child, Preschool; Dacarbazine; Drug Administration Schedule; Etoposide; Feasibility Studies; Female; Humans; Male; Neoplasm Recurrence, Local; Neoplasms; Pilot Projects; Pyrazoles; Sulfonamides; Temozolomide; Treatment Outcome; Tretinoin

To determine the maximum tolerated dose and describe the toxicities of 9-cis-retinoic acid (9cRA, ALRT1057) administered p.o. tid in pediatric patients with refractory cancer and to study the pharmacokinetics of 9cRA and determine whether systemic drug exposure changes with chronic dosing.. Children with refractory cancer (stratified by age, < or =12 and >12 years) were treated with p.o. 9cRA for 28 consecutive days. The starting dose was 50 mg/m(2)/day divided into 3 doses with planned escalations to 65, 85, and 110 mg/m(2)/day. Pharmacokinetic sampling was performed on days 1 and 29 of the first cycle.. Of the 37 patients entered, 18 patients < or =12 years of age and 11 patients >12 years of age were evaluable for toxicity. In patients >12 years of age, dose-limiting headache occurred in 2/2 patients at the 110 mg/m(2)/day dose level; 1/8 patients at 85 mg/m(2)/day developed dose-limiting pseudotumor cerebri. In patients < or =12 years of age, 3/5 patients at the starting dose level of 50 mg/m(2)/day developed dose-limiting pseudotumor cerebri; and 0/6 patients experienced dose-limiting toxicity at 35 mg/m(2)/day. Reversible non-dose-limiting hepatotoxicity was observed in 15 patients across all of the dose levels. There was considerable interpatient variability in 9cRA plasma concentrations. Peak plasma concentrations of 9cRA occurred at a median of 1.5 h after a p.o. dose, and the harmonic-mean terminal half-life was 43 min. By day 29 of 9cRA administration, the plasma 9cRA area under the curve declined by an average of 65% from day 1 values.. The dose-limiting toxicity of 9cRA in pediatric patients was neurotoxicity, primarily pseudotumor cerebri. Younger children tolerate significantly lower doses of 9cRA than older children. Similar to all-trans-retinoic acid, the pharmacokinetics of 9cRA demonstrated a wide degree of interpatient variability and decreased over time when administered on a daily basis. The recommended Phase II dose of 9cRA in patients < or =12 and >12 years of age is 35 and 85 mg/m(2)/day, respectively.

Topics: Adolescent; Adult; Age Factors; Alitretinoin; Antineoplastic Agents; Area Under Curve; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Headache; Humans; Liver; Male; Nausea; Neoplasms; Skin Diseases; Transaminases; Treatment Outcome; Tretinoin; Triglycerides; Vomiting

To determine whether the treatment known as Di Bella multitherapy exerts antitumour activity worthy of further controlled clinical evaluation.. 11 independent multicentre uncontrolled phase II trials relevant to 8 different types of cancer.. 26 Italian hospitals specialising in cancer treatment.. 386 patients with advanced cancer were enrolled in the trials between March and July 1998 and followed to 31 October 1998.. Melatonin, bromocriptine, either somatostatin or octreotide, and retinoid solution, the drugs that constitute Di Bella multitherapy, were given to patients daily. Cyclophosphamide and hydroxyurea were added in some trials.. Responses were assessed every 1, 2, or 3 months, depending on the specific trial, and toxicity was evaluated using criteria developed by the World Health Organisation.. No patient showed complete remission. Three patients showed partial remission: 1 of the 32 patients with non-Hodgkin's lymphoma; 1 of the 33 patients with breast cancer; and 1 of the 29 patients with pancreatic cancer. At the second examination, 12% (47) of the patients had stable disease; 52% (199) progressed; and 25% (97) died.. Di Bella multitherapy did not show sufficient efficacy in patients with advanced cancer to warrant further clinical testing.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bromocriptine; Complementary Therapies; Female; Humans; Male; Melatonin; Middle Aged; Neoplasms; Octreotide; Somatostatin; Survival Analysis; Treatment Outcome; Tretinoin

9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring hormones. The nuclear receptors that mediate the effects of retinoids are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of this study were to determine the safety, tolerability, pharmacokinetics, and metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. Headache was the most frequent adverse event and was dose limiting in 3 of 41 patients. Skin toxicity was the next most common toxicity and was seen in 11 of 41 patients; it was typically mild and limited to skin dryness and erythema. Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the plasma concentration-time curve and peak plasma concentration values were dose-proportional over all dose levels, whereas day 15 area under the plasma concentration-time curve and peak plasma concentration values were nonlinear above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist with a more favorable pharmacokinetic and toxicity profile than that observed with previously studied retinoids and merits further investigation.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Alitretinoin; Antineoplastic Agents; Capsules; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neoplasms; Tretinoin

A phase I trial of all-trans-retinoic acid (ATRA) was conducted to establish the maximum tolerable dose (MTD) of ATRA given once daily to patients with solid tumors. Cancer patients for whom no standard therapy was available were treated with ATRA once daily. Doses were escalated in cohorts of at least three patients. The pharmacokinetics of ATRA were assessed on day 1 for all patients and weekly for 31 patients who received doses of > or = 110 mg/m2 per day. Patients were followed for toxicity and response. Correlations of toxicity frequency and grade with pharmacokinetic parameters were sought. In addition, correlation of changes in ATRA pharmacokinetics with the concentration of ATRA metabolites in plasma were sought. A total of 49 patients received ATRA at doses ranging from 45 to 309 mg/m2 per day. Hypertriglyceridemia was dose-limiting at 269 mg/m2 per day. Other frequent toxicities included mucocutaneous dryness and headache. With chronic dosing, plasma ATRA concentrations fell in 59% of patients. Stable, low, or variable [ATRA] were seen in 16%, 6%, and 16% of patients respectively. Age, gender, smoking, or concurrent medication did not correlate with the pharmacokinetic pattern. Severe toxicities tended to occur with initial peak [ATRA] of > or = 0.5 microgram/ml (1.7 microM), and the toxicity frequency did not change if [ATRA] decreased with continued dosing. No consistent change in 4-oxo-ATRA or retinoid glucuronide concentrations was observed with decreases in plasma [ATRA]. The recommended once-daily ATRA dose is 215 mg/m2, although significant interpatient variability is observed in toxicity and plasma retinoid concentrations. Although not statistically significant, more frequent and severe toxicity tended to occur in patients with higher plasma peak ATRA concentrations. Other factors, such as responses at target tissues, may be at least as important as the plasma ATRA concentration in predicting toxicity and/or response.

Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Hypertriglyceridemia; Male; Middle Aged; Neoplasms; Tretinoin

To determine the maximum-tolerated dose (MTD) of all-trans-retinoic acid (ATRA) administered on an intermittent oral schedule with interferon-alpha2a (IFN-alpha2a) in children with refractory cancer, and whether the marked reduction in plasma ATRA concentrations observed with chronic daily oral dosing could be circumvented with an intermittent dosing schedule.. Thirty-three children with refractory cancer (stratified by age, < or = 12 and > 12 years) were treated with ATRA 3 consecutive days per week and IFN-alpha2a 3 x 10(6) U/m2 5 consecutive days per week, both repeated weekly. The starting dose of ATRA was 60 mg/m2/d divided into three doses, with planned escalations to 90 and 120 mg/m2/d. Because severe headaches have been noted to occur on the initial day of ATRA administration, only two of three doses of ATRA were administered on day 1 of each week.. Pseudotumor cerebri or dose-limiting headache was observed in two of five patients older than 12 years treated at the 120-mg/m2/d dose level and in one of six < or = 12 years at the 90-mg/m2/d level. Other non-dose-limiting toxicities of ATRA included reversible elevations in hepatic transaminases and triglycerides, dry skin, cheilitis, and nausea/vomiting. One child with recurrent neuroblastoma had an objective response of 6 months' duration, and one with recurrent Wilms' tumor had histologic maturation of multiple tumors. This intermittent schedule allowed for exposure to relatively high plasma concentrations of ATRA on a repetitive basis. Following 30-mg/m2 doses, the ATRA area under the concentration-time curve (AUC) decreased from 96 +/- 14 micromol/L/min on day 1 to 26 +/- 24 micromol/L/min by day 3 of drug administration, but on day 1 of the fourth consecutive week of therapy, the AUC averaged 110 +/- 16 micromol/L/min. The recommended pediatric phase II dose of ATRA administered on this schedule is 90 mg/m2/d.. An intermittent schedule of ATRA administration appears to circumvent the low plasma drug exposure that is a result of the sustained upregulation of metabolism when this drug is administered on a chronic daily schedule. Based on the results of this trial, a phase II trial of ATRA/IFN-alpha2a in neuroblastoma and Wilms' tumor using this schedule is in progress.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Child; Chromatography, High Pressure Liquid; Drug Administration Schedule; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Neoplasms; Recombinant Proteins; Tretinoin; Wilms Tumor

The Eastern Cooperative Oncology Group conducted a Phase I trial to determine the maximally tolerated doses of combination therapy with alpha interferon (IFN-alpha) and all-trans-retinoic acid (tRA). Fifty patients with incurable malignancies received IFN-alpha administered subcutaneously three times weekly, and tRA administered by mouth at bedtime. Doses were escalated between patient groups, starting at tRA dose level of 45 mg/m2 and 3 million units of IFN-alpha. Major, dose-limiting toxicities were attributable to either the tRA (rash, chelitis) or IFN (constitutional symptoms), and were observed only at tRA dose levels of 224 mg/m2 and 291 mg/m2, or 6 million units of IFN-alpha. The maximally tolerated dose level of 172.5 mg/m2 of tRA and 3 million units of IFN-alpha was well-tolerated, with no grade 3 or 4 toxicities attributable to therapy. One patient at the third dose level (75 mg/m2 of tRA and 3 million units of IFN-alpha) developed acute hepatic and renal failure and a metabolic encephalopathy of unclear etiology. We conclude that tRA and IFN-alpha may be safely administered together at the maximally tolerated dose of tRA as a single agent without unexpected side effects. The recommended doses of IFN-alpha and tRA for Phase II trials are 3 million units of IFN-alpha and 172.5 mg/m2 of tRA.

Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Interferon Type I; Male; Middle Aged; Neoplasms; Recombinant Proteins; Tretinoin

We administered liposome-encapsulated all-trans retinoic acid (L-ATRA) to 48 patients with refractory hematologic malignancies using an every-other-day schedule for 28 days and doses of 15 to 175 mg/m2. In 19 patients, pharmacology studies were conducted after the first (day 1) and seventh (day 15) doses. In contrast to the decline in tretinoin concentration seen within 3 to 4 days of administration of daily oral ATRA, there were no differences between the area under the curve (AUC) of tretinoin concentration versus time on day 1 and day 15 (P = .98, Wilcoxon signed-rank test). Peak day 1 concentrations after 15 mg/m2 were higher than those reported after 45 mg/m2 oral ATRA. Six patients with relapsed acute promyelocytic leukemia (APL) were treated. Three, each in first relapse and at least year from the last exposure to oral ATRA, achieved a complete response (CR). Disease recurred in two (one at 3 months despite maintenance L-ATRA and similarity in tretinoin AUC on days 1 and 85, and the other at 5 months, 2 months after discontinuation of L-ATRA) and the third was transplanted 1 month into CR. The three nonresponders were in at least a second relapse and failed to respond to oral ATRA before or immediately after receiving L-ATRA. Severe toxicity developed in three of eight patients treated at 175 mg/m2 (joint pains in two, skin in one). The maximum tolerated dose (MTD) was determined to be 140 mg/m2, at which dose grade 2 toxicity (primarily headache and skin) occurred in eight of eight patients, but grade 3 to 4 toxicity in none. Compared with oral ATRA, L-ATRA apparently results in greater exposure to tretinoin and for a longer time.

Topics: Drug Carriers; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Liposomes; Neoplasms; Recurrence; Tretinoin

Retinoids have been shown to be potent inhibitors of epithelial carcinogenesis. Recent evidence has demonstrated that retinoid actions are mediated through nuclear receptors, which are proteins encoded by the retinoic acid receptor and retinoid X receptor gene families. These receptors are activated by binding to specific retinoids; of the known naturally occurring retinoids, 9-cis retinoic acid is unique in its ability to bind to both receptor families. Because of its unique receptor-binding characteristics, 9-cis retinoic acid may have biological activity not possible with other retinoids. For this reason, we conducted a Phase I trial of 9-cis retinoic acid in adult patients with solid tumors. Twenty-two patients were treated twice daily with p.o. 9-cis retinoic acid at doses ranging from 20 mg/m2/day to 150 mg/m2/day. The patients had non-small cell lung cancer (n = 8), breast cancer (n = 5), colorectal cancer (n = 3), head and neck cancer (n = 2), nonmelanoma skin cancer (n = 2), or ovarian cancer (n = 2). The dose-limiting (WHO grade III) toxic effects, which occurred at the 150-mg/m2/day dose level, were headaches and diarrhea. Less severe (grades I and II) toxic effects included cheilitis, dry skin, conjunctivitis, fatigue, hypertriglyceridemia, alkaline phosphatase elevation, myalgia/arthralgia, and hypercalcemia. Of the 15 patients evaluable for tumor response, no objective responses were observed. Pharmacokinetic analysis revealed a reduction in peak 9-cis retinoic acid plasma levels with chronic administration. Based on this study, the recommended Phase II dose of 9-cis retinoic acid in adult patients with solid tumors is 100 mg/m2/day administered in a divided dose twice daily.

Topics: Adult; Aged; Aged, 80 and over; Alitretinoin; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Neoplasms; Tretinoin

The retinoid response is mediated by families of nuclear receptors, the retinoic acid receptors (RARs), and the retinoid X receptors. All-trans retinoic acid (RA) binds only RARs and induces its own metabolism. In contrast, 9-cis RA is a newly identified agonist for both RARs and retinoid X receptors. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of 9-cis RA in patients with advanced cancer. Thirty-four patients received once daily p.o. doses of 9-cis RA (administered as LGD1057) ranging from 5 to 230 mg/m2 for 4 weeks. Pharmacokinetic studies were performed on 28 patients at seven dose levels. 9-cis RA was generally well tolerated. Headache was the most common dose-limiting adverse effect. Other prominent reactions included facial flushing, myalgia, dyspnea, hypertriglyceridemia, and hypercalcemia. Relative to other retinoids, mucocutaneous reactions were mild. No major antitumor responses were observed. Pharmacokinetic analysis revealed that the day 1 area under the plasma concentration x time curves (AUCs) were proportional to the dose. Up through doses of 140 mg/m2, the day 1 AUCs were similar to those on days 15 and 29. At higher doses, however, AUCs tended to decline with repeat dosing. 9-cis RA is a novel compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor cell proliferation and differentiation. We recommend a dose of 140 mg/m2 for single-agent trials utilizing a once-daily schedule of administration.

Topics: Adult; Aged; Alitretinoin; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Neoplasms; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors; Tretinoin

All-trans retinoic acid (RA) induces accelerated plasma all-trans RA clearance, presumably via cytochrome P450 enzymes. This accelerated metabolism has been shown to be inhibited in the short term by the cytochrome P450 inhibitor ketoconazole. This study was conducted to evaluate the efficacy of ketoconazole in maintaining plasma all-trans RA levels over time.. Using a randomized crossover study design, we randomly assigned six patients to receive all-trans RA (45 mg/m2 orally twice per day for 14 days of a 21-day cycle) for cycle 1 and the same dose of all-trans RA plus ketoconazole (400 mg orally for one dose, then 200 mg orally three times per day for 14 days) for cycle 2, and seven patients to receive the same treatment in the reverse order. Plasma all-trans RA levels were measured during the initial 8-hour period after all-trans RA ingestion on days 1 and 15 of cycles 1 and 2.. There was a marked decrease in plasma all-trans RA levels after 14 days of treatment, as measured by the area under the concentration-time curve (AUC), regardless of whether ketoconazole was given (from a baseline value of 857 to 44 ng/mL/h; P = .025) or not (from 1,355 to 308 ng/mL/h; P = .123). This lack of effect on plasma all-trans RA levels was not due to inadequate plasma ketoconazole levels. Ketoconazole administration was associated with more toxicity. No objective tumor responses were observed.. Ketoconazole does not appear to maintain adequate plasma all-trans RA levels over time.

Topics: Adult; Aged; Female; Humans; Ketoconazole; Male; Middle Aged; Neoplasms; Tretinoin

The clinical pharmacology of all-trans retinoic acid (RA) has distinct differences from that of its widely studied stereoisomer 13-cis retinoic acid (cRA). RA is much more rapidly cleared from plasma following oral administration; their respective half-lives are < 1 h and 13 h. There is extensive accumulation of the 4-oxo-cRA in plasma following repeated doses of cRA, while 4-oxo-RA is only a minor metabolite in plasma following RA administration. The extent of isomerization in vivo differs for the two retinoids. In contrast to cRA, where up to a 1:3 ratio of RA to cRA is observed in patient plasma following drug administration, cRA concentrations in excess of 10 ng/ml are rarely observed in plasma of patients receiving exogenous RA. RA administration produces autoinduction of its own oxidative catabolism; this effect does not occur with cRA. These pharmacokinetic differences have been observed in leukemia and solid tumor patients. Detailed analysis of the results of the population studied suggest that both constitutive and RA-induced hypercatabolism of RA occurs. Both of these hypercatabolic states can be modulated by concurrent administration of ketoconazole, an inhibitor of cytochrome P-450 and lipoxygenase-mediated oxidations.

Topics: Antineoplastic Agents; Drug Administration Schedule; Half-Life; Humans; Ketoconazole; Neoplasms; Stereoisomerism; Tretinoin

This review will summarize the rationale for pursuing investigations into the use of retinoids for pediatric patients with cancer, describe the phase I results of all-trans-retinoic acid (ATRA) in children, and discuss the results of a series of preclinical and clinical pharmacokinetic studies of ATRA. The prognosis for children with advanced stage neuroblastoma, the most common extracranial solid tumor of childhood, has remained poor despite significant increases in the intensity of multi-modality therapy. Observations that neuroblastoma has the potential in vivo to differentiate into the more mature neuronal phenotype of a ganglioneuroma or to spontaneously regress, combined with the ability of ATRA to induce differentiation of neuroblastoma cell lines in vitro, suggests that neuroblastoma may be a prime candidate for a retinoid-based approach to differentiation therapy. We previously performed a standard pediatric phase I trial of ATRA and defined the maximum tolerated dose (MTD) in children to be 60 mg/m2/day, significantly lower than the MTD in adult patients. Pharmacokinetic results revealed that the plasma half-life of ATRA was short (45 min) relative to 13-cis-RA (12-24 h), and that plasma drug exposure decreased significantly by day 28 of daily drug administration. Preclinical studies using an i.v. formulation of ATRA in a Rhesus monkey pharmacokinetic model then demonstrated that ATRA is eliminated by a capacity-limited (saturable) process. This elimination process was rapidly induced within the first week of daily i.v. ATRA administration, and suggested that an intermittent schedule of drug administration might allow for down-regulation of the elimination process. These pre-clinical studies formed the basis for investigating whether an intermittent schedule of ATRA administration would allow for repeated periods of relatively higher plasma drug concentrations. Preliminary results of two clinical trials using intermittent schedules of administration suggest that this approach may result in significantly higher plasma drug exposure over time. Plans to study the role of intermittent schedules of ATRA administration in pediatric phase II trials in patients with neuroblastoma are underway.

Topics: Adolescent; Antineoplastic Agents; Child; Child, Preschool; Female; Humans; Male; Neoplasms; Neuroblastoma; Tretinoin; Up-Regulation

Continuous oral dosing with all-trans retinoic acid (RA) is associated with a progressive decrease in plasma drug concentrations that has been linked to relapse and retinoid resistance in patients with acute promyelocytic leukemia (APL). Since oxidation by cytochrome P-450 enzymes is critical in the catabolism of this drug, we evaluated whether pretreatment with an inhibitor of this system, liarozole, could attenuate this phenomenon. A total of 20 patients with solid tumors completed a 4-week course of all-trans RA therapy. On days 1, 2, 28, and 29, serial plasma samples were obtained from these patients after ingestion of a single oral dose (45 mg/m2) of all-trans RA. On days 2 and 29, liarozole was given 1 h prior to ingestion of all-trans RA at single doses ranging from 75 to 300 mg. The areas under the plasma RA concentration x time curves (AUCs) were then compared in the presence and absence of pretreatment. Following continuous oral treatment, the mean day-28 AUC of all-trans RA was significantly lower than the group mean level on day 1 (504 vs 132 ng h-1 ml-1; P = 0.05). This decline in plasma concentrations on day 28 was partially reversed by liarozole, which increased the mean plasma all-trans RA AUC on day 29 to 243 ng h-1 ml-1 (P = 0.004). The lowest dose of liarozole that reliably produced this effect was 300 mg. No enhanced toxicity was associated with liarozole administration. We conclude that liarozole at a dose of 300 mg effectively attenuates the induced decline in all-trans RA plasma concentrations that occurs with continuous treatment. This combination may be useful in attenuating or reversing retinoid resistance.

Topics: Antineoplastic Agents; Humans; Imidazoles; Neoplasms; Tretinoin

This review will summarize the rationale for pursuing investigations into the use of retinoids for pediatric patients with cancer, describe the phase I results of all-trans-retinoic acid (ATRA) in children, and discuss the results of a series of preclinical and clinical pharmacokinetic studies of ATRA. The prognosis for children with advanced stage neuroblastoma, the most common extracranial solid tumor of childhood, has remained poor despite significant increases in the intensity of multi-modality therapy. Observations that neuroblastoma has the potential in vivo to differentiate into the more mature neuronal phenotype of a ganglioneuroma or to spontaneously regress, combined with the ability of ATRA to induce differentiation of neuroblastoma cell lines in vitro, suggests that neuroblastoma may be a prime candidate for a retinoid-based approach to differentiation therapy. We previously performed a standard pediatric phase I trial of ATRA and defined the maximum tolerated dose (MTD) in children to be 60 mg/m2/day, significantly lower than the MTD in adult patients. Pharmacokinetic results revealed that the plasma half-life of ATRA was short (45 min) relative to 13-cis-RA (12-24 h), and that plasma drug exposure decreased significantly by day 28 of daily drug administration. Preclinical studies using an i.v. formulation of ATRA in a Rhesus monkey pharmacokinetic model then demonstrated that ATRA is eliminated by a capacity-limited (saturable) process. This elimination process was rapidly induced within the first week of daily i.v. ATRA administration, and suggested that an intermittent schedule of drug administration might allow for down-regulation of the elimination process. These pre-clinical studies formed the basis for investigating whether an intermittent schedule of ATRA administration would allow for repeated periods of relatively higher plasma drug concentrations. Preliminary results of two clinical trials using intermittent schedules of administration suggest that this approach may result in significantly higher plasma drug exposure over time. Plans to study the role of intermittent schedules of ATRA administration in pediatric phase II trials in patients with neuroblastoma are underway.

Topics: Adolescent; Child; Humans; Metabolic Clearance Rate; Neoplasms; Tretinoin

Topics: Administration, Oral; Adult; Aged; Colorectal Neoplasms; Dose-Response Relationship, Drug; Humans; Middle Aged; Neoplasms; Tretinoin

All-trans-retinoic acid (all-trans RA) induces complete remission in most patients with acute promyelocytic leukemia (APL). However, continuous oral dosing results in progressive decline in plasma drug concentrations, which is associated with relapse and resistance to this retinoid. We speculated that the decline in drug levels, indicating acquired resistance, resulted partly from inducible cytochrome-P450 oxidative enzymes, which can catabolize all-trans RA.. We studied the clinical pharmacology of all-trans RA in cancer patients to determine possible mechanisms of acquired resistance and evaluated the potential for reversal by ketoconazole, an inhibitor of cytochrome-P450 oxidative enzymes.. Serial plasma samples were obtained from 54 patients with APL or advanced lung cancer after a single oral dose of all-trans RA (45 mg/m2). In the 34 patients with advanced lung cancer, all-trans RA (45 mg/m2) was administered twice daily for 4 weeks, and, on days 2, 28, and 29, serial plasma samples were again obtained after a single 45-mg/m2 dose. One hour prior to drug administration on days 2 and 29, a single oral dose (200-1200 mg) of ketoconazole was administered. Endogenous plasma concentrations of all-trans RA and 13-cis-retinoic acid were measured in a subset of these patients and in 11 with early-stage lung cancer.. The mean area under the curve for plasma drug concentration times time (AUC) for all-trans RA on day 1 varied substantially among patients. Compared with patients with APL, the 28 patients with advanced lung cancer who completed therapy demonstrated significantly lower AUC levels on day 1 (P = .06); a subgroup with levels less than 300 ng/mL per hour on day 1 had lower endogenous plasma all-trans RA concentrations than patients with APL or early-stage lung cancer or 14 normal subjects. Following continuous oral treatment, the mean day 28 AUC for all-trans RA was significantly lower than that on day 1 (213 ng/mL per hour versus 467 ng/mL per hour; P < .01), a decline significantly attenuated by ketoconazole, which increased the mean plasma all-trans RA AUC on day 29 to 375 ng/mL per hour (P < .01).. Reported variability for the pharmacokinetics of all-trans RA may result from disease-related or population-based differences in basal catabolic rates influenced by genetic or environmental factors. However, the pattern of inducible catabolism of all-trans RA is not disease specific. Ketoconazole attenuates this accelerated catabolism, suggesting that oxidation by cytochrome-P450 enzymes is an important pathway for both constitutive and induced pathways of all-trans RA metabolism.

Topics: Carcinoma, Non-Small-Cell Lung; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Humans; Ketoconazole; Leukemia, Promyelocytic, Acute; Lung Neoplasms; Neoplasms; Tretinoin

Prompted by recent demonstrations that all-trans-retinoic acid (all-trans-RA) had efficacy in acute promyelocytic leukemia, a phase I trial of all-trans-RA was conducted to establish the maximum-tolerated dose (MTD) before phase II testing.. Forty patients with a histologic or cytologic diagnosis of malignancy other than leukemia were treated with single daily oral doses of all-trans-RA ranging from 45 mg/m2 to 200 mg/m2. Doses of all-trans-RA were escalated in the next cohort of patients until the MTD was determined if the preceding dose level was not associated with significant toxicity.. Lung cancer was the most common type of tumor included in the study (26 cases) followed by head and neck squamous cell carcinomas (three cases), and squamous cell carcinoma of the skin (two cases); other miscellaneous solid tumors were also represented. Toxicities included cheilitis, skin reactions, headache, and nausea and vomiting, as well as transient elevations of liver enzymes and triglyceride levels. Skin toxicities, consisting of erythema with desquamation and paronychia, were considered to be the dose-limiting toxicity, and were observed in two of six patients who received 175 mg/m2/d, and in two of five patients who received 200 mg/m2/d. Of the 30 patients with assessable lesions, response was evaluated in 26 patients and no major objective tumor response was observed. Two patients were able to receive the drug for longer than 1 year without significant toxicities. There was considerable variation in individual patients' peak plasma all-trans-RA levels, and a decrease in the area under the curve of all-trans-RA plasma concentration was observed in all four patients evaluated.. For phase II study of adult patients, we recommend 150 mg/m2 of all-trans-RA administered orally once a day. However, for better optimization of drug administration schedules, further studies are needed.

Topics: Adult; Aged; Alkaline Phosphatase; Cheilitis; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Headache; Hearing Disorders; Humans; Liver; Liver Diseases; Male; Middle Aged; Nausea; Neoplasms; Skin Diseases; Tretinoin; Vomiting

Recent reports of the dramatic antitumor effect of all-trans-retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have renewed interest in the oncologic indications for retinoids. Furthermore, a variety of pediatric tumors are responsive to RA in vitro, which provides additional rationale for a phase I evaluation of RA in children with cancer that is refractory to standard therapy.. A phase I trial of RA administered orally twice daily for 28-day treatment courses was performed. Cohorts of at least three pediatric cancer patients were entered at successive RA dose levels (from 45 to 80 mg/m2/d) until dose-limiting toxicity (DLT) was consistently observed.. The maximum-tolerated dose (MTD) of RA was 60 mg/m2/d. Three of eight patients at the 80-mg/m2/d dose level developed reversible pseudotumor cerebri that necessitated discontinuation of the agent. Both patients with APL achieved complete remission (CR), whereas no patients with solid tumors had objective responses. Pharmacokinetic studies demonstrated a relatively short terminal half-life for RA (45 minutes), with diminution in plasma levels after chronic dosing.. The MTD and recommended phase II dose for RA in children is 60 mg/m2/d given twice daily. Reversible CNS toxicity related to RA-induced pseudotumor cerebri is dose-limiting. Two children with APL achieved a CR to RA, which supports the inclusion of pediatric patients in clinical trials that evaluate the use of RA for patients with APL.

Topics: Administration, Oral; Adolescent; Adult; Capsules; Child; Child, Preschool; Cohort Studies; Drug Administration Schedule; Half-Life; Humans; Neoplasms; Pseudotumor Cerebri; Tretinoin

Topics: beta Carotene; Carotenoids; Dose-Response Relationship, Drug; Humans; Leukoplakia, Oral; Neoplasms; Tretinoin

Three cancer prevention trials are currently in their early phases at The Fred Hutchinson Cancer Research Center, the University of Washington School of Public Health and Community Medicine, and the Swedish Hospital. All 3 studies are randomized and placebo controlled. One large-scale study involves the daily administration of retinoids to persons with asbestos-related lung disease in an attempt toward reduction of their high risk for bronchogenic carcinomas and mesotheliomas. A second study involves administration of the same agents to long-term heavy smokers; a substantial feasibility and toxicity pilot study will precede a full-scale prevention trial. In the third trial, folic acid administration is evaluated in relation to the progression and regression of cervical dysplasia among women with abnormal Pap smears. We report here the rationale and the design for these 3 studies.

Topics: Asbestosis; Clinical Trials as Topic; Female; Humans; Lung Neoplasms; Male; Neoplasms; Random Allocation; Research Design; Retinoids; Smoking; Tretinoin; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Washington

Orally administered retinoids are synthetic derivatives of vitamin A. This new group of drugs (not yet available for general use in the United States) has been effective in experimental trials for treatment of a wide range of skin diseases. The current status of two of these drugs, isotretinoin (13-cis-retinoic acid) and etretinate (Ro 10-9359), is herein reviewed.

Topics: Acne Vulgaris; Administration, Oral; Child; Clinical Trials as Topic; Facial Dermatoses; Female; Humans; Isomerism; Isotretinoin; Keratins; Keratitis; Neoplasms; Psoriasis; Skin Diseases; Tretinoin; Xerostomia

13-cis-Retinoic acid (13-CRA) is a synthetic analog of vitamin A effective reversing preneoplastic lesions in both humans and animals. To study its physiochemical properties and disposition kinetics, we developed a rapid, sensitive, and precise high-performance liquid chromatography assay for 13-CRA in biological samples. This assay system resulted in a clear separation of 13-CRA from all-trans-retinoic acid and retinol and had a detection limit of 20 ng/ml plasma. Recovery was 89 +/- 6% (S.D.) at equivalent physiological concentrations with a precision of 8%. To study the disposition kinetics in humans, 13 patients received a p.o. bolus of 13-CRA and had blood samples collected at timed intervals. For the 10 patients studied on the first day of 13-CRA administration, the mean time to peak plasma concentration was 222 +/- 102 min. Interpatient peak 13-CRA plasma concentrations were found to be variable, suggesting irregular gastrointestinal absorption. Beta-Phase t 1/2 was approximately 25 hr. The prolonged terminal-phase plasma half-life may represent biliary excretion and enterohepatic circulation.

Topics: Adult; Aged; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Drug Evaluation; Female; Half-Life; Humans; Intestinal Absorption; Isotretinoin; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Reference Values; Tretinoin; Vitamin A

Topics: Abnormalities, Drug-Induced; Australia; Clinical Trials as Topic; Etretinate; Female; Humans; Isotretinoin; Neoplasms; Pregnancy; Skin Diseases; Tretinoin; Vitamin A

The early and recent investigations in the field of retinoids and cancer are reviewed. The retinoids, including natural vitamin A compounds and their synthetic analogs, present a new class of substances exerting a prophylactic and a therapeutic effect both in certain experimental tumor models and in certain clinical conditions of preneoplastic and neoplastic lesions. Because of a particular physiological mechanism of action, the retinoids offer a new approach to the cancer problem, which is different from those of surgery, X-ray therapy, conventional chemotherapy, and immunotherapy.

Topics: Animals; Cell Division; Cell Transformation, Neoplastic; Clinical Trials as Topic; Humans; Neoplasms; Neoplasms, Experimental; Tretinoin; Vitamin A

Ferroptosis is an iron-dependent form of regulated cell death induced by the lethal overload of lipid peroxides in cellular membranes. In recent years, modulating ferroptosis has gained attention as a potential therapeutic approach for tumor suppression. In the current study, retinol saturase (RETSAT) was identified as a significant ferroptosis mediator using a publicly accessible CRISPR/Cas9 screening dataset. RETSAT depletion protected tumor cells from lipid peroxidation and subsequent cell death triggered by various ferroptosis inducers. Furthermore, exogenous supplementation with retinoids, including retinol (the substrate of RETSAT) and its derivatives retinal and retinoic acid, also suppressed ferroptosis, whereas the product of RETSAT, 13, 14-dihydroretinol, failed to do so. As effective radical-trapping antioxidant, retinoids protected the lipid membrane from autoxidation and subsequent fragmentation, thus terminating the cascade of ferroptosis. Pseudotargeted lipidomic analysis identified an association between retinoid regulation of ferroptosis and lipid metabolism. Retinoic acid, but not 13, 14-dihydroretinoic acid, interacted with its nuclear receptor and activated transcription of stearoyl-CoA desaturase, which introduces the first double bond into saturated fatty acid and thus catalyzes the generation of monounsaturated fatty acid, a known ferroptosis suppressor. Therefore, RETSAT promotes ferroptosis by transforming retinol to 13, 14-dihydroretinol, thereby turning a strong anti-ferroptosis regulator into a relatively weak one.. Retinoids have ferroptosis-protective properties and can be metabolized by RETSAT to promote ferroptosis, suggesting the possibility of targeting retinoid metabolism in cancer as a treatment strategy to trigger ferroptosis.

Topics: Ferroptosis; Humans; Lipid Metabolism; Neoplasms; Retinoids; Tretinoin; Vitamin A

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.

Topics: Adipose Tissue, White; Animals; Cachexia; Humans; Male; Mice; Neoplasms; Signal Transduction; Tretinoin

Pediatric acute promyelocytic leukemia (APL) is one of the most curable subtypes of acute myeloid leukemia of childhood. But it may have many early complications, especially in developing countries. This study aims to describe the outcome and complications of pediatric APL patients in Bangladesh. This prospective observational study was conducted in the pediatric hematology and oncology department of Bangabandhu Sheikh Mujib Medical University, Dhaka from September 2017 to March 2019. In this study, PML:RAR-α (Promyelocytic leukemia-retinoic acid receptor-α) positive APL cases were included and observed while being treated with risk-directed ATRA (All-trans-retinoic acid) based chemotherapy. Among twenty PML:RAR-α positive APL cases, 13 children were in the high risk group and hemorrhagic manifestations were present in 95% of patients. Post-induction remission was achieved in 85% of the patients. 3-year overall survival was 70% (45-85% with 95% confidence interval). There was no refractory disease or relapses. Neutropenic sepsis was the most common complication and also the most common cause of mortality. In Bangladesh, the 3-year overall survival of pediatric APL is 70% (45-85% with 95% CI). Post-chemotherapy neutropenic sepsis is the most common complication and also the most common cause of mortality in this potentially curable malignancy in Bangladesh.

Topics: Bangladesh; Child; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Sepsis; Tretinoin

Myeloid Derived Suppressor Cells (MDSCs) play important roles in constituting the immune suppressive environment promoting cancer development and progression. They are consisted of a heterogeneous population of immature myeloid cells including polymorphonuclear MDSC (PMN-MDSC) and monocytes MDSC (M-MDSC) that are found in both the systemic circulation and in the tumor microenvironment (TME). While previous studies had shown that all-trans retinoic acid (ATRA) could induce MDSC differentiation and maturation, the very poor solubility and fast metabolism of the drug limited its applications as an immune-modulator for cancer immunotherapy. We aimed in this study to develop a drug encapsulated liposome formulation L-ATRA with sustained release properties and examined the immuno-modulation effects. We showed that the actively loaded L-ATRA achieved stable encapsulation and enabled controlled drug release and accumulation in the tumor tissues.

Topics: Animals; Drug Liberation; Homeostasis; Immunosuppression Therapy; Liposomes; Mice; Neoplasms; Retinoids; Tretinoin; Tumor Microenvironment

Memory T cells play an essential role in infectious and tumor immunity. Vitamin A metabolites such as retinoic acid are immune modulators, but the role of vitamin A metabolism in memory T-cell differentiation is unclear. In this study, we identified retinol dehydrogenase 10 (Rdh10), which metabolizes vitamin A to retinal (RAL), as a key molecule for regulating T cell differentiation. T cell-specific Rdh10 deficiency enhanced memory T-cell formation through blocking RAL production in infection model. Epigenetic profiling revealed that retinoic acid receptor (RAR) signaling activated by vitamin A metabolites induced comprehensive epigenetic repression of memory T cell-associated genes, including TCF7, thereby promoting effector T-cell differentiation. Importantly, memory T cells generated by Rdh deficiency and blocking RAR signaling elicited potent anti-tumor responses in adoptive T-cell transfer setting. Thus, T cell differentiation is regulated by vitamin A metabolism and its signaling, which should be novel targets for memory T cell-based cancer immunotherapy.

Topics: Alcohol Oxidoreductases; Immunotherapy; Memory T Cells; Neoplasms; Tretinoin; Vitamin A

Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency.. Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively.. The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects.. The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy.

Topics: Acitretin; Animals; Antineoplastic Agents; Cell Line, Tumor; Docetaxel; Drug Carriers; Excipients; Female; Methanol; Mice; Micelles; Neoplasms; Polysorbates; Rats; Surface-Active Agents; Taxoids; Tretinoin

Iodine has shown promise in enhancing radiotherapy. However, conventional iodine compounds show fast clearance and low retention inside cancer cells, limiting their application as a radiosensitizer. Herein, we synthesize poly(maleic anhydride-

Topics: Animals; Cell Line, Tumor; Iodides; Mice; Nanoparticles; Neoplasms; Potassium Iodide; Tretinoin

Radiotherapy (RT) is an important anti-cancer treatment modality that activates innate and adaptive immune responses. When all-trans retinoic acid (RA) was administered with radiation, we observed superior antitumor responses compared to ionizing radiation (IR) alone or RA alone. The superior antitumor effects of combination treatment were accompanied by a dramatic increase of TNF-α- and inducible nitric oxide synthase (iNOS)-producing inflammatory macrophages in local and distal non-irradiated (distal) tumors. Inflammatory macrophages are essential for the therapeutic efficacy of combination treatment by inducing effector T cell infiltration and enhancing the effector T cell to regulatory T cell ratio in local and distal tumors. T cells and T cell-derived IFN-γ are crucial for increasing inflammatory macrophage levels in IR and RA treated tumors. Notably, whereas CD8

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Chemoradiotherapy; Disease Models, Animal; Humans; Interferon-gamma; Macrophages; Mice; Mice, Knockout; Neoplasms; Radiation Tolerance; Receptors, CCR2; Tretinoin; Tumor Microenvironment

Drug delivery is crucial for therapeutic efficacy and gap junction communication channels (GJIC) facilitate movement within the tumour. Pro-drug activation, a modality of cancer therapy leads to Ganciclovir triphosphate (GCV-TP) incorporation into newly synthesized DNA resulting in cell death. The objective was to enhance, with Histone deacetylase inhibitors (HDACi) and All Trans Retinoic Acid (ATRA), GJIC, crucial for drug delivery, and with combination, abrogate the observed detrimental effect of Dexamethasone (DXM).. Cell lines (NT8E, and HeLa) were pre-treated with Valproic Acid (VPA) (1 mM), 4 Phenyl Butyrate (4PB) (2 mM), ATRA (10 μM) and Dexamethasone (1 μM). Protein quantitated with the Bicinchoninic (BCA) assay for cell lysates, membrane and soluble fractions was assessed with Western blotting for Connexins (43, 26 and 32) and E-Cadherin. A qRT-PCR was done for CX 43-GJA1, CX 26-GJB2, CX 32-GJB1 and E-Cadherin, and normalized with Glyceraldehyde Phosphate dehydrogenase (GAPDH). Further, localization of Connexins (CX) and E-Cadherin, GJIC competence, pre-clinical in-vitro studies and the mechanism of cell death were evaluated.. There was no toxicity or change in growth patterns observed with the drugs. In both the cell lines CX 43 localized to the membrane whereas CX 32 and CX 26 were present but not membrane bound. E-Cadherin was present on the membrane in NT8E and completely absent in HeLa cells. Effects of HDACi, DXM and ATRA were seen on the expression of Connexins and E-Cadherin in both the cell lines. NT8E and HeLa cell lines showed enhanced GJIC with 4PB [30 %], VPA [36 %] and ATRA [54 %] with a 60 % increase in cytotoxicity and an abrogation of Dexamethasone inhibition on combination with VPA or ATRA.. An enhancement of GJIC function by HDACi and ATRA increased cytotoxicity and could be effective in the presence of Dexamethasone, when combined with ATRA or VPA.

Topics: Antineoplastic Agents; Apoptosis; Cadherins; Cell Communication; Cell Line, Tumor; Cell Membrane; Connexins; Dexamethasone; Ganciclovir; Gap Junctions; Gene Expression Regulation, Neoplastic; HeLa Cells; Histone Deacetylase Inhibitors; Humans; Molecular Targeted Therapy; Neoplasms; Tretinoin; Valproic Acid

Myeloid-derived suppressor cells (MDSC) are known to inhibit functions of T and NK cells. MDSC have been shown to be generated and to accumulate under chronic inflammatory conditions that are typical for cancer. Therefore, it would be highly beneficial to find ways to diminish the number and immunosuppressive functions of these cells in tumor-bearing hosts. Here we describe current protocols to deplete MDSC or induce their maturation in preclinical tumor models that could lead to the attenuation of their immunosuppressive functions.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Cell Differentiation; Disease Models, Animal; Mice, Inbred C57BL; Mice, Transgenic; Myeloid-Derived Suppressor Cells; Neoplasms; Paclitaxel; Tretinoin

Here we describe two protocols for the construction of responsive and activable nanomedicines that regulate the tumor microenvironment (TME). The TME is composed of all non-cellular and cellular components surrounding a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules, and extracellular matrix and has a crucial role in tumor initiation, growth, and metastasis. Owing to the relatively stable properties of the TME compared to tumor cells, which exhibit frequent genetic mutations and epigenetic changes, therapeutic strategies targeting the TME using multifunctional nanomedicines hold great potential for anti-tumor therapy. By regulating tumor-associated platelets and pancreatic stellate cells (PSCs), the two major players in the TME, we can effectively manipulate the physiological barriers for enhanced drug delivery and significantly improve the tumor penetration and therapeutic efficacy of chemotherapeutics. The preparation and characterization of the multifunctional nanoparticles takes ~10 h for tumor-associated platelet regulation and 16 h for PSC regulation. These nanoformulations can be readily applied to regulate other components in the TME to realize synergistic or additive anti-tumor activity.

Topics: Animals; Antineoplastic Agents; Delayed-Action Preparations; Doxorubicin; Drug Delivery Systems; Female; Gold; Humans; Mice, Inbred BALB C; Nanomedicine; Nanoparticles; Neoplasms; Polymers; RNA, Small Interfering; Tretinoin; Tumor Microenvironment

Retinoic acid (RA) binding proteins, CRABP1 and CRABP2, are molecular chaperones that mediate intracellular activity of RA, the key promoter of cell differentiation with tumor suppressor activity. One of the main functions of CRABP2 is delivery and transfer of RA to the nuclear receptors RAR/RXR, which leads to activation of the transcription of a wide range of retinoid-responsive genes. The functions of CRABP1 are less studied but are apparently associated with sequestration of RA in cytoplasm and limitation of its transcriptional activity, suggesting involvement of this protein in the development of RA resistance. The mechanisms regulating activity of CRABP1 are also poorly understood. Comparison of the CRABP1 level in tumor cell lines of various origins, performed for the first time here, showed absence of the CRABP1 protein in the cell lines of tumors considered to be RA-resistant, and pronounced production of this protein in the RA-sensitive cells. However, analysis carried out with a panel of breast cancer cell lines with different levels of RA-sensitivity showed that there was no correlation between the production of CRABP1 protein and the sensitivity of the cells to RA. At the same time, we found strong correlation between the expression of CRABP1 and CRABP2 proteins in all studied cell types, regardless of their origin and RA-sensitivity/resistance. Moreover, suppression of the CRABP1 level in both RA-sensitive and RA-resistant cells was shown in the cells with cells with knockdown of CRABP2 gene. The revealed CRABP2-dependent regulation of CRABP1 production is a new mechanism of the intracellular retinoic signaling system.

Topics: A549 Cells; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Neoplasms; Receptors, Retinoic Acid; Signal Transduction; Tretinoin

The existence of cancer stem cells (CSCs) poses a major obstacle for the success of current cancer therapies, especially the fact that non-CSCs can spontaneously turn into CSCs, which lead to the failure of the treatment and tumor relapse. Therefore, it is very important to develop effective strategies for the eradication of the CSCs. In this work, we have developed a CSCs-specific targeted, retinoic acid (RA)-loaded gold nanostars-dendritic polyglycerol (GNSs-dPG) nanoplatform for the efficient eradication of CSCs. The nanocomposites possess good biocompatibility and exhibit effective CSCs-specific multivalent targeted capability due to hyaluronic acid (HA) decorated on the multiple attachment sites of the bioinert dendritic polyglycerol (dPG). With the help of CSCs differentiation induced by RA, the self-renewal of breast CSCs and tumor growth were suppressed by the high therapeutic efficacy of photothermal therapy (PTT) in a synergistic inhibitory manner. Moreover, the stemness gene expression and CSC-driven tumorsphere formation were significantly diminished. In addition, the

Topics: Glycerol; Gold; Neoplasms; Neoplastic Stem Cells; Photothermal Therapy; Polymers; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Syndrome; Tomography, X-Ray Computed; Tretinoin

Tumor-derived retinoic acid promotes monocyte differentiation into immunosuppressive macrophages.

Topics: Cell Differentiation; Humans; Immunity; Monocytes; Neoplasms; Tretinoin

All-trans retinoic acid (ATRA) is widely employed in the treatment of various proliferative and inflammatory diseases. However, its therapeutic efficacy is imperiled due to its poor solubility and stability. Latter was surmounted by its incorporation into a solid matrix of lipidic nanoparticles (SLNs).. ATRA loaded SLNs (ATRA-SLNs) were prepared using a novel microemulsification technique (USPTO 9907758) and an optimal composition and were characterized in terms of morphology, differential scanning calorimetry (DSC), and powder X-ray diffraction studies (PXRD). In vitro release, oral plasma pharmacokinetics (in rats) and stability studies were also done.. Rod-shaped ATRA-SLNs could successfully incorporate 3.7 mg/mL of ATRA, increasing its solubility (from 4.7 μg/mL) by 787 times, having an average particle size of 131.30 ± 5.0 nm and polydispersibility of 0.283. PXRD, DSC, and FTIR studies confirmed the formation of SLNs. Assay/total drug content and entrapment efficiency of ATRA-SLNs was 92.50 ± 2.10% and 84.60 ± 3.20% (n=6), respectively, which was maintained even on storage for one year under refrigerated conditions as an aqueous dispersion. In vitro release in 0.01 M phosphate buffer (pH 7.4) with 3% tween 80 was extended 12 times from 2h for free ATRA to 24 h for ATRA-SLNs depicting Korsmeyer Peppas release. Oral administration in rats showed 35.03 times enhanced bioavailability for ATRA-SLNs.. Present work reports preparation and evaluation of bioenhanced ATRA-SLNs containing a high concentration of ATRA (>15 times than that reported by others). Latter is attributed to the novel preparation process and intelligent selection of components. Lay Summary: All-trans retinoic acid (ATRA) shows an array of pharmacological activities but its efficacy is limited due to poor solubility, stability and side effects. In present study its solubility and efficacy is improved by 787 and 35.5 times, respectively upon incorporation into solid lipid nanoparticles (ATRA-SLNs). Latter extended its release by 12 times and provided stability for at least a year under refrigeration. A controlled and sustained release will reduce dose related side effects. ATRA-SLNs reported presently can thus be used in treatment /prophylaxis of disorders like cancers, tuberculosis, age related macular degeneration and acne and as an immune-booster.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Calorimetry, Differential Scanning; Drug Carriers; Drug Compounding; Drug Stability; Emulsions; Lipids; Male; Models, Animal; Nanoparticles; Neoplasms; Particle Size; Rats; Rats, Wistar; Solubility; Tretinoin; X-Ray Diffraction

Clinical studies have shown that all-trans retinoic acid (RA), which is often used in treatment of cancer patients, improves hemostatic parameters and bleeding complications such as disseminated intravascular coagulation (DIC). However, the mechanisms underlying this improvement have yet to be elucidated. In vitro studies have reported that RA upregulates thrombomodulin (TM) expression on the endothelial cell surface. The objective of this study was to investigate how and to what extent the TM concentration changes after RA treatment in cancer patients, and how this variation influences the blood coagulation cascade.. In this study, we introduced an ordinary differential equation (ODE) model of gene expression for the RA-induced upregulation of TM concentration. Coupling the gene expression model with a two-compartment pharmacokinetic model of RA, we obtained the time-dependent changes in TM and thrombomodulin-mRNA (TMR) concentrations following oral administration of RA. Our results indicated that the TM concentration reached its peak level almost 14 h after taking a single oral dose (110 [Formula: see text]) of RA. Continuous treatment with RA resulted in oscillatory expression of TM on the endothelial cell surface. We then coupled the gene expression model with a mechanistic model of the coagulation cascade, and showed that the elevated levels of TM over the course of RA therapy with a single daily oral dose (110 [Formula: see text]) of RA, reduced the peak thrombin levels and endogenous thrombin potential (ETP) up to 50 and 49%, respectively. We showed that progressive reductions in plasma levels of RA, observed in continuous RA therapy with a once-daily oral dose (110 [Formula: see text]) of RA, did not affect TM-mediated reduction of thrombin generation significantly. This finding prompts the hypothesis that continuous RA treatment has more consistent therapeutic effects on coagulation disorders than on cancer.. Our results indicate that the oscillatory upregulation of TM expression on the endothelial cells over the course of RA therapy could potentially contribute to the treatment of coagulation abnormalities in cancer patients. Further studies on the impacts of RA therapy on the procoagulant activity of cancer cells are needed to better elucidate the mechanisms by which RA therapy improves hemostatic abnormalities in cancer.

Topics: Blood Coagulation; Blood Coagulation Disorders; Cell Line, Tumor; Computer Simulation; Endothelial Cells; Gene Expression Regulation, Neoplastic; Humans; Models, Biological; Neoplasms; Thrombin; Thrombomodulin; Tretinoin

Retinoic acid, an active metabolite of vitamin A, exerts multiple effects on regulating embryonic development and inducing differentiation, proliferation, apoptosis as well as resistance in various cancer cells. Apart from the classic genomic action (binding to the nuclear receptors to regulate the expression of its downstream target genes), retinoic acids also play important roles in anti-cancer effect through non-genomic pathways (via extranuclear and non-transcriptional effects).. 维甲酸是维生素A的活性代谢物，在胚胎发育和多种肿瘤细胞的分化、增殖、凋亡及耐药方面发挥重要作用。维甲酸除可通过经典的基因途径(即通过与核受体家族成员结合调节下游靶基因表达)外，也可通过非基因途径(即核外和非转录效应)而发挥抗肿瘤效应。.

Topics: Apoptosis; Cell Differentiation; Genomics; Humans; Neoplasms; Receptors, Retinoic Acid; Tretinoin

Novel chitosan-cystamine-retinoic acid conjugate (CS-SS-RA) was synthesized and could self-assemble into redox-sensitive micelles in aqueous environment with low critical micelle concentration value. CS-SS-RA micelles were characterized with spherical shape, desirable particle size, negative zeta potential, high paclitaxel (PTX) loading and encapsulation efficiency and redox-sensitivity. Hemolysis and cytotoxicity studies proved the safety of CS-SS-RA micelles for intravenous administration. Cytotoxicity study against HepG2 cells and the growth inhibition study on three-dimensional multicellular tumor spheroids (MCTSs) revealed that PTX-loaded CS-SS-RA micelles exhibited higher antitumor activity than free PTX. The in vitro cellular uptake profiles of FITC-labeled CS-SS-RA micelles evaluated via confocal laser scanning microscopy and flow cytometry indicated that CS-SS-RA micelles could enhance cellular uptake efficiency of PTX, and their internalization by HepG2 cells were mediated by clathrin-mediated endocytosis and macropinocytosis. These results demonstrated that CS-SS-RA micelles could be developed as a promising platform for intracellular delivery of hydrophobic antitumor agents.

Topics: Antineoplastic Agents; Cell Survival; Chitosan; Cystamine; Drug Carriers; Drug Liberation; Hep G2 Cells; Humans; Micelles; Neoplasms; Oxidation-Reduction; Paclitaxel; Particle Size; Tretinoin

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinogens; Caspases; Drugs, Chinese Herbal; Gastric Mucosa; Gene Expression Regulation, Neoplastic; Ki-67 Antigen; Male; Methylnitronitrosoguanidine; Neoplasms; Rats; Rats, Wistar; Severity of Illness Index; Signal Transduction; Stomach; Transcription Factor RelA; Tretinoin; Tumor Suppressor Protein p53

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but their mechanisms of action and efficacy are not fully understood. ATRA inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1's active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, like Pin1 knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic targeting of Pin1 by ATO and ATRA offers an attractive approach to combating breast and other cancers.

Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Cell Proliferation; Female; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Promyelocytic, Acute; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasm Transplantation; Neoplasms; NIMA-Interacting Peptidylprolyl Isomerase; Proteomics; Signal Transduction; Tretinoin

In this letter to editor, I hypothesize a potential affinity of retinol saturase (RetSat) enzyme towards a conjugated trienoic fatty acid; alpha-eleostearic acid (α-ESA) and subsequent hindrance of the action on its usual substrate; all trans retinol. Hence, RetSat is speculated to be involved in a rapid unusual conversion of α-ESA to conjugated linoleic acid (CLA), giving a less priority to its usual substrate all trans retinol, which would subsequently be converted into "all trans retinoic acid" (atRA). Otherwise, all trans retinol is converted by RetSat into all-trans-13,14-dihydroretinol and eventually forms all-trans-13,14-dihydroretinoic acid, but not the atRA. The atRA controls differentiation, proliferation and apoptosis of cells and it's deficiencies end up as neoplasms. Thus, here it is emphasized that safeguarding atRA would help controlling cell division and growth in a favourable manner. Hence, inhibition of RetSat could be a hot target to control unwarranted cell growths within the body. This hypothesis could be easily tested in a RetSat ablated (RetSat -/-) animal model or using antagonists on RetSat activity or α-ESA.

Topics: Animals; Cell Differentiation; Cell Division; Humans; Linoleic Acid; Linoleic Acids, Conjugated; Linolenic Acids; Lipid Metabolism; Metabolomics; Neoplasms; Tretinoin; Vitamin A

Co-delivery all-trans-retinoic acid (ATRA) and paclitaxel (PTX) is an effective strategy for cancer therapy. However, in many previous reported ATRA conjugated co-delivery systems, the ATRA was released slower than PTX, and the total drug release of ATRA far lower than that of PTX.. We designed and prepared a pH and redox dual responsive drug delivery system (DA-ss-NPs) co-delivery ATRA and PTX for cancer therapy. The surface charge of DA-ss-NPs could change from negative to positive under tumor slightly acidic microenvironment, and both drugs could be quickly released from DA-ss-NPs under intracellular high concentration of glutathione (GSH).. The DA-ss-NPs were constructed by encapsulating PTX into the hydrophobic core of the polymer micelles, in which the polymer was synthesized by conjugating ATRA and 2,3-Dimethylmalefic anhydride (DMA) on side chains of Cystamine dihydrochloride (Cys) modified PEG-. The zeta potential of DA-ss-NPs was -16.3 mV at pH 7.4, and which changed to 16 mV at pH 6.5. Cell uptake experiment showed that more DA-ss-NPs were internalized by A549 cells at pH 6.5 than that at pH 7.4. In addition, in presence of 10 mM GSH at pH 7.4, about 75%-85% ATRA was released from DA-ss-NPs within 48 h; but less than 20% ATRA was released without GSH. In vivo antitumor efficiency showed that the DA-ss-NPs could affectively inhibite the tumor in compared with control groups.. The charge-reversal and GSH-responsive DA-ss-NPs provide an excellent platform for potential tumor therapy.

Topics: A549 Cells; Adsorption; Animals; Antineoplastic Agents; Cell Death; Drug Delivery Systems; Drug Liberation; Drug Therapy, Combination; Humans; Hydrogen-Ion Concentration; Male; Mice, Inbred BALB C; Mice, Nude; Micelles; Nanoparticles; Neoplasms; Oxidation-Reduction; Paclitaxel; Particle Size; Polymers; Serum Albumin, Bovine; Tretinoin

Hypersegmentation of nuclei is considered a distinct characteristic of the antitumoral phenotype of neutrophils. Retinoic acid, a metabolite of retinol, reorganizes and induces segmentation of the nucleus during the differentiation of neutrophils. However, the role of retinoic acid in the phenotype polarization of neutrophils has not been fully established. Here, we investigated the effect of retinoic acid on phenotype polarization of neutrophils. Retinoic acid-induced the hypersegmentation of human neutrophils via retinoic acid receptors and mTOR pathways. Retinoic acid-induced hypersegmented neutrophils enhanced neutrophil extracellular traps (NETs) formation in response to phorbol-12-myristate 13-acetate (PMA) and fMLP (N-Formylmethionine-leucyl-phenylalanine) stimulation, and increased cytotoxicity against various tumor cells. Moreover, retinoic acid treatment attenuated tumor growth in a murine model of tumor. Taken together, these results suggests that retinoic acid induces the phenotype polarization of neutrophils to exert antitumor effects.

Topics: Animals; Cytotoxicity, Immunologic; Extracellular Traps; Female; Humans; Leukocyte Disorders; Mice; Neoplasms; Neutrophils; Reactive Oxygen Species; Receptors, Retinoic Acid; TOR Serine-Threonine Kinases; Tretinoin; Tumor Microenvironment

Co-delivery of multiple agents via nanocarriers is of great interest in cancer therapy, but subcellular delivery to the corresponding site of action remains challenging. Here we report a smart nanovehicle which enables two different site-oriented payloads to reach their targeted organelles based on stimulus-responsive release and nucleus-targeted modification. First, all trans retinoic acid (RA) conjugated camptothecin (RA-CPT) was loaded in a polyhedral oligomericsilsesquioxane (POSS)-based core; docetaxel (DTX) was grafted on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers. The POSS core grafted with semitelechelic HPMA copolymers then self-assembled into micelles. Once internalized into the cell, the two drugs were unleashed environment-responsively, and nuclear targeted RA remarkably facilitated the nuclear transport of CPT. Compared with single drug-loaded micelles, the dual drug-loaded platform showed superior synergic cytotoxicity, which was further strengthened by the involvement of RA. The ability to induce DNA damage and apoptosis was also enhanced by nucleus-targeted modification. Finally, dual drug-loaded micelles exhibited much better in vivo tumor inhibition (87.1%) and less systemic toxicity than the combination of single drug-loaded systems or the dual drug-loaded micelles without RA. Therefore, our study provides a novel "one platform, two targets" strategy in combinatory anti-cancer therapy.

Topics: Acrylamides; Animals; Antineoplastic Agents; Apoptosis; Camptothecin; Cell Line, Tumor; DNA Damage; Docetaxel; Drug Delivery Systems; Humans; Male; Mice; Mice, Inbred BALB C; Micelles; Neoplasms; NIH 3T3 Cells; Organosilicon Compounds; Polymers; Taxoids; Tretinoin; Xenograft Model Antitumor Assays

Vitamin A is an essential nutrient that is obtained from the daily diet. The major forms of vitamin A in the body consist of retinol, retinal, retinoic acid (RA), and retinyl esters. Retinal is fundamental for vision and RA is used in clinical therapy of human acute promyelocytic leukemia. The actions of retinol and retinyl palmitate (RP) are not known well. Recently, we found that retinol is a potent anti-proliferative agent against human refractory cancers, including gallbladder cancer, being more effective than RA, while RP was inactive. In the current study, we determined serum retinol concentrations in xenograft mice bearing tumors derived from four refractory cancer cell lines. We also examined the effects of vitamin A on proliferation of human gallbladder cancer cells in vivo. Serum retinol concentrations were significantly lower in xenograft mice with tumors derived from various refractory cancer cell lines as compared with control mice. The growth of tumors was inhibited with increasing serum retinol concentrations obtained post-administration of RP. In addition, pre-administration of RP increased serum retinol concentrations and suppressed tumor growth. These results indicate that administration of RP can maintain retinol concentrations in the body and that this might suppress cancer cell growth and attachment. The regulation of vitamin A concentration in the body, which is critical biomarker of health, could be beneficial for cancer prevention and therapy.

Topics: Animals; Carcinogenesis; Cell Line, Tumor; Diet, Healthy; Diterpenes; Drug Resistance, Neoplasm; Humans; Male; Mice; Mice, Nude; Neoplasms; Retinyl Esters; Specific Pathogen-Free Organisms; Tretinoin; Vitamin A; Vitamins; Xenograft Model Antitumor Assays

All trans retinoic acid (ATRA), an active vitamin-A derivative, has been shown to regulate gene expression program and thus imparts anti-proliferative activity to cancer cells. Previously, we identified a dual histone reader ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), to be a novel target of ATRA. In the present study, we attempted to decipher the detail mechanism of its transcription regulation. ATRA can reprogram the epigenetic landscape in the upstream regulatory region of ZMYND8 thereby promoting its expression. Interestingly, there is a unique H3K27Me3 to H3K27Ac switch upon ATRA-treatment. We show here that ATRA causes dynamic changes in recruitment of transcription factor YY1 in concert with HDAC1 at ZMYND8 promoter. Further, we show that ATRA treatment triggers an anti-proliferative activity in cancer cells through regulation of ZMYND8 expression. Subsequently, in 4T1-induced syngenic tumor mouse model, ATRA injection caused significant upregulation of ZMYND8. Overall our findings highlight a novel mechanism underlying ATRA-mediated changes in ZMYND8 expression which, in turn, activates the anti-proliferative program in a cancer cell. Thus, histone reader mediated modulation of epigenetic language could play a significant role in retinoid based therapeutic strategy which is well exploited to combat tumor growth.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Chromatin; Chromatin Immunoprecipitation; Fluorescent Antibody Technique; Histone Deacetylases; Histones; Humans; Lysine; Methylation; Mice; Neoplasms; Polymerase Chain Reaction; Promoter Regions, Genetic; Receptors for Activated C Kinase; Receptors, Cell Surface; Response Elements; RNA Polymerase II; Time Factors; Tretinoin; Tumor Suppressor Proteins; YY1 Transcription Factor

All-

Topics: Animals; Antineoplastic Agents; Biopharmaceutics; Drug Design; Drug Interactions; Humans; Mice; Neoplasms; Retinoic Acid 4-Hydroxylase; Tissue Distribution; Tretinoin

Vitamin A constituents include retinal, which plays a role in vision, and retinoic acid (RA), which has been used in the therapy of human acute promyelocytic leukemia. However, the effects on cancer of retinol (Rol) and its ester, retinyl palmitate (RP) are not known well. In the current study, we examined the effects of these agents on proliferation and adhesion of various cancer cells. Rol exhibited dose-dependent inhibition of the proliferation of human refractory and prostate cancer cells, while RA and RP showed little or no effect. In contrast, RA inhibited the growth of human breast cancer cells to a greater extent than Rol at low concentrations, but not at high concentrations. Rol suppressed adhesion of refractory and prostate cancer cells to a greater extent than RA, while it suppressed adhesion of breast cancer cells as well as RA and of JHP-1 cells less effectively than RA. These results indicate that Rol is a potent suppressor of cancer cell growth and adhesion, which are both linked to metastasis and tumor progression. Rol might be useful for the clinical treatment of cancer.

Topics: Antineoplastic Agents; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Diterpenes; Drug Resistance, Neoplasm; Humans; Neoplasms; Retinyl Esters; Tretinoin; Vitamin A

All trans retinoic acid (atRA) is one of the most potent therapeutic agents, but extensive toxicity caused by nuclear RA receptors (RARs) limits its clinical application in treating cancer. AtRA also exerts non-genomic activities for which the mechanism remains poorly understood. We determine that cellular retinoic acid binding protein 1 (Crabp1) mediates the non-genomic activity of atRA, and identify two compounds as the ligands of Crabp1 to rapidly and RAR-independently activate extracellular signal regulated kinase 1/2 (ERK1/2). Non-canonically activated ERK activates protein phosphatase 2A (PP2A) and lengthens cell cycle duration in embryonic stem cells (ESC). This is abolished in Crabp1-null ESCs. Re-expressing Crabp1 in Crabp1-negative cancer cells also sensitizes their apoptotic induction by atRA. This study reveals a physiological relevance of the non-genomic action of atRA, mediated by Crabp1, in modulating cell cycle progression and apoptosis induction, and provides a new cancer therapeutic strategy whereby compounds specifically targeting Crabp1 can modulate cell cycle and cancer cell apoptosis in a RAR-independent fashion, thereby avoiding atRA's toxicity caused by its genomic effects.

Topics: Animals; Apoptosis; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; Mice; Mitogen-Activated Protein Kinase 3; Neoplasm Proteins; Neoplasms; Phosphorylation; Receptors, Retinoic Acid; Tretinoin

CYP2W1 is a recently discovered human cytochrome P450 enzyme with a distinctive tumor-specific expression pattern. We show here that CYP2W1 exhibits tight binding affinities for retinoids, which have low nanomolar binding constants, and much poorer binding constants in the micromolar range for four other ligands. CYP2W1 converts all-transretinoic acid (atRA) to 4-hydroxyatRA and all-transretinol to 4-OH all-transretinol, and it also oxidizes retinal. The enzyme much less efficiently oxidizes 17β-estradiol to 2-hydroxy-(17β)-estradiol and farnesol to a monohydroxylated product; arachidonic acid is, at best, a negligible substrate. These findings indicate that CYP2W1 probably plays an important role in localized retinoid metabolism that may be intimately linked to its involvement in tumor development.

Topics: Arachidonic Acid; Catalysis; Cytochrome P450 Family 2; Estradiol; Humans; Ligands; Neoplasms; Oxidation-Reduction; Protein Binding; Retinoids; Tretinoin

This study aimed to evaluate the outcome and predictors of survival in hemodialysis patients of Hasheminejad Kidney Center where a comprehensive dialysis care program has been placed since 2004.. Data of 560 hemodialysis patients were used to evaluate 9-year survival rates and predictors of mortality. Cox regression models included comorbidities as well as averaged and 6-month-averaged time-dependent values of laboratory findings as independent factors.. Survival rates were 91.9%, 66.0%, 46.3%, and 28.5%,  at 1, 3, 5, and 9 years, respectively, in all patients and 90.8%, 61.6%, 42.1%, and 28.0% in 395 incident patients starting hemodialysis after 2004. Adjusted survival models demonstrated age, male sex, diabetes mellitus, cardiovascular disease, and high-risk vascular access as baseline predictors of mortality, as well as averaged low hemoglobin level (hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.36 to 2.90) and a single-pool KT/V < 1.2 (HR, 2.28; 95% CI, 1.60 to 3.26). The averaged high-density lipoprotein cholesterol (HR, 0.67; 95% CI, 0.55 to 0.81) and serum creatinine (HR, 0.71; 95% CI, 0.64 to 0.79) levels demonstrated protective effects. The adjusted time-dependent model further revealed the significant association of hypocalcemia (HR, 1.63; 95% CI, 1.13 to 2.34), hypercalcemia (HR, 1.50; 95% CI, 1.02 to 2.21), and hyperphosphatemia (HR, 1.68; 95% CI, 1.20 to 2.37) with death.. Our patients have relatively comparable survival rates with high-profile dialysis centers. Aiming to better achieve the recommended targets, especially hemoglobin and nutritional and bone metabolism factors, should be considered for optimal dialysis outcomes.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Cardiovascular Diseases; Cause of Death; Cerebrovascular Disorders; Child; Cholesterol, HDL; Creatinine; Diabetes Mellitus; Female; Humans; Hypercalcemia; Hyperphosphatemia; Hypocalcemia; Infections; Iran; Kidney Failure, Chronic; Male; Middle Aged; Mortality; Neoplasms; Proportional Hazards Models; Renal Dialysis; Retrospective Studies; Risk Factors; Sex Factors; Survival Rate; Time Factors; Tretinoin; Young Adult

A series of α-branched α,β-unsaturated ketones were prepared via boron trifluoride etherate mediated reaction between arylalkynes and carboxaldehydes. The evaluation of the antiproliferative activity over hematological (NB4) and solid cancer (A549, MCF-7) cell lines provided a structure-activity relationship. 5-Parameter QSAR equations were built which were able to explain 80%-92% of the variance in activity. The resulting selective lead compound showed IC50 value 0.6 μM against the hematological cell line and did not cause apoptosis, but blocked cell cycle in G0/G1. Moreover, it was demonstrated that this compound enhances and accelerates retinoic acid induced granulocytic differentiation.

Topics: Cell Line, Tumor; Cell Proliferation; Hematologic Neoplasms; Humans; Ketones; Neoplasms; Quantitative Structure-Activity Relationship

Combination treatment through simultaneous delivery of two or more drugs with nanoparticles has been demonstrated to be an elegant and efficient approach for cancer therapy. Herein, we employ a combination therapy for eliminating both the bulk tumor cells and the rare cancer stem cells (CSCs) that have a high self-renewal capacity and play a critical role in cancer treatment failure. All-trans-retinoic acid (ATRA), a powerful differentiation agent of cancer stem cells and the clinically widely used chemotherapy agent doxorubicin (DOX) are simultaneously encapsulated in the same nanoparticle by a single emulsion method. It is demonstrated that ATRA and DOX simultaneous delivery-based therapy can efficiently deliver the drugs to both non-CSCs and CSCs to differentiate and kill the cancer cells. Differentiation of CSCs into non-CSCs can reduce their self-renewal capacity and increase their sensitivity to chemotherapy; with the combined therapy, a significantly improved anti-cancer effect is demonstrated. Administration of this combinational drug delivery system can markedly augment the enrichment of drugs both in tumor tissues and cancer stem cells, prodigiously enhancing the suppression of tumor growth while reduce the incidence of CSC in a synergistic manner.

Topics: Animals; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Drug Delivery Systems; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Injections, Intravenous; Mice, Inbred NOD; Mice, SCID; Nanoparticles; Neoplasms; Neoplastic Stem Cells; Particle Size; Proliferating Cell Nuclear Antigen; Static Electricity; Tretinoin

Retinoic acid (RA), the major bioactive metabolite of retinol or vitamin A, induces a spectrum of pleiotropic effects in cell growth and differentiation that are relevant for embryonic development and adult physiology. The RA activity is mediated primarily by members of the retinoic acid receptor (RAR) subfamily, namely RARα, RARβ and RARγ, which belong to the nuclear receptor (NR) superfamily of transcription factors. RARs form heterodimers with members of the retinoid X receptor (RXR) subfamily and act as ligand-regulated transcription factors through binding specific RA response elements (RAREs) located in target genes promoters. RARs also have non-genomic effects and activate kinase signaling pathways, which fine-tune the transcription of the RA target genes. The disruption of RA signaling pathways is thought to underlie the etiology of a number of hematological and non-hematological malignancies, including leukemias, skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are employed as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In humans, retinoids reverse premalignant epithelial lesions, induce the differentiation of myeloid normal and leukemic cells, and prevent lung, liver, and breast cancer. Here, we provide an overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways. Moreover, mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined. Finally, the therapeutic effects of retinoids are reported.

Topics: Animals; Antineoplastic Agents; Female; Humans; Male; Neoplasms; Receptors, Retinoic Acid; Response Elements; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Tretinoin

Substantial evidence now demonstrates that interactions between the tumor microenvironment and malignant cells are a critical component of clinical drug resistance. However, the mechanisms responsible for microenvironment-mediated chemoprotection remain unclear. We showed that bone marrow (BM) stromal cytochrome P450 (CYP)26 enzymes protect normal hematopoietic stem cells (HSCs) from the pro-differentiation effects of retinoic acid. Here, we investigated if stromal expression of CYPs is a general mechanism of chemoprotection. We found that similar to human hepatocytes, human BM-derived stromal cells expressed a variety of drug-metabolizing enzymes. CYP3A4, the liver's major drug-metabolizing enzyme, was at least partially responsible for BM stroma's ability to protect multiple myeloma (MM) and leukemia cells from bortezomib and etoposide, respectively, both in vitro and in vivo. Moreover, clarithromycin overcame stromal-mediated MM resistance to dexamethasone, suggesting that CYP3A4 inhibition plays a role in its ability to augment the activity of lenalidomide and dexamethasone as part of the BiRd regimen. We uncovered a novel mechanism of microenvironment-mediated drug resistance, whereby the BM niche creates a sanctuary site from drugs. Targeting these sanctuaries holds promise for eliminating minimal residual tumor and improving cancer outcomes.

Topics: Animals; Antineoplastic Agents; Bone Marrow; Cell Line, Tumor; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dexamethasone; Drug Resistance, Neoplasm; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Interleukin Receptor Common gamma Subunit; Lenalidomide; Mesenchymal Stem Cells; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Thalidomide; Tretinoin; Tumor Microenvironment; Xenograft Model Antitumor Assays

Let-7c, an intronic microRNA (miRNA) embedded in the long non-coding gene LINC00478, can act as a tumor suppressor by targeting oncogenes. Previous studies indicated that in acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia (AML) bearing the leukemia promoting PML/RARα fusion protein, let-7c expression seems to be controlled by the host gene promoter, in which canonical Retinoic Acid Responsive Elements (RAREs) are bound by PML/RARα in an all transretinoic acid (ATRA)-sensitive manner. Here, let-7c transcriptional regulation was further investigated and a novel intronic promoter upstream of the pre-miRNA was identified. This new promoter has transcriptional activity strongly indicating that at least two promoters need to be considered for let-7c transcription: the distal host gene and the proximal intronic promoter. Therefore, epigenetic modifying enzymes and histone acetylation and methylation status were analyzed on both let-7c promoters. It was demonstrated that ATRA treatment leads to let-7c upregulation inducing a more open chromatin conformation of the host gene promoter, with an enrichment of epigenetic marks that correlate with a more active transcriptional state. Conversely, the epigenetic marks on the intronic promoter are not significantly affected by ATRA treatment. Interestingly, in solid tumors such as prostate and lung adenocarcinoma it was found that both host and intronic promoters are functional. These data suggest that while the host gene promoter may control let-7c expression in AML, in a nonleukemic tumor context instead the intronic promoter contributes or preferentially regulates let-7c transcription.. Alternative promoter usage represents a regulatory mechanism of let-7c expression in different tissues. Mol Cancer Res; 12(6); 878-89. ©2014 AACR.

Topics: Acetylation; Animals; Base Sequence; Cell Line, Tumor; Epigenomics; Gene Expression Regulation, Leukemic; Gene Expression Regulation, Neoplastic; Histones; Humans; Introns; Leukemia; Leukemia, Promyelocytic, Acute; MicroRNAs; Molecular Sequence Data; Neoplasms; Promoter Regions, Genetic; Transcription, Genetic; Transfection; Tretinoin

BORIS/CTCFL is an 11 zinc finger protein, which is the paralog of CTCF, a ubiquitously expressed protein with diverse roles in gene expression and chromatin organization. Several studies have shown that the expression of BORIS is restricted to normal adult testis, pluripotent cells, and diverse cancer cell lines. Thus, it is known as a cancer-testis (CT) gene that has been hypothesized to exhibit oncogenic properties and to be involved in cancer cell proliferation. On the contrary, other reports have shown that its expression is more widespread and can be detected in differentiated and normal somatic cells; hence, it might have roles in general cellular functions. The present study was aimed to analyze the expression of BORIS in different cell states of pluripotent, differentiated, cancerous and non-cancerous.We found that the two cell states of pluripotency and differentiation are not accompanied with significant variations of BORIS expression. Furthermore, Boris transcripts were detected at approximately the same level in cancer and non-cancer cell lines. These findings suggest that, in contrast to some previous reports, the expression of mouse BORIS is not limited to only cancerous cells or pluripotent cell states.

Topics: Animals; Base Sequence; Cell Differentiation; DNA Primers; DNA-Binding Proteins; Flow Cytometry; Humans; Mice; Neoplasms; Pluripotent Stem Cells; Polymerase Chain Reaction; RNA, Messenger; Tretinoin

Here, we report a self-assembled polymeric micellar immunomodulator (SPI) for enhanced cancer treatment based on cationic amphiphilic polymers. To obtain the cationic amphiphilic polymer, the hydrophobic all-trans-retinoic acid (ATRA) was conjugated with a hydrophilic low-molecular-weight PEI (LowPEI, Mn = 1.8 kDa). The ATRA-LowPEI conjugates could self-assemble in aqueous media, forming micelles with a strong positive charge (∼+40 mV) and particle sizes of ~70 nm. Compared to conventional therapeutic agents (e.g., cisplatin), the SPI exhibited enhanced anti-cancer activity regardless of drug resistance. After mechanistic in vitro cell death studies, we revealed that the mechanical disruptive force generated by the cationic charge of SPI primarily induced necrotic cell death. Furthermore, the organelle fragments induced by the necrotic cell death triggered antitumoral immune responses. Therefore, SPI induced synergistic effects of the cationic charge-induced necrosis and antitumoral immune responses could produce an effective cancer treatment. In addition, the SPI was shielded by hyaluronic acid (HA/SPI complex) to enhance its tumor selectivity in vivo. Finally, the HA/SPI complex accumulated selectively into tumor sites after systemic administration into tumor-bearing mice, exhibiting effective antitumoral effects without systemic toxicity. Therefore, this technology holds great potential for translation into a clinical cancer treatment.

Topics: Animals; Antineoplastic Agents; Cations; Cell Line, Tumor; Cytokines; Immunologic Factors; Mice; Mice, Inbred BALB C; Mice, Nude; Micelles; Neoplasms; Polyethyleneimine; Surface-Active Agents; Tretinoin

Targeting tumor-specific metabolic adaptations is a promising anticancer strategy when tumor defense mechanisms are restrained. Here, we show that redox-modulating drugs including the retinoid N-(4-hydroxyphenyl)retinamide (4HPR), the synthetic triterpenoid bardoxolone (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester), arsenic trioxide (As2O3), and phenylethyl isothiocyanate (PEITC), while affecting tumor cell viability, induce sustained Ser9 phosphorylation of the multifunctional kinase glycogen synthase kinase 3β (GSK3β). The antioxidant N-acetylcysteine decreased GSK3β phosphorylation and poly(ADP-ribose) polymerase cleavage induced by 4HPR, As2O3, and PEITC, implicating oxidative stress in these effects. GSK3β phosphorylation was associated with up-regulation of antioxidant enzymes, in particular heme oxygenase-1 (HO-1), and transient elevation of intracellular glutathione (GSH) in cells surviving acute stress, before occurrence of irreversible damage and death. Genetic inactivation of GSK3β or transfection with the non-phosphorylatable GSK3β-S9A mutant inhibited HO-1 induction under redox stress, while tumor cells resistant to 4HPR exhibited increased GSK3β phosphorylation, HO-1 expression, and GSH levels. The above-listed findings are consistent with a role for sustained GSK3β phosphorylation in a signaling network activating antioxidant effector mechanisms during oxidoreductive stress. These data underlie the importance of combination regimens of antitumor redox drugs with inhibitors of survival signaling to improve control of tumor development and progression and overcome chemoresistance.

Topics: Antineoplastic Agents; Apoptosis; Cell Death; Cell Line; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Gene Silencing; Glucose; Glutathione; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heme Oxygenase-1; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasms; Oxidation-Reduction; Oxidative Stress; Phosphorylation; Reactive Oxygen Species; Signal Transduction; Tretinoin

Toll-like receptor 3 (TLR3) is a key effector of the innate immune system against viruses. Activation of TLR3 exerts an antitumoral effect through a mechanism of action still poorly understood. Here we show that TLR3 activation by polyinosinic:polycytidylic acid induces up-regulation of microRNA-29b, -29c, -148b, and -152 in tumor-derived cell lines and primary tumors. In turn, these microRNAs induce reexpression of epigenetically silenced genes by targeting DNA methyltransferases. In DU145 and TRAMP-C1 prostate and MDA-MB-231 breast cancer cells, we demonstrated that polyinosinic:polycytidylic acid-mediated activation of TLR3 induces microRNAs targeting DNA methyltransferases, leading to demethylation and reexpression of the oncosuppressor retinoic acid receptor beta (RARβ). As a result, cancer cells become sensitive to retinoic acid and undergo apoptosis both in vitro and in vivo. This study provides evidence of an antitumoral mechanism of action upon TLR3 activation and the biological rationale for a combined TLR3 agonist/retinoic acid treatment of prostate and breast cancer.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Male; Mice; Mice, Nude; MicroRNAs; Neoplasms; Poly I-C; Prostatic Neoplasms; Receptors, Retinoic Acid; Reverse Transcriptase Polymerase Chain Reaction; Toll-Like Receptor 3; Tretinoin; Xenograft Model Antitumor Assays

Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)-derived splenic CD11b(+)CD8α(-)Esam(high) DCs and the developmentally related CD11b(+)CD103(+) subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC-derived CD11b(-)CD8α(+) and CD11b(-)CD103(+) nor monocyte-derived CD11b(+)CD8α(-)Esam(low) or CD11b(+)CD103(-) DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b(+)CD8α(-) subset, whereas transfer into vitamin A-deficient (VAD) hosts caused diversion to the CD11b(-)CD8α(+) lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II-restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC-derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation.

Topics: Animals; Cell Differentiation; Cell Proliferation; Cell Survival; Dendritic Cells; Female; Histocompatibility Antigens Class II; Homeostasis; Humans; Immunophenotyping; Intestinal Mucosa; Intestines; Mice; Neoplasms; Organ Specificity; Phenotype; Receptors, Retinoic Acid; Signal Transduction; Spleen; Tretinoin; Vitamin A; Whole-Body Irradiation

The objective of this investigation was aimed to explore the cancer targeting potential of folate conjugated dendrimer (polypropylene imine, PPI) under strategic influence of folate receptor up-regulators (all trans Retinoic acid, ATRA and Dexamethasone, DEXA). The folate conjugated dendrimer nanoconjugate (FPPI) was synthesized and characterized by FTIR, and (1)H-NMR spectroscopy. The cell line studies investigations were performed on MCF-7 cells. ATRA and DEXA caused 2.17 and 1.65 folds selective up-regulation of folate receptor respectively, when compared with untreated control, after 48 h of pretreatment. ATRA caused 50.47±2.11% more up regulation of folate receptor, than DEXA treated cell. Both up regulators showed a lag phase of 12 h in up-regulating the folate receptors. After 48 h, the IC50 values of naked docetaxel (DTX) and DTX loaded dendrimer (PPI-DTX) were found to be 678.93±11.99 nM and 663.51±15.23 nM, respectively, while DTX loaded folate-anchored dendrimer (FPPI-DTX) showed a selectively lowered IC50 value of 468.56±20.86 nM. FPPI-DTX further showed a significant reduction in IC50 value in ATRA and DEXA pretreated cells, wherein IC50 values of 184.21 nM and 290.40±14.05 nM, respectively were observed. The study also concludes ATRA to be a superior receptor up-regulator as well as promoter of folate based targeting compared to DEXA.

Topics: Cell Survival; Dendrimers; Dexamethasone; Erythrocytes; Folate Receptors, GPI-Anchored; Folic Acid; Hemolysis; Humans; MCF-7 Cells; Nanoparticles; Neoplasms; Polypropylenes; Tretinoin

Myeloid-derived suppressor cells (MDSCs), which accumulate during tumor progression, have been shown to function as important suppressor cells. In a previous study, we showed that immunosuppressive MDSCs could function as immunogenic antigen-presenting cells (APCs) with the help of activated natural killer T (NKT) cells. In the current study, however, we found that MDSCs harvested at a late time point after tumor injection (late MDSCs) were poorly immunogenic even when stimulated with activated NKT cells. As tumor growth progressed, the expression of MHC and costimulatory molecules on MDSCs was gradually down-regulated. Late MDSCs also had innate defects in activation and differentiation mediated by cytokine stimuli. Although late MDSCs treated only with all-trans-retinoic acid (ATRA), a stimulating agent for MDSC differentiation, could not become immunogenic, NKT ligand-loaded, ATRA-treated late MDSCs could be converted into immunogenic APCs to induce incremental immune responses. Furthermore, these effects were mediated by NKT cells secreting IFNγ, and ATRA-mediated increases in glutathione (GSH) levels. Thus, combined treatment with differentiating and activating agents is a prerequisite for the conversion of late MDSCs into immunogenic APCs. Collectively, these results suggest that combined treatments are required for the differentiation and activation of late MDSCs in late stage cancer.

Topics: Animals; Antigen Presentation; Antigen-Presenting Cells; Cell Differentiation; Cell Line, Tumor; Glutathione; Interferon-gamma; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myeloid Cells; Natural Killer T-Cells; Neoplasms; Tretinoin

Amphiphilic low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate, as a drug carrier for cancer therapy, was found to have markedly low toxicity and to form self-assembled nanoparticles for simultaneous delivery of paclitaxel (PTX) and all-trans-retinoid acid (ATRA) in our previous study. In the present study, PTX-loaded LHR nanoparticles were prepared and demonstrated a spherical shape with particle size of 108.9 nm. Cellular uptake analysis suggested rapid internalization and nuclear transport of LHR nanoparticles. In order to investigate the dynamic behaviors and targeting ability of LHR nanoparticles on tumor-bearing mice, near-infrared fluorescent (NIFR) dye DiR was encapsulated into the nanoparticles for ex vivo optical imaging. The results indicated that LHR nanoparticles could enhance the targeting and residence time in tumor site. Furthermore, in vivo biodistribution study also showed that the area under the plasma concentration time curve (AUC (0→inf)) values of PTX and ATRA for PTX-loaded LHR nanoparticles in tumor were 1.56 and 1.62-fold higher than those for PTX plus ATRA solution. Finally, PTX-loaded LHR nanoparticles demonstrated greater tumor growth inhibition effect in vivo without unexpected side effects, compared to PTX solution and PTX plus ATRA solution. These results suggest that PTX-loaded LHR nanoparticles can be considered as promising targeted delivery system for combination cancer chemotherapy to improve therapeutic efficacy and minimize adverse effects.

Topics: Animals; Cell Line, Tumor; Drug Delivery Systems; Heparin, Low-Molecular-Weight; Humans; Mice; Microscopy, Atomic Force; Microscopy, Confocal; Nanoparticles; Neoplasms; Paclitaxel; Particle Size; Tissue Distribution; Treatment Outcome; Tretinoin; Tumor Burden; Whole Body Imaging

Retinoic acid (RA) plays a role in cancer therapy. However, its long-term treatment is hindered by the acquired resistance which is not fully understood. Our previous study indicated that the transcriptional activity of RA receptor (RAR) is enhanced by association of MED25 with CREB-binding protein (CBP) through the PTOV domain, which is also present in prostate tumor over-expressed protein 1 (PTOV1). Here, we show that MED25 and PTOV1 reciprocally regulate RAR transcriptional activity through competitive bindings to CBP and opposite regulation of CBP recruitment to the RA-responsive gene promoter. Finally, we demonstrate that MED25 and PTOV1 differentially modulate RA sensitivity in cancer cells depending on their expression levels, suggesting a potential molecular mechanism underlying RA resistance which frequently emerges during cancer treatments.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Cell Line; Chromatin; Chromatin Immunoprecipitation; CREB-Binding Protein; Drug Resistance, Neoplasm; Humans; Mediator Complex; Neoplasm Proteins; Neoplasms; Receptors, Retinoic Acid; Transcriptional Activation; Tretinoin

Homeobox genes murine Rhox5 and human RHOXF1 are expressed in early embryonic stages and then mostly restricted to germline tissues in normal adult, yet they are aberrantly expressed in cancer cells in vitro and in vivo . Here we study the epigenetic regulation and potential functions of Rhox5 gene.. In Rhox5-silenced or extremely low expresser cells, we observed low levels of active histone epigenetic marks (H3ac, H4ac and H3K4me2) and high levels of repressive mark H3K9me2 along with DNA hypermethylation in the promoter. In Rhox5 low expresser cells, we typically observed modest levels of both active and repressive histone marks along with moderate DNA methylation. In Rhox5 highly expressed CT26 cancer cells, we observed DNA hypomethylation along with high levels of both active and repressive histone marks. Epigenetic drugs (retinoic acid and MS-275) induced F9 cell differentiation with enhanced Rhox5 expression and dynamic changes of epigenetic marks. Finally, Rhox5 knockdown by small hairpin RNA (shRNA) in CT26 colon cancer decreased cell proliferation and migration in vitro and tumor growth in vivo .. Both DNA methylation and histone methylation/acetylation play key roles in modulating Rhox5 expression in various cell types. The stem cell-like "bivalent domain", an epigenetic feature originally identified in key differentiation genes within stem cells, exists in the Rhox5 gene promoter in not only embryonic stem cells but also cancer cells, cancer stem cells, and differentiated Sertoli cells. As Ras signaling-dependent Rhox5 expression promotes tumor growth, Rhox5 may be an ideal target for therapeutic intervention in cancer.

Topics: Animals; Benzamides; Cell Differentiation; Cell Line, Tumor; Cell Movement; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histones; Homeodomain Proteins; Humans; Methylation; Mice; Mice, Nude; Neoplasms; Promoter Regions, Genetic; Pyridines; RNA, Messenger; Stem Cells; Transcription Factors; Tretinoin; Tumor Burden; Xenograft Model Antitumor Assays

A novel furocoumarin derivative named oxyalloimperatorin (1), together with seventeen furocoumarins 2-18 were isolated from the radix of Angelica dahurica. The chemical structure of new metabolite was characterized by analysis of IR, NMR, and HR-ESI-MS spectroscopic data. Among the isolated compounds, 13, 16, and 18 (each at 20 μM) could significantly promote the gene transcriptional function of nuclear receptor RXRα. While 7-9, 13, 14, and the new structure 1 (each at 20 μM) showed significant reduction in RXRα gene transcriptional activities induced by 9-cis-retinoid acid. The findings indicated that these furocoumarin skeleton derivatives might hold beneficial effects on many intractable diseases, such as cancer and metabolic diseases, due to their potential activities on regulating the transcriptional activation function of RXRα.

Topics: Acetates; Alitretinoin; Angelica; Diabetes Mellitus; Furocoumarins; Gene Expression; Genes, Reporter; HEK293 Cells; Humans; Luciferases; Magnetic Resonance Spectroscopy; Mass Spectrometry; Neoplasms; Plant Extracts; Plant Roots; Plasmids; Retinoid X Receptor alpha; Transcriptional Activation; Transfection; Tretinoin

We have recently isolated novel IFN-inducible gene, Gene associated with Retinoid-Interferon-induced Mortality-1 (GRIM-1), using a genetic technique. Moderate ectopic expression of GRIM-1 caused growth inhibition and sensitized cells to retinoic acid (RA)/IFN-induced cell death while high expression caused apoptosis. GRIM-1 depletion, using RNAi, conferred a growth advantage. Three protein isoforms (1α, 1β and 1γ) with identical C-termini are produced from GRIM-1 mRNA. We show that GRIM-1 isoforms interact with NAF1 and DKC1, two essential proteins required for box H/ACA sno/sca RNP biogenesis and suppresses box H/ACA RNA levels in mammalian cells by delocalizing NAF1. Suppression of these small RNAs manifests as inefficient rRNA maturation and growth suppression. Interestingly, yeast Shq1p also caused growth suppression in mammalian cells. Consistent with its growth-suppressive property, GRIM-1 expression is lost in a number of human primary prostate tumors. Our observations support a recent study that GRIM-1 might act as a co-tumor suppressor in the prostate.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Cell Cycle Proteins; Cell Growth Processes; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Immunohistochemistry; Interferon-beta; Male; Neoplasms; Nuclear Proteins; Prostatic Neoplasms; Protein Binding; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleoproteins; RNA, Ribosomal; RNA, Small Nucleolar; RNA, Small Untranslated; Saccharomyces cerevisiae Proteins; Tretinoin

Vitamin A deficiency (VAD) is associated with increased susceptibility to carcinogenesis in animal models and elevated risk for a number of human cancers. Here, we found that CYP26A1, the gene encoding a cytochrome P450 enzyme specifically involved in metabolic inactivation of retinoic acid (RA), the most active vitamin A derivative, is highly expressed in 42% (27/65) of primary breast cancers. We also showed that enhanced expression of CYP26A1 suppresses cellular responses to anoikis and consequently promotes anchorage-independent growth. This transformed phenotype was sufficient to markedly increase tumorigenic and metastatic potential. Suppression of CYP26A1 significantly reversed the CYP26A1-mediated oncogenic characteristics, suggesting a direct link between intracellular RA status and tumorigenicity. Our observations provide strong evidence for oncogenic and cell survival properties of CYP26A1 in carcinogenesis, and suggest mechanisms whereby VAD might promote cancer development.

Topics: Animals; Anoikis; Breast Neoplasms; Carcinogenicity Tests; Carcinogens; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cytochrome P-450 Enzyme System; Disease Models, Animal; Drug Interactions; Gene Expression Profiling; Humans; Mice; Mice, Knockout; Neoplasms; Retinoic Acid 4-Hydroxylase; Reverse Transcriptase Polymerase Chain Reaction; Tretinoin; Tumor Cells, Cultured; Vitamin A; Vitamin A Deficiency

Macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15), a divergent member of the TGF-beta superfamily is induced by a range of proinflammatory cytokines and oxidized low-density lipoprotein (oxLDL) and is highly expressed in macrophages in atherosclerotic and tumor lesions. MIC-1/GDF15, a major p53 target gene, is largely described to have anti-tumorigenic activity and more recently high MIC-1/GDF15 serum levels in late stage cancer were shown to be the major cause of cancer-associated weight loss. MIC-1/GDF15 serum levels independently predict both atherosclerotic events and severity of rheumatoid arthritis (RA), suggesting serum levels are important in modifying disease expression. Controlling serum levels is the ratio of latent unprocessed MIC-1/GDF15 stromal stores to soluble mature MIC-1/GDF15 generated by the cell. Here, we investigate MIC-1/GDF15 secretion from U937 monocytoid cells and identify novel mechanisms designed to ensure secretion of unprocessed cytokine and creation of latent stromal stores. We find that endogenous MIC-1/GDF15 is secreted as both processed and unprocessed forms. Pulse chase analysis of MIC-1/GDF15 secretion reveals that unprocessed MIC-1/GDF15 precursor is rapidly secreted, while mature MIC-1/GDF15 generated within the cell by intracellular processing is secreted much slower, possibly via an alternate secretory route. The COOH-T 47 amino acids of the propeptide are responsible for rapid secretion of MIC-1/GDF15 precursor and this effect occurs in the trans-Golgi network (TGN)/post TGN compartment. Thus, variations in MIC-1/GDF15 intracellular processing, regulating the presence or absence of propeptide, are a powerful mechanism modulating rate of MIC-1/GDF15 secretion and proMIC-1/GDF15 stromal storage, with major impact on circulating levels of mature MIC-1/GDF15.

Topics: Arthritis, Rheumatoid; Atherosclerosis; Cell Differentiation; Cell Hypoxia; Cloning, Molecular; Cobalt; Growth Differentiation Factor 15; Humans; Immunization; Lipopolysaccharides; Macrophages; Neoplasms; Protein Processing, Post-Translational; Secretory Pathway; Transforming Growth Factor beta; Transgenes; Tretinoin; U937 Cells

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Oxides; Prognosis; Tretinoin

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their anticancer effects through cyclooxygenase-2 (COX-2)-dependent and independent mechanisms. Here, we report that Sulindac, an NSAID, induces apoptosis by binding to retinoid X receptor-alpha (RXRalpha). We identified an N-terminally truncated RXRalpha (tRXRalpha) in several cancer cell lines and primary tumors, which interacted with the p85alpha subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-alpha (TNFalpha) promoted tRXRalpha interaction with the p85alpha, activating PI3K/AKT signaling. When combined with TNFalpha, Sulindac inhibited TNFalpha-induced tRXRalpha/p85alpha interaction, leading to activation of the death receptor-mediated apoptotic pathway. We designed and synthesized a Sulindac analog K-80003, which has increased affinity to RXRalpha but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRalpha-dependent AKT activation and tRXRalpha tumor growth in animals.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; bcl-2-Associated X Protein; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytoplasm; Dinoprostone; Drug Design; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Molecular; Neoplasms; Phosphatidylinositol 3-Kinases; Prostaglandin-Endoperoxide Synthases; Protein Binding; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Retinoid X Receptor alpha; Sequence Deletion; Signal Transduction; Sulindac; Transcriptional Activation; Transfection; Tretinoin; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

We describe here the syntheses and the biological properties of new alkylaminooxysterols. Compounds were synthesized through the trans-diaxial aminolysis of 5,6-alpha-epoxysterols with various natural amines including histamine, putrescine, spermidine, or spermine. The regioselective synthesis of these 16 new 5alpha-hydroxyl-6beta-aminoalkylsterols is presented. Compounds were first screened for dendrite outgrowth and cytotoxicity in vitro, and two leads were selected and further characterized. 5alpha-Hydroxy-6beta-[2-(1H-imidazol-4-yl)ethylamino]cholestan-3beta-ol, called dendrogenin A, induced growth control, differentiation, and the death of tumor cell lines representative of various cancers including metastatic melanoma and breast cancer. 5alpha-Hydroxy-6beta-[3-(4-aminobutylamino)propylamino]cholest-7-en-3beta-ol, called dendrogenin B, induced neurite outgrowth on various cell lines, neuronal differentiation in pluripotent cells, and survival of normal neurones at nanomolar concentrations. In summary, we report that two new alkylaminooxysterols, dendrogenin A and dendrogenin B, are the first members of a class of compounds that induce cell differentiation at nanomolar concentrations and represent promising new leads for the treatment of cancer or neurodegenerative diseases.

Topics: Amines; Animals; Cell Differentiation; Cell Line, Tumor; Cell Survival; Cholestanols; Dendrites; Drug Discovery; Humans; Mice; Neoplasms; Neurodegenerative Diseases; Spermidine; Stereoisomerism; Sterols

Retinoids have significant clinical activity in several human cancers, yet the factors determining retinoid sensitivity in cancer cells are still unclear. Retinoid-induced expression of retinoic acid receptor (RAR) beta(2) is a necessary component of the retinoid anticancer signal in cancer cells. We have previously identified the Estrogen-responsive B Box Protein (EBBP), a member of the Tripartite Motif (TRIM) protein family, as a novel RARbeta2 transcriptional regulator in the retinoid signal. Here we examined the mechanism of the EBBP effect on the retinoid anticancer signal. We assessed retinoid-responsive RARbeta2 transcription in retinoid-resistant breast and lung cancer cells in the presence of chromatin modifying agents. A histone deacetylase (HDAC) inhibitor alone, or in combination with retinoid, was more effective than a demethylating agent in restoring RARbeta2 transcription in resistant cells. Overexpression of EBBP alone markedly increased histone acetylation. The effect of EBBP on retinoid-responsive transcription appeared to be limited to genes with the retinoic acid response element (betaRARE) regulatory sequence, such as CYP26A1. EBBP inhibited cell growth by effects on cyclin D1 and Phospho-Rb, and, reduced cell viability in retinoid-resistant cancer cells. The viability of non-cancer cells was unaffected by EBBP overexpression. Taken together our data suggests that EBBP acts to de-repress transcription of RARbeta2 and CYP26A1, by modifying histone acetylation in retinoid-resistant cancer cells, and, is an important target for drug discovery in retinoid-resistant cancers.

Topics: Acetylation; Apoptosis; Cell Line, Tumor; Cell Survival; Cyclin D1; Cytochrome P-450 Enzyme System; DNA-Binding Proteins; Drug Resistance, Neoplasm; Histones; Humans; Neoplasms; Phosphorylation; Receptors, Retinoic Acid; Retinoblastoma Protein; Retinoic Acid 4-Hydroxylase; Transcription Factors; Tretinoin; Tripartite Motif Proteins; Ubiquitin-Protein Ligases

Experimental data from in vitro and in vivo models indicate that peroxisome proliferator-activated receptor (PPAR) ligand activation regulates differentiation and induces cell growth arrest and apoptosis in a variety of cancer types. Thiazolidinediones such as ciglitazone (CGZ) constitute the most well-known synthetic ligands for PPARgamma. We previously reported a remarkable antitumor effect of the retinoid 6-OH-11-O-hydroxyphenantrene (IIF), synthetic retinoid X receptors (RXRs) agonist, on many cancer cell lines. Since PPARs bind to DNA as heterodimers with RXRs, in this study we investigated if IIF potentiates the antitumoral properties of the PPARgamma ligand CGZ in glioblastoma U87MG and melanoma G361 cells. Our results show that either IIF or CGZ inhibited cell growth and tissue invasion ability, but these properties were enhanced by using IIF and CGZ in combined treatment. Since matrix metalloproteinases (MMPs) play a major role in tumor cell invasion, we analyzed the effect of IIF and CGZ on MMP2 and MMP9 activity and expression. The addition of IIF to CGZ resulted in a decrease of MMP2 and MMP9 expression and activity, higher than when each agent was used alone. Furthermore, treatment with IIF and/or CGZ enhanced PPARgamma expression but both agents in combined treatment caused the maximum efficiency. Finally, we demonstrated that IIF can potentiate PPARgamma trascriptional activity induced by CGZ, by evaluation of peroxisome proliferator-responsive element transactivation. In conclusion, these findings suggest that the RXR selective retinoid IIF, in combination with the PPARgamma ligand CGZ, may provide a therapeutic advantage in cancer treatment.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Drug Synergism; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasms; PPAR gamma; Retinoid X Receptors; Thiazolidinediones; Tretinoin

Attempts to prepare substituted chromones as novel retinoids revealed that some chromones were unstable under Wadsworth-Horner-Emmons reaction conditions. Hence, Wittig reactions were used to prepare chromone-based compounds as potential retinoids. Firstly, Wittig reagents prepared from 3-bromomethyl-chromen-4-one were reacted with olefinic-aldehydes to provide the target compounds with all-trans side chains in good yield. The approach supplies a useful general route to structurally diverse chromone-based compounds possessing a variety of side chains. Sequential Wittig reactions were used also to prepare a chromone-based retinoid. These novel compounds were evaluated in binding assays and a high affinity RAR ligand was identified. Crystal structures obtained for two key precursors aided the interpretation of binding data.

Topics: Aldehydes; Alitretinoin; Alkenes; Antineoplastic Agents; Cell Proliferation; Chemistry, Pharmaceutical; Drug Design; Humans; Ligands; Models, Chemical; Molecular Conformation; Molecular Structure; Neoplasms; Retinoids; Tretinoin

Epigenetic silencing of genes in association with aberrant promoter DNA hypermethylation has emerged as a significant mechanism in the development of human cancers. Such genes are also often targets of the polycomb group repressive complexes in embryonic cells. The polycomb repressive complex 2 (PRC2) has been best studied in this regard. We now examine a link between PRC1 and cancer-specific gene silencing. Here, we show a novel and direct association between a constituent of the PRC1 complex, CBX7, with gene repression and promoter DNA hypermethylation of genes frequently silenced in cancer. CBX7 is able to complex with DNA methyltransferase (DNMT) enzymes, leading us to explore a role for CBX7 in maintenance and initiation of gene silencing. Knockdown of CBX7 was unable to relieve suppression of deeply silenced genes in cancer cells; however, in embryonal carcinoma (EC) cells, CBX7 can initiate stable repression of genes that are frequently silenced in adult cancers. Furthermore, we are able to observe assembly of DNMTs at CBX7 target gene promoters. Sustained expression of CBX7 in EC cells confers a growth advantage and resistance to retinoic acid-induced differentiation. In this setting, especially, there is increased promoter DNA hypermethylation for many genes by analysis of specific genes, as well as through epigenomic studies. Our results allow us to propose a potential mechanism through assembly of novel repressive complexes, by which the polycomb component of PRC1 can promote the initiation of epigenetic changes involving abnormal DNA hypermethylation of genes frequently silenced in adult cancers.

Topics: Antineoplastic Agents; Cell Differentiation; Cell Line, Tumor; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; DNA Methyltransferase 3B; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Neoplasms; Polycomb Repressive Complex 1; Promoter Regions, Genetic; Repressor Proteins; Tretinoin

(E)-4-[3-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell-cycle arrest and apoptosis of leukemia and cancer cells. Studies demonstrated that 3-Cl-AHPC bound to the atypical orphan nuclear receptor small heterodimer partner (SHP). Although missing a DNA-binding domain, SHP heterodimerizes with the ligand-binding domains of other nuclear receptors to repress their abilities to induce or inhibit gene expression. 3-Cl-AHPC analogues having the 1-adamantyl and phenolic hydroxyl pharmacophoric elements replaced with isosteric groups were designed, synthesized, and evaluated for their inhibition of proliferation and induction of human cancer cell apoptosis. Structure-anticancer activity relationship studies indicated the importance of both groups to apoptotic activity. Docking of 3-Cl-AHPC and its analogues to an SHP computational model that was based on the crystal structure of ultraspiracle complexed with 1-stearoyl-2-palmitoylglycero-3-phosphoethanolamine suggested why these 3-Cl-AHPC groups could influence SHP activity. Inhibitory activity against Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp-2) was also assessed. The most active Shp-2 inhibitor was found to be the 3'-(3,3-dimethylbutynyl) analogue of 3-Cl-AHPC.

Topics: Adamantane; Antineoplastic Agents; Apoptosis; Cell Division; Cell Line, Tumor; Cinnamates; Dimerization; Enzyme Inhibitors; Humans; Models, Molecular; Neoplasms; Protein Tyrosine Phosphatase, Non-Receptor Type 11

The present study is aimed at developing and evaluating a combined strategy of dual drug delivery, receptor up-regulation, and drug targeting. The dendritic architectures were synthesized and characterized by IR, (1)H-NMR, and (13)C-NMR spectroscopy. The pH-responsive simultaneous release behavior of the loaded bioactive from the carrier was also explored. The cell line studies for MTT cytotoxicity, receptor blockade, and receptor up-regulation assays were performed on HeLa cells. Treatment of cells with low concentration of all-trans retinoic acid (ATRA, approximately 1 microM) caused a selective up-regulation of folate receptors by 2.21-folds when compared with that of untreated control, after 48 h. ATRA showed a lag phase of 12 h in up-regulating the folate receptors. After 48 h, the IC(50) value of naked methotrexate (MTX)-ATRA combination and dendrimer-loaded MTX-ATRA combination were found to be approximately 0.1 and 10 microM, respectively, while folate-anchored dendrimer loaded with MTX-ATRA showed a selectively lowered IC(50) value of 0.04 microM. It was concluded that in allied ailments like cancer, the proposed dual-drug delivery modality bearing anti-cancer bioactive in conjunction with folate receptor up-regulating cargo may prove to be a promising approach toward the development of a flourishing cancer therapy.

Topics: Antineoplastic Agents; Carrier Proteins; Dendrimers; Dose-Response Relationship, Drug; Drug Delivery Systems; Folate Receptors, GPI-Anchored; HeLa Cells; Humans; Methotrexate; Molecular Structure; Neoplasms; Receptors, Cell Surface; Tretinoin; Up-Regulation

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Topics: Animals; Cell Survival; Cells, Cultured; Mice; Molecular Structure; Neoplasms; Neurons; Pharmaceutical Preparations; Sensitivity and Specificity; Stem Cells

Combination of retinoic acids (RAs) and interferons (IFNs) has synergistic apoptotic effects and is used in cancer treatment. However, the underlying mechanisms remain unknown. Here, we demonstrate that mitochondrial respiratory chain (MRC) plays an essential role in the IFN-beta/RA-induced cancer cell death. We found that IFN-beta/RA upregulates the expression of MRC complex subunits. Mitochondrial-nuclear translocation of these subunits was not observed, but overproduction of reactive oxygen species (ROS), which causes loss of mitochondrial function, was detected upon IFN-beta/RA treatment. Knockdown of GRIM-19 (gene associated with retinoid-interferon-induced mortality-19) and NDUFS3 (NADH dehydrogenase (ubiquinone) Fe-S protein 3), two subunits of MRC complex I, by siRNA in two cancer cell lines conferred resistance to IFN-beta/RA-induced apoptosis and reduced ROS production. In parallel, expression of late genes induced by IFN-beta/RA that are directly involved in growth inhibition and cell death was also repressed in the knockdown cells. Our data suggest that the MRC regulates IFN-beta/RA-induced cell death by modulating ROS production and late gene expression.

Topics: Apoptosis Regulatory Proteins; Cell Death; Cell Nucleus; Cytoplasm; Drug Synergism; Electron Transport; Electron Transport Complex I; Gene Expression; HeLa Cells; Humans; Interferon-beta; Mitochondria; Models, Biological; NADH Dehydrogenase; NADH, NADPH Oxidoreductases; Neoplasms; Protein Subunits; Protein Transport; Reactive Oxygen Species; Signal Transduction; Tretinoin; Up-Regulation

Topics: Antineoplastic Agents; Cell Differentiation; Cell Division; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Spiro Compounds; Tretinoin

NK cell receptors (NKRs) modulate T lymphocyte responses by modifying the Ag activation threshold. However, what governs their expression on T cells remains unclear. In this study we show that different NKRs are imprinted on CD8 T cells in the gut mucosa and periphery during the same Ag challenge. After a viral, bacterial, and tumor challenge, most CD8 peritoneal exudate lymphocytes expressed NKG2A but not 2B4. In contrast, most CD8 intraepithelial lymphocytes exhibited 2B4 but not NKG2A. Our data suggest that tissue-specific factors may determine the pattern of NKR expression. In the gut, CD70 licensing appears to promote 2B4 induction on mucosal CD8 T cells. Conversely, retinoic acid produced by the intestinal dendritic cells may suppress NKG2A expression. Thus, tissue-specific factors regulate NKR expression and may confer T cells with differing effector functions in a tissue and site-specific manner.

Topics: Animals; Antigens; CD27 Ligand; CD8-Positive T-Lymphocytes; Down-Regulation; Immunity, Mucosal; Intestines; Killer Cells, Natural; Mice; Mice, Inbred C57BL; Mucous Membrane; Neoplasms; NK Cell Lectin-Like Receptor Subfamily C; Organ Specificity; Receptors, Immunologic; Receptors, Natural Killer Cell; Tretinoin

This review highlights the relevance of the neural crest (NC) as a developmental control mechanism involved in several pediatric surgical conditions and the investigative interest of following some of its known signaling pathways.. The participation of the NC in facial clefts, ear defects, branchial fistulae and cysts, heart outflow tract and aortic arch anomalies, pigmentary disorders, abnormal enteric innervation, neural tumors, hemangiomas, and vascular anomalies is briefly reviewed. Then, the literature on clinical and experimental esophageal atresia-tracheoesophageal fistula (EA-TEF) and congenital diaphragmatic hernia (CDH) is reviewed for the presence of associated NC defects. Finally, some of the molecular signaling pathways involved in both conditions (sonic hedgehog, Hox genes, and retinoids) are summarized.. The association of facial, cardiovascular, thymic, parathyroid, and C-cell defects together with anomalies of extrinsic and intrinsic esophageal innervation in babies and/or animals with both EA-TEF and CDH strongly supports the hypothesis that NC is involved in the pathogenesis of these malformative clusters. On the other hand, both EA-TEF and CDH are observed in mice mutant for genes involved in the previously mentioned signaling pathways.. The investigation of NC-related molecular pathogenic pathways involved in malformative associations like EA-TEF and CDH that are induced by chromosomal anomalies, chemical teratogens, and engineered mutations is a promising way of clarifying why and how some pediatric surgical conditions occur. Pediatric surgeons should be actively involved in these investigations.

Topics: Abnormalities, Multiple; Blood Vessels; Branchial Region; Cardiovascular Abnormalities; Cell Lineage; Cell Movement; Child; Child, Preschool; Enteric Nervous System; Esophageal Atresia; Face; Genes, Homeobox; Hedgehog Proteins; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Homeodomain Proteins; Humans; Infant; Infant, Newborn; Neoplasms; Neural Crest; Patched Receptors; Pigmentation Disorders; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Retinoic Acid; Signal Transduction; Smoothened Receptor; Syndrome; Transcription Factors; Tretinoin; Zinc Finger Protein GLI1

Myeloid-derived suppressor cells (MDSC) play an important role in tumor escape by suppressing T-cell responses. MDSC represent a group of cells of myeloid lineage at different stages of differentiation. Increased arginase activity and production of reactive oxygen species (ROS) are among the main functional characteristics of these cells. Recent studies have shown that all-trans retinoic acid (ATRA) had a potent activity in eliminating MDSC in cancer patients and in tumor-bearing mice. ATRA differentiates these cells into mature myeloid cells. However, the mechanism of this effect is unclear. Here, we have shown that ATRA dramatically and specifically up-regulated gene expression and protein level of glutathione synthase (GSS) in MDSC. This resulted in accumulation of glutathione (GSH) in these cells, observed in both mice and cancer patients. Blockade of GSH synthesis cancelled the effect of ATRA on MDSC. Accumulation of GSH in these cells using N-acetyl-L-cysteine mimicked the effect of ATRA on MDSC differentiation. Analysis of potential mechanisms of ATRA effect on GSS revealed that ATRA regulates its expression not by directly binding to the promoter but primarily via activation of extracellular signal-regulated kinase 1/2. Thus, ATRA induced differentiation of MDSC primarily via neutralization of high ROS production in these cells. This novel mechanism involves specific up-regulation of GSS and accumulation of GSH and could be used in developing and monitoring therapeutic application of ATRA.

Topics: Animals; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myeloid Cells; Neoplasm Transplantation; Neoplasms; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Reactive Oxygen Species; Tretinoin

Isothiocyanates and phenolic antioxidants can prevent cancer through activation of Nrf2 (NF-E2 p45-related factor 2), a transcription factor that controls expression of cytoprotective genes through the antioxidant response element (ARE) enhancer. Using a human mammary MCF7-derived AREc32 reporter cell line, we now report that all-trans retinoic acid (ATRA), and other retinoic acid receptor alpha (RARalpha) agonists, markedly reduces the ability of Nrf2 to mediate induction of ARE-driven genes by cancer chemopreventive agents including the metabolite of butylated hydroxyanisole, tert-butylhydroquinone (tBHQ). The basal and tBHQ-inducible expression of aldo-keto reductase (AKR) AKR1C1 and AKR1C2 genes, which are regulated by Nrf2, was also repressed by ATRA in AREc32 cells. Antagonists of RARalpha augmented induction of ARE-driven gene expression by tBHQ, as did knockdown of RARalpha by using RNAi. The expression of the ARE-gene battery was increased in the small intestine of mice fed on a vitamin A-deficient diet, and this increase was repressed by administration of ATRA. By contrast, in the small intestine of Nrf2 null mice, the expression of ARE-driven genes was not affected by vitamin A status. In MCF7 cells, ATRA did not block the nuclear accumulation of Nrf2 but reduced the binding of Nrf2 to the ARE enhancer as a consequence of forming a complex with RARalpha. These data suggest that cross-talk between Nrf2 and RARalpha could markedly influence the sensitivity of cells to electrophiles and oxidative stressors and, as a consequence, to carcinogenesis.

Topics: 20-Hydroxysteroid Dehydrogenases; Animals; Antineoplastic Agents; Antioxidants; Cell Line, Tumor; Cell Nucleus; Chemoprevention; Enhancer Elements, Genetic; Gene Expression; Humans; Hydroquinones; Hydroxysteroid Dehydrogenases; Luciferases; Mice; Mice, Mutant Strains; Neoplasms; NF-E2 Transcription Factor, p45 Subunit; Receptors, Retinoic Acid; Response Elements; Retinoic Acid Receptor alpha; Tretinoin

Elevated telomerase activity is an important molecular signature of cancer cells and primitive cells in regenerative tissues. However, isolation of single living cells with endogenous telomerase activity has not yet been possible. Here, we developed adenovirus serotype 35 tropism-based vectors encoding destabilized enhanced green fluorescence protein with a half-life of 2 h (d2EGFP) driven by the human telomerase reverse transcriptase (hTERT) promoter. As assessed in telomerase-positive or -negative cell lines, the d2EGFP expression positively correlated with hTERT transcript content and telomerase activity. In retinoic acid-induced differentiating HL-60 cells, the d2EGFP expression is diminished in the same manner as the hTERT expression. Individual cells from HeLa and HL-60 cell lines exhibited heterogeneous d2EGFP expression, which was cell cycle dependent, as the sorted d2EGFP+ HL-60 cells contained twice as many cells in S/G2/M phase of the cell cycle compared with the d2EGFP- HL-60 cells. However, both cell populations exhibited the same proliferation and regeneration capacities. Heterogeneous d2EGFP expression was also detected in xenograft glioblastoma multiforme cells with tumor formation capacity. Thus, d2EGFP expression reported cell cycle- and differentiation stage-dependent hTERT expression. Our study facilitates isolation and characterization of single living cells with telomerase activity.

Topics: Adenoviridae; Animals; Cell Cycle; Cell Differentiation; Cell Line; Cell Line, Tumor; Cells, Cultured; DNA-Binding Proteins; Gene Expression Regulation, Enzymologic; Genetic Therapy; Genetic Vectors; Green Fluorescent Proteins; HeLa Cells; HL-60 Cells; Humans; K562 Cells; Mice; Mice, SCID; Models, Genetic; Neoplasms; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Telomerase; Tretinoin; Xenograft Model Antitumor Assays

Occludin is the first identified integral protein for the tight junction (TJ), and its long COOH-terminal domain is considered to have functions in receiving and transmitting cell survival signals. Loss of TJ-associated molecules, such as occludin, has been correlated with tumor progression in carcinogenesis; however, the precise molecular mechanisms explaining its loss of expression and whether occludin expression has any effects on cancer phenotypes remain to be clarified. Here, we show that forced expression of occludin in cancer cells exhibits enhanced sensitivity to differently acting apoptogenic factors, and thus inhibits the tumorigenicity of transformed cells, via modulation of unique sets of apoptosis-associated genes. In addition, studies using deletion mutants of occludin constructs show that 44 amino acids at the COOH-terminal end play a critical role in modifying the cellular phenotypes. Interestingly, occludin decreases cellular invasiveness and motility, thereby abrogating metastatic potencies of cancer cells. We also found that occludin expression is silenced by CpG island hypermethylation on its promoter region. Synergy with a demethylator and histone deacetylase inhibitor or retinoids that stimulate retinoic acid receptor alpha induces endogenous occludin, which is sufficient for apoptotic sensitization. Our results show the functional diversity of occludin and suggest that methylator phenotype of occludin provides enhanced tumorigenic, invasive, and metastatic properties of cancer cells, identifying occludin as a likely candidate for a tumor-suppressor gene in certain types of cancer.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Female; Gene Silencing; Genes, Tumor Suppressor; HeLa Cells; Humans; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Neoplasms; Occludin; Rats; RNA, Messenger; Signal Transduction; Transfection; Tretinoin

The 10th International Conference on Differentiation Therapy was held between April 29 and May 3, 2004, in Shanghai, China. In the tradition of previous conferences from this series, which have been held biannually since the first meeting organized 20 years ago by Samuel Waxman and Giovanni Rossi in Sardinia, the organizers of the 10th International Conference on Differentiation Therapy aimed to gather basic and clinical cancer investigators in a setting of plenary sessions, workshops, and poster presentations to maximize the effective exchange of information and foster the establishment of collaborative interactions. Approximately 300 scientists attended the meeting with a mission to discuss targeted approaches to cancer treatment, which stem from our understanding of basic biological processes and the mechanisms of their deregulation during tumorigenesis.

Topics: Apoptosis; Cell Differentiation; Clinical Trials as Topic; Humans; Neoplasms; Tretinoin

Most human cancers express telomerase but its activity is highly variable and regulated by complex mechanisms. Recently, several studies have suggested that retinoic acid (RA) downregulates telomerase activity and that this effect could be a major determinant of its therapeutic activity. To elucidate possible mechanisms of RA-mediated downmodulation of telomerase activity, we measured the kinetics of concentration changes of several transcription regulators by using standard biochemical techniques at low (10 muM) and high (100 muM) RA concentrations. We further evaluated the global impact of the RA treatment on gene expression profiles using microarray. It was found that the kinetics of c-Myc correlates most closely with the telomerase activity suggesting in agreement with previous studies that this protein is a major intermediate of the RA-induced downregulation of telomerase activity. Other telomerase regulators as Sp1 and Mad1 did not exhibit significant correlation. The dominant role of c-Myc in RA-induced telomerase downmodulation is confirmed by microarray data. Additionally, a number of proteins were found as possible correlates of telomerase activity by microarray analysis. These data suggest a complex interplay between c-Myc and other proteins that may be important determinants of the RA effects on telomerase activity in human cancer cells. The complex mechanism through which telomerase activity is controlled during differentiation and cancer transformation is also reflected.

Topics: Cell Line, Tumor; DNA-Binding Proteins; Down-Regulation; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Male; Neoplasms; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Telomerase; Transcription Factors; Tretinoin

Topics: Alcohol Dehydrogenase; Aldehyde Dehydrogenase; Animals; Bacteria; Breast Neoplasms; Carcinogenicity Tests; Cell Transformation, Neoplastic; Ethanol; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Inactivation, Metabolic; Neoplasms; Polymorphism, Genetic; Rats; Tretinoin

Retinoidal gamma-hydroxybutenolides 2a-d having various lengths of conjugated double bond were prepared in three steps from the corresponding aldehyde 4. Their biological activities were then measured. Of these compounds, only compound 2c possessing a structure similar to that of retinoic acid showed differentiation-inducing activity and very strong apoptosis-inducing activity in HL-60 cells.

Topics: 4-Butyrolactone; Apoptosis; Cell Differentiation; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Hydrogen; Molecular Structure; Neoplasms; Transcription, Genetic; Tretinoin

The differentiating properties of retinoic acid (RA) have been used beneficially for the treatment of Acute Promyelocytic Leukemia (APL) for more than a decade. However, the molecular mechanisms of how RA induces APL cell differentiation are still poorly understood. In our previous work, we provided a novel mechanism to explain the unique sensitivity to RA of APL cells. We proposed that C/EBPbeta is an ATRA-dependent PML/RARA target gene and that its activation is critical during ATRA-induced differentiation of APL cells. Here, I discuss how C/EBPbeta could be an important gene in APL pathogenesis.

Topics: CCAAT-Enhancer-Binding Protein-beta; Cell Cycle; Cell Differentiation; Cyclic AMP; Enzyme Activation; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Signal Transduction; Transcriptional Activation; Tretinoin

E-selectin mediated tumor cell adhesion plays an important role in metastasis. Here we show that ionizing radiation (IR) induces E-selectin gene and protein expression in human endothelial cells at therapeutically relevant dose level. E-selectin expression is accompanied by an increase in the adhesion of human colon carcinoma cells to primary human umbilical vein endothelial cells (HUVEC). The HMG-CoA reductase inhibitor lovastatin impairs IR-stimulated E-selectin expression as analyzed at the level of the protein, mRNA and promoter. Inactivation of Rho GTPases either by use of Clostridium difficile toxin A or by co-expression of dominant-negative Rho blocked IR-induced E-selectin gene induction, indicating Rho GTPases to be essential. Radiation-induced expression of E-selectin was also blocked by all-trans retinoic acid (at-RA), whereas 9-cis retinoic acid was ineffective. Abrogation of IR-stimulated E-selectin expression by lovastatin and at-RA reduced tumor cell adhesion in a dose-dependent manner. Combined treatment with lovastatin and at-RA exerted additive inhibitory effects on radiation-induced E-selectin expression and tumor cell adhesion. Therefore, application of statins and at-RA might have clinical impact in protecting against E-selectin-promoted metastasis, which might arise as an unwanted side effect from radiation treatment.

Topics: Blotting, Western; Cell Adhesion; Cell Line, Tumor; Cells, Cultured; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; E-Selectin; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Adhesion Molecule-1; Lovastatin; Neoplasms; NF-kappa B; Promoter Regions, Genetic; Radiation, Ionizing; Reverse Transcriptase Polymerase Chain Reaction; rho GTP-Binding Proteins; RNA, Messenger; Transcriptional Activation; Tretinoin; Tumor Necrosis Factor-alpha

A variety of tumor suppressor genes are down-regulated by hypermethylation during carcinogenesis. Using methylated CpG amplification-representation difference analysis, we identified a DNA fragment corresponding to the Tazarotene-induced gene 1 (TIG1) promoter-associated CpG island as one of the genes hypermethylated in the leukemia cell line K562. Because TIG1 has been proposed to act as a tumor suppressor, we tested the hypothesis that cytosine methylation of the TIG1 promoter suppresses its expression and causes a loss of responsiveness to retinoic acid in some neoplastic cells. We examined TIG1 methylation and expression status in 53 human cancer cell lines and 74 primary tumors, including leukemia and head and neck, breast, colon, skin, brain, lung, and prostate cancer. Loss of TIG1 expression was strongly associated with TIG1 promoter hypermethylation (P < 0.001). There was no correlation between TIG1 promoter methylation and that of retinoid acid receptor beta2 (RARbeta2), another retinoic-induced putative tumor suppressor gene (P = 0.78). Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine for 5 days restored TIG1 expression in all eight silenced cell lines tested. TIG1 expression was also inducible by treatment with 1 micro M all-trans-retinoic acid for 3 days except in densely methylated cell lines. Treatment of the K562 leukemia cells with demethylating agent combined with all-trans-retinoic acid induced apoptosis. These findings indicate that silencing of TIG1 promoter by hypermethylation is common in human cancers and may contribute to the loss of retinoic acid responsiveness in some neoplastic cells.

Topics: Antineoplastic Agents; Azacitidine; Cell Division; Cell Line, Tumor; Decitabine; DNA Methylation; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, Tumor Suppressor; Humans; Membrane Proteins; Neoplasms; Promoter Regions, Genetic; Protein Biosynthesis; Proteins; Receptors, Retinoic Acid; Tretinoin

Topics: Antineoplastic Agents; Epidermal Growth Factor; ErbB Receptors; Genes, abl; Genes, erbB-2; Humans; Neoplasms; Proto-Oncogene Proteins c-kit; Tretinoin

All-trans retinoic acid (ATRA) is used as differentiation therapy for acute promyelocytic leukemia (APL). The two major adverse effects of ATRA therapy are hyperleukocytosis and retinoic acid syndrome. In order to prevent these adverse effects, low-dose ATRA therapy (25 mg/m2/d) has been tried in adults. Accordingly we assessed the pharmacokinetics of low-dose ATRA in children with cancer. Four children (one with APL and three with other advanced cancer) were administered ATRA and its pharmacokinetics were evaluated. In three patients, the pharmacokinetic parameters of ATRA were similar to those previously determined for APL patients in remission, but the values were lower in one patient. Low-dose ATRA was effective for APL, but not for the solid tumors. This therapy did not cause any severe toxicity. Further studies are needed to determine the optimum ATRA regimen and to evaluate low-dose ATRA combined with chemotherapy in children with APL.

Topics: Adolescent; Child; Child, Preschool; Female; Humans; Japan; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Neoplasms; Remission Induction; Tretinoin

Retinoic acids are natural derivatives of vitamin A, and play important roles in modulating tumor cell growth by regulating differentiation, thus suggesting the potential use of these derivatives in cancer therapy and prevention. To visualize the intranuclear responses of functional retinoic acid receptors, we have developed a dual-imaging reporter gene system based on the use of sodium/iodide symporter (NIS) and luciferase in cancer cell lines. NIS and luciferase genes were linked with an internal ribosome entry site, and placed under the control of an artificial cis-acting retinoic acid responsive element (pRARE/NL). After retinoic acid treatment, I-125 uptake by pRARE/NL transfected cells was found to have increased by up to about five times that of nontreated cells. The bioluminescence intensity of pRARE/NL transfected cells showed dose-dependency. In vivo luciferase images showed higher intensity in retinoic acid treated SK-RARE/NL tumors, and scintigraphic images of SK-RARE/NL tumors showed increased Tc-99m uptake after retinoic acid treatment. The NIS/luciferase imaging reporter system was sufficiently sensitive to allow the visualization of intranuclear retinoic acid receptor activity. This cis-enhancer imaging reporter system may be useful in vitro and in vivo for the evaluation of retinoic acid responses in such areas as cellular differentiation and chemoprevention.

Topics: Animals; Biological Transport; Cell Line, Tumor; Diagnostic Imaging; Gene Expression; Genes, Reporter; Humans; Iodine Radioisotopes; Luciferases; Luminescent Measurements; Male; Mice; Mice, Inbred BALB C; Neoplasms; Radionuclide Imaging; Receptors, Retinoic Acid; Response Elements; Symporters; Technetium Tc 99m Medronate; Tretinoin

Several ubiquitin-like proteins recently discovered have been confirmed to modify proteins akin to ubiquitinization for fine-regulation of intracellular proteins. In the present study, we report a novel ubiquitin-like protein from human dendritic cells (DC), named as dendritic cell-derived ubiquitin-like protein (DC-UbP). The full-length of DC-UbP cDNA is 565bp and encodes 106 amino acids. Ubiquitin domain (UBQ) in DC-UbP shares 28.6% identity and 55% similarity to ubiquitin, but does not possess the conserved C-terminus Gly-Gly of ubiquitin required for ubiquitinization. DC-UbP localized in cytoplasm, especially in mitochondrion, indicating that it may play a role in mitochondrial biology. DC-UbP mRNA was expressed in various tumor cells, but not in adult human normal tissues, suggesting that DC-UbP might be related to tumor genesis. In addition, DC-UbP mRNA expression decreased in the HL60 cells undergoing apoptosis after being stimulated with TRAIL and in the differentiated HL60 cells induced by ARTA. Taken together, DC-UbP might be downregulated during cellular differentiation and apoptosis.

Topics: Amino Acid Sequence; Apoptosis; Apoptosis Regulatory Proteins; Base Sequence; Blotting, Northern; Cell Differentiation; Cloning, Molecular; Dendritic Cells; Gene Expression Regulation, Neoplastic; Humans; Membrane Glycoproteins; Mitochondria; Molecular Sequence Data; Neoplasms; Nerve Tissue Proteins; Organ Specificity; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Subcellular Fractions; TNF-Related Apoptosis-Inducing Ligand; Tretinoin; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Ubiquitin; Ubiquitins

Topics: Endothelium, Vascular; Hemorrhage; Hemostasis; Humans; Neoplasms; Thrombosis; Treatment Outcome; Tretinoin

To examine the role cytoplasmic retinoic acid binding protein type 1 (CRABP I) and retinoic acid receptor beta 2 (RAR-beta 2) in mediating radiosensitization of human tumour cells in vitro by retinoic acid.. Human squamous cell carcinoma cell lines of different types were treated with retinoic acid followed by irradiation. Radiation response under drug treatment was detected by colony-formation assay. mRNA and protein expression levels of CRABP I, RAR-beta and cyclin D1 were investigated under different treatment conditions by room temperature polymerase chain reaction and Western blotting. The retinoic acid-sensitive cell line HTB35 was transfected for inducible CRABP I overexpression to test the role of this protein in modulating the sensitivity to retinoic acid and radiation as well as in regulating RAR-beta 2 and cyclin D1 expression.. The basal CRABP I level clearly correlated with the clonogenic survival of tumour cells and normal fibroblasts after treatment with retinoic acid and ionizing irradiation (IR). Cells expressing high basal CRABP I were more resistant to combined retinoic acid radiation treatment than cells with low basal expression. Overexpression of CRABP I in retinoic acid-sensitive HTB35 cells induced a retinoic acid-insensitive phenotype resistant to combined treatment with retinoic acid and radiation. This effect was independent of RAR-beta 2 expression. CRABP I overexpression resulted in stimulated cyclin D1 expression indicating the dependency of this cell cycle control protein on retinoic acid metabolism.. CRABP I plays an important role not only in mediating the retinoid effects, but also in modulating the radiation sensitivity of tumour cells after combined retinoic acid radiation treatment.

Topics: Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Fibroblasts; Humans; Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; Receptors, Retinoic Acid; Tretinoin; Tumor Stem Cell Assay

SOX proteins are a family of transcription factors with high-mobility-group DNA-binding domain (HMG box) homologous to SRY, which play key roles in embryogenesis. Xenopus Sox17alpha, Sox17beta, Sox3 and mouse Sox7 are reported to be negative regulators of the WNT-beta-catenin-TCF signaling pathway. SOX7, SOX17, and SOX18 constitute a subfamily among the SOX gene family. Here, expression of SOX18 mRNA was investigated using Northern blot analysis, RNA dot blot analysis, and cDNA-PCR. SOX18 mRNA was significantly highly expressed in ventricles and inter-ventricular septum of adult heart among various normal human tissues. SOX18 mRNA was relatively highly expressed in stomach and jejunum in the gastrointestinal tract. SOX18 mRNA was relatively highly expressed in TMK1 and MKN45 among 7 gastric cancer cell lines. SOX18 mRNA was expressed in all out of 7 pancreatic cancer cell lines, and was relatively highly expressed in PANC-1, Hs700T, Hs766T and MIA PaCa-2. Expression level of SOX18 mRNA in MCF-7 cells (breast cancer) was not affected by beta-estradiol. SOX18 mRNA was expressed in all out of 5 embryonal tumor cell lines, and was relatively highly expressed in NT2 with the potential to differentiate into neuronal cells. Expression level of SOX18 mRNA in NT2 cells was down-regulated by all-trans retinoic acid. This is the first report on comprehensive expression analyses of SOX18 mRNA in normal human tissues and tumors.

Topics: Blotting, Northern; Databases as Topic; DNA Primers; DNA-Binding Proteins; DNA, Complementary; Down-Regulation; Estradiol; High Mobility Group Proteins; Humans; Mutation; Neoplasms; Poly A; Protein Biosynthesis; RNA; RNA, Messenger; SOXF Transcription Factors; Time Factors; Tissue Distribution; Transcription Factors; Tretinoin; Tumor Cells, Cultured; Xenopus Proteins

Topics: Animals; Humans; Neoplasms; Tretinoin

Defective dendritic cell (DC) function caused by abnormal differentiation of these cells is an important mechanism of tumor escape from immune system control. Previously, we have demonstrated that the number and function of DC were dramatically reduced in cancer patients. This effect was closely associated with accumulation of immature cells (ImC) in peripheral blood. In this study, we investigated the nature and functional role of those ImC. Using flow cytometry, electron microscopy, colony formation assays, and cell differentiation in the presence of different cell growth factors, we have determined that the population of ImC is composed of a small percentage (<2%) of hemopoietic progenitor cells, with all other cells being represented by MHC class I-positive myeloid cells. About one-third of ImC were immature macrophages and DC, and the remaining cells were immature myeloid cells at earlier stages of differentiation. These cells were differentiated into mature DC in the presence of 1 microM all-trans-retinoic acid. Removal of ImC from DC fractions completely restored the ability of the DC to stimulate allogeneic T cells. In two different experimental systems ImC inhibited Ag-specific T cell responses. Thus, immature myeloid cells generated in large numbers in cancer patients are able to directly inhibit Ag-specific T cell responses. This may represent a new mechanism of immune suppression in cancer and may suggest a new approach to cancer treatment.

Topics: Adult; Aged; Cell Differentiation; Cytokines; Dendritic Cells; Growth Substances; Humans; Immune Tolerance; Immunophenotyping; Leukocyte Count; Middle Aged; Monocytes; Myeloid Cells; Neoplasms; Tretinoin; Tumor Cells, Cultured

The silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) mediates transcriptional repression by recruiting histone deacetylases (HDACs) to the DNA-bound nuclear receptor complex. The full-length SMRT (SMRTe) contains an N-terminal sequence that is highly conserved to the nuclear receptor corepressor N-CoR. To date, little is known about the activity and function of the full-length SMRTe protein, despite extensive studies on separated receptor interaction and transcriptional repression domains. Here we show that SMRTe inhibits MEF2C transcriptional activation by targeting selective HDACs to unique subnuclear domains. Indirect immunofluorescence studies with anti-SMRTe antibody reveal discrete cytoplasmic and nuclear speckles, which contain RARalpha in an RA-sensitive manner. Formation of the SMRTe nuclear speckles results in recruitment of several class I and class II HDACs to these subnuclear domains in a process depending on HDAC enzymatic activity. Intriguingly, although HDAC4 is located primarily in the cytoplasm, coexpression of SMRTe dramatically translocates HDAC4 from the cytoplasm into the nucleus, where HDAC4 prevents MEF2C from activating muscle differentiation. SMRTe also translocates HDAC5 from diffusive nucleoplasm into discrete nuclear domains. Accordingly, SMRTe synergizes with HDAC4 and 5 to inhibit MEF2C transactivation of target promoter, suggesting that nuclear domain targeting of HDAC4/5 may be important in preventing muscle cell differentiation. These results highlight an unexpected new function of the nuclear receptor corepressor SMRTe for its role in regulating cellular trafficking of nuclear receptor and selective HDACs that may play an important role in regulation of cell growth and differentiation.

Topics: Active Transport, Cell Nucleus; Cell Nucleus; DNA-Binding Proteins; HeLa Cells; Histone Deacetylases; Humans; MADS Domain Proteins; MEF2 Transcription Factors; Myogenic Regulatory Factors; Neoplasms; Nuclear Receptor Co-Repressor 2; Receptors, Retinoic Acid; Repressor Proteins; Retinoic Acid Receptor alpha; Transcriptional Activation; Tretinoin

Topics: Alitretinoin; Antineoplastic Agents; Bexarotene; Humans; Isotretinoin; Neoplasms; Retinoids; Tetrahydronaphthalenes; Tretinoin

WNT signaling pathway is implicated in carcinogenesis and embryogenesis. We have previously cloned and characterized WNT10A, and demonstrated up-regulation of WNT10A in gastric cancer. Here, we investigated expression of WNT10A mRNA in various types of human cancer. WNT10A mRNA was detected in 10 out of 12 esophageal cancer cell lines by cDNA-PCR, and was significantly up-regulated in esophageal cancer cell lines TE2, TE3, TE4, and a brain tumor cell line A-172. WNT10A mRNA was not up-regulated by retinoic acid in a teratocarcinoma cell line NT2. TFF1/pS2 mRNA, but not WNT10A mRNA, was up-regulated by beta-estradiol in a breast cancer cell line MCF-7. Expression of WNT10A mRNA in various types of primary cancers was next investigated by using Matched tumor/normal expression array filter. WNT10A mRNA was significantly up-regulated in 2 out of 8 cases of primary gastric cancer, and in 1 out of 7 cases of primary rectal cancer. Expression of WNT10A mRNA in esophageal cancer was not investigated, because such samples were not blotted on the expression array filter. Up-regulation of WNT10A mRNA might play key roles in some cases of esophageal, gastric, and colorectal cancer.

Topics: Cell Differentiation; DNA Primers; Estradiol; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Nerve Tissue Proteins; Proto-Oncogene Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Tretinoin; Tumor Cells, Cultured; Wnt Proteins

WNT2 is one of proto-oncogenes to activate the beta-catenin - TCF signaling pathway. WNT2B is a paralogue of WNT2, which encodes WNT2B1 and WNT2B2 isoforms due to alternative splicing using alternative promoter. Here, regulation of WNT2, WNT2B1, and WNT2B2 mRNAs in MCF-7 cells (breast cancer), NT2 cells (teratocarcinoma), and MKN45 cells (gastric cancer) were investigated. WNT2B2, but not WNT2 and WNT2B1, was expressed in MCF-7 cells. beta-estradiol (100 nM) induced a transient up-regulation of WNT2 in MCF-7 cells, and also induced down-regulation of WNT2B2. WNT2B2, but not WNT2B1, was expressed in NT2 cells, and WNT2 was slightly expressed in NT2 cells. Retinoic acid (10 microM) induced a transient up-regulation of WNT2 in NT2 cells. WNT2B2, but not WNT2 and WNT2B1, was slightly expressed MKN45 cells, and tumor necrosis factor alpha did not affect expression of WNT2, WNT2B1, and WNT2B2 mRNAs in MKN45 cells. This is the first report on differential regulation of WNT2, WNT2B1, and WNT2B2 mRNAs in human cancer cell lines. Up-regulation of WNT2 mRNA by estrogen might play a key role in some cases of human breast cancer through activation of the beta-catenin - TCF signaling pathway.

Topics: Estradiol; Female; Gene Expression Regulation, Neoplastic; Glycoproteins; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Neoplasms; Proto-Oncogene Proteins; RNA, Messenger; Tretinoin; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Wnt Proteins; Wnt2 Protein

These studies investigated the effects of retinoic acids on endothelial cell proliferation. Three human neoplastic cell lines, U-373 MG glioblastoma, DU-145 prostate carcinoma, and TCCSUP bladder transitional cell carcinoma, were treated with all-trans, 9-cis, or 13-cis retinoic acids at 0.0001 to 10 microM. Hypoxia was used to ensure the expression of the angiogenic phenotype. Conditioned media (CM) were prepared by hypoxic culturing of the tumor cells with retinoic acids for 24 hours. Then CM were transferred to bovine capillary endothelial cells for 48 hours of normoxic culturing, counted and compared to controls. CM from U-373 MG and DU-145 cells, but not TCCSUP cells, treated with all-trans or 9-cis retinoic acids at several concentrations below 1 microM, caused significant (P<0.05) increases in endothelial cell proliferation of between 13 to 18%. Both nonconditioned and conditioned media, for retinoic acid concentrations above 1 microM, inhibited endothelial cell proliferation. All CM for 13-cis retinoic acid decreased endothelial cell proliferation. These results show that the cytotoxicity of retinoic acids and the growth promoting/inhibiting ability of the conditioned media is retinoic acid isoform, time, concentration, and cell type dependent. Most importantly, the conditioned media from tumor cells treated with low concentrations of all-trans or 9-cis retinoic acids significantly increased endothelial cell proliferation.

Topics: Animals; Antineoplastic Agents; Cattle; Cell Count; Cell Division; Cell Hypoxia; Culture Media, Conditioned; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Neoplasms; Neovascularization, Pathologic; Tretinoin; Tumor Cells, Cultured

The metallothionein (MT)3 gene is expressed predominantly in the brain and the organs of the reproductive system, and fails to respond to metal ions in vivo. A CTG repeat was proposed to function as a potential repressor element in nonpermissive cells, and a sequence similar to the JC virus silencer element was found to function as a negative element in permissive primary astrocytes. The objective of this study was to characterize further the mechanisms governing cell-type specific MT-3 gene transcription. We searched for a suitable cell line expressing the MT-3 gene to be used for determination of MT-3 promoter tissue specificity, and showed that MT-3 expression is activated during neuroectodermal differentiation of P19 cells induced by retinoic acid to levels similar to those found in whole brain. Deletion of the CTG repeat or of the JC virus silencer did not promote MT-3 promoter activity in nonpermissive cells, or enhance expression in permissive cells. We identified MT-3 promoter sequences interacting with liver and brain nuclear proteins, as assayed by DNase I footprinting analyses and electrophoretic mobility shift assay, and assessed the role of these sequences in the regulation of MT-3 expression by cotransfection experiments. We generated stable transfectants in permissive C6 and nonpermissive NIH-3T3 cells, and analysed the methylation status of the MT-3 gene. These studies show that regulation of tissue-specific MT-3 gene expression does not appear to involve a repressor, and suggest that other mechanisms such as chromatin organization and epigenetic modifications could account for the absence of MT-3 gene transcription in nonpermissive cells.

Topics: 3T3 Cells; Animals; Base Sequence; Cell Differentiation; Cells, Cultured; Chlorocebus aethiops; COS Cells; DNA; Gene Expression Regulation, Neoplastic; Humans; Metallothionein; Metallothionein 3; Mice; Molecular Sequence Data; Mutagenesis, Site-Directed; Neoplasms; Neoplasms, Experimental; Neuroglia; Neurons; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; RNA, Messenger; RNA, Neoplasm; Species Specificity; Teratocarcinoma; Transcriptional Activation; Transfection; Tretinoin; Tumor Cells, Cultured

Telomerase, an enzymatic activity responsible for the replication of chromosome end structures, is strongly upregulated in most human cancers. In contrast, most differentiated tissues are telomerase negative. The rate-limiting step for telomerase activity seems to be the expression of the catalytic subunit of the enzyme, encoded by the human telomerase reverse transcriptase (hTERT) gene. The precise mechanism of how hTERT is regulated has not been elucidated yet. We show here that the down-regulation of hTERT mRNA during 12-O-tetradecanoylphorbol-13-acetate-induced differentiation of human U937 cells is a consequence of a fast decrease in the rate of transcription rather than changes in its half-life. The only transcription factor that has so far been implicated in the regulation of hTERT expression is the c-Myc oncoprotein. Our analysis shows that another member of the myc/marx/mad network, mad1, encoding a transcriptional repressor that is significantly increased by 12-O-tetra-decanoylphorbol-13-acetate treatment, represses hTERT promoter-driven reporter gene activity in transient transfection assays. This effect is dependent on the NH2 terminal domain of Madl, which mediates the association with the transcriptional corepressor mSin3. Our findings suggest the involvement of an additional transcription factor in the regulation of hTERT expression and may provide a model for how hTERT activity is controlled during the differentiation process in human somatic tissues.

Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Catalytic Domain; Cell Differentiation; DNA-Binding Proteins; Down-Regulation; Gene Expression Regulation; Half-Life; Histone Deacetylases; Humans; Kinetics; Neoplasms; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc; Repressor Proteins; Response Elements; RNA; RNA Stability; RNA, Messenger; Saccharomyces cerevisiae Proteins; Sequence Deletion; Telomerase; Tetradecanoylphorbol Acetate; Transcription Factors; Transcription, Genetic; Transfection; Tretinoin; U937 Cells

Topics: Antineoplastic Agents, Hormonal; Biomarkers; Biopsy; Clinical Trials as Topic; Health Services Research; Humans; Imidazoles; Mouth; Mucous Membrane; Neoplasms; Treatment Outcome; Tretinoin

Topics: Antineoplastic Agents; Brain Neoplasms; Canada; Child; Chromosomes, Human, Pair 1; Congenital Abnormalities; Gene Deletion; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Neuroblastoma; Occupations; Tretinoin

Telomerase, a ribonucleoprotein complex, adds hexameric repeats called telomeres to the growing ends of chromosomal DNA. The enzyme telomerase activity is present in a vast majority of tumors but is repressed in most normal tissues. Recently, two groups have reported the molecular cloning of the putative catalytic subunit (hEST2/hTRT) of the telomerase gene. We investigated the expression of this gene in diverse tumor-derived cell lines and tumors as well as in various normal tissues. The expression of hEST2/hTRT was detectable in tumor-derived cell lines, primary breast tumors, pancreatic tumors, and kidney tumors. Furthermore, the expression of hEST2/hTRT was down-regulated in response to a differentiation inducer. However, several normal tissues also expressed varying levels of hEST2/hTRT. Early passage cultures of endothelial fibroblasts and some epithelial cells also expressed the telomerase gene, albeit at low levels. In contrast, the expression of TLP1/TP1, the human homologue of Tetrahymena p80 telomerase subunit, was similar in all of these samples. Our results indicate that the differences in expression of hEST2/hTRT in tumor versus normal cells are relative and are not absolute.

Topics: Breast Neoplasms; Cell Differentiation; Cells, Cultured; Down-Regulation; Gene Expression; HL-60 Cells; Humans; Neoplasms; Polymerase Chain Reaction; Telomerase; Tissue Distribution; Tretinoin; Tumor Cells, Cultured

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

In order to better understand the mechanisms that underlie the antiproliferative effect of retinoids, we have examined the response of human carcinoma cell lines to all-trans retinoic acid (RA) and N-(4-hydroxyphenyl) retinamide (4HPR) in terms of cell growth, apoptosis and regulation of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mRNA. GLC82 (lung adenocarcinoma), BGC823 (stomach adenocarcinoma) and EC109 (esophageal squamous carcinoma) cells were treated with 10 microM of RA or 4HPR for various length of time and analyzed. The results show that growth inhibition by RA and 4HPR in GLC82 and BGC823 cells correlates with the induction of RARbeta2 gene, whereas RA resistance in EC109 cells parallels loss of RARbeta2 induction. Exogenous RARbeta2 expression did not restore RA responsiveness in EC109 cells, but potentiated 4HPR-induced growth inhibition, suggesting that 4HPR acts at least in part via the RARbeta receptor. We speculate that the loss of RARbeta2 inducibility in EC109 cells may be due to an unknown repressor.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Division; Drug Resistance, Neoplasm; Esophageal Neoplasms; Fenretinide; Humans; Lung Neoplasms; Neoplasms; Receptors, Retinoic Acid; Retinoid X Receptors; Stomach Neoplasms; Transcription Factors; Transfection; Tretinoin; Tumor Cells, Cultured

ERV3 (HERV-R) is a complete, single copy human endogenous retrovirus located on the long arm of chromosome 7. The open reading frame in its envelope gene has been conserved during evolution but the gag and pol genes contain in-frame termination codons. To find a suitable experimental model system for analysis of the functions of the ERV3 genome, an extensive screening study of different normal and neoplastic human tissues was performed. Most tissues express low levels of the ERV3 env mRNA although high expression levels are observed in placenta, sebaceous glands, adrenals, testis, bronchial, epithelium and the monocytic cell line U-937. In U-937 cells the ERV3 env expression varied in a manner related to the differentiation status of the cells; being highest in the terminally differentiated non proliferating cells. U-937 cells can be induced to differentiate from the monoblastic to the mature monocyte/macrophage stage upon stimulation by several substances such as phorbolesters (TPA), Vitamin D3, Retinoic Acid (RA) and combinations of some cytokines. We conclude that the ERV3 locus is expressed in a tissue and differentiation specific way and that the U-937 cell line is a suitable model system to further analyze the proposed functions of ERVs such as immunomodulation, cell fusion and protection against exogenous retroviral infections.

Topics: Cell Differentiation; Cell Line; Cholecalciferol; Cytokines; Female; Gene Expression Regulation, Viral; Gene Products, env; Genes, env; Humans; Male; Monocytes; Neoplasms; Organ Specificity; Pregnancy; Reference Values; Retroviridae; Tetradecanoylphorbol Acetate; Tretinoin

High levels of expression of GSTP1-1 are associated with cell proliferation, embryogenesis and malignancy. Given the role of glutathione S-transferase (GST) in detoxication, it is possible that GSTP1-1 evolved specifically to protect proliferating cells and share regulatory mechanisms with other cellular genes which are involved in cell division and tumorigenesis. We have previously shown that the expression of GSTP1 is suppressed by retinoic acid (RA) in the presence of the retinoic acid receptor (RAR) as a result of decreased transcription from its promoter. Through deletion analysis, we show here that the RA-RAR-dependent repression is mediated by the region -73 to +8. Further mutation analysis of this region indicates that the DNA sequence required for RA-RAR-dependent repression co-localizes with a consensus activator protein-1 (AP1) site essential for the promoter activity. The degree of repression correlates with the residual activity of the AP1 site. There are two adjacent G/C boxes. The one immediately downstream from the AP1 site is not essential for the promoter activity, but mutation of the second, further downstream, impairs the promoter. On the other hand, mutation of either of these two G/C boxes has little effect on RA-RAR suppression. We also show that the expression of GSTP1 is regulated by the redox status of the cell. Using the chloramphenicol acetyltransferase assay system, we have demonstrated that treatment with H2O2 induced transcription from the promoter and that this effect can be blocked by pre-incubation with N-acetylcysteine (NAC). It was shown that the induction by H2O2 is mediated by trans-acting factor NF-kappa B (nuclear factor kappa B), via a putative NF-kappa B site, 'GGGACCCTCC', located from -96 to -86. Co-transfection with an NF-kappa B (p65) expression construct increased the promoter activity, an effect which could be blocked by co-transfection with an I kappa B (MAD-3) expression construct. Deletion of the NF-kappa B site abolished the effect of both H2O2 and co-transfection of NF-kappa B. Interestingly, NAC is also an inducer for GSTP1. The effect of NAC was shown to be mediated largely by the AP1 site, since mutation of this site abolished the induction by NAC.

Topics: Base Sequence; Gene Expression Regulation, Enzymologic; Glutathione Transferase; HeLa Cells; Humans; Molecular Sequence Data; Neoplasms; NF-kappa B; Oxidation-Reduction; Promoter Regions, Genetic; Receptors, Retinoic Acid; Transcription Factor AP-1; Transfection; Tretinoin; Tumor Cells, Cultured

Retinoic acid (RA)-induced maturation mediated by the retinoic acid receptor alpha (RAR alpha) has been implicated in myeloid development. We have used differential hybridization analysis of a cDNA library constructed from the murine RA-inducible MPRO promyelocyte cell line to identify immediate-early genes induced by RA during granulocytic differentiation. E3, one of nine sequences identified, was upregulated in an immediate-early manner, with transcript levels peaking after 60 minutes exposure to RA. E3 transcripts were RA-inducible in HL60 cells, but not in an RA-resistant subclone, HL60R, that harbors a mutated RAR alpha gene. However, when HL60R cells were transduced with a functional copy of the RAR alpha gene, RA induced a 10-fold increase in E3 mRNA levels. E3 transcripts are present in the myeloid, B-lymphoid, and erythroid lineages, absent in nonhematopoietic cells, and encode a highly hydrophobic, potentially phosphorylated polypeptide of unknown function with significant homology to a putative protein expressed in myeloid cells. The murine E3 promoter harbors a single bipartite retinoic acid response element which in transient transfection assays conferred RA sensitivity. These results indicate that E3 is a hematopoietic-specific gene that is an immediate target for the activated RAR alpha during myelopoiesis.

Topics: Amino Acid Sequence; Animals; Base Sequence; Cell Differentiation; Cells, Cultured; Consensus Sequence; DNA, Complementary; Gene Expression Regulation; Genes, Immediate-Early; Granulocytes; Hematopoietic Stem Cells; HL-60 Cells; Humans; Immediate-Early Proteins; Leukemia, Promyelocytic, Acute; Membrane Proteins; Mice; Molecular Sequence Data; Neoplasms; Phosphorylation; Promoter Regions, Genetic; Protein Processing, Post-Translational; Receptors, Retinoic Acid; Regulatory Sequences, Nucleic Acid; Retinoic Acid Receptor alpha; RNA, Messenger; RNA, Neoplasm; Sequence Homology, Nucleic Acid; Transfection; Tretinoin

Spontaneous tumorigenesis was evaluated in male p53-knockout (p53-/-) mice treated with dehydroepiandrosterone (DHEA), quercetin, d-limonene, or all-trans retinoic acid to determine whether tumor development in these mice can be modulated by cancer-chemopreventive agents. DHEA-treated mice experienced a delay in tumorigenesis (particularly lymphomas) and subsequent mortality (P < 0.01) relative to untreated control mice. Quercetin, d-limonene, and all-trans retinoic acid each had no effect on spontaneous tumor development in p53-/- mice. These data demonstrate that tumor development in p53-/- mice can be delayed by DHEA and suggest that p53-/- mice provide a useful model for evaluating strategies to offset the increased risk of tumorigenesis resulting from loss of p53 tumor suppressor function.

Topics: Animals; Anticarcinogenic Agents; Cyclohexenes; Dehydroepiandrosterone; Gene Deletion; Genes, p53; Limonene; Male; Mice; Mice, Inbred C57BL; Neoplasms; Quercetin; Terpenes; Tretinoin

The addition of lipid hydroperoxides greatly accelerates the rate of oxidative catabolism of all-trans-retinoic acid (RA) in human cell microsomes; hydroperoxy metabolites of the arachidonate cascade are particularly active in the microsomal system. We have measured the plasma content of lipid peroxides in cancer patients during the course of therapy with RA, seeking to assess whether a correlation exists between the rate of oxidative catabolism of exogenously administered RA and whole body lipid peroxide levels. The assay used for plasma lipid peroxides is the capacity to react with thiobarbituric acid under specified conditions; the result is expressed as TBARS (thiobarbituric acid reactive substances). RA administration produced its own accelerated clearance RA within 72 h. Patients were considered to have "normal" or "rapid" baseline catabolism of RA if their Day 1 area under RA concentration over time curve was greater or less than 300 ng.h/ml, respectively. The mean plasma TBARS levels were: 12 normal volunteers = 0.14 microM; 19 "normal" RA catabolizers = 0.25 microM; and 14 "rapid" catabolizers = 0.82 microM. P = 0.008 (rapid catabolizers versus normal volunteers) and 0.05 (rapid catabolizers versus normal catabolizers). Repeat TBARS determinations were made during the course of therapy in 17 patients, all of whom converted to "rapid" RA catabolism on therapy. An increase in plasma TBARS levels > or = 20% of baseline was observed in 5 of 5 prostate cancer patients and 8 of 12 lung cancer patients treated with continuous RA therapy for 2 and 4 weeks, respectively. These observations support the hypothesis that high levels of lipid peroxides and rapid oxidative catabolism of RA are positively correlated.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Leukemia, Promyelocytic, Acute; Lipid Peroxides; Lung Neoplasms; Male; Metabolic Clearance Rate; Multiple Myeloma; Neoplasms; Prostatic Neoplasms; Reference Values; Thiobarbituric Acid Reactive Substances; Tretinoin

Retinoic acid (RA) has profound effects on cell proliferation and differentiation both in vitro and in vivo. Many human cell lines are known to be sensitive to the growth-inhibitory action of RA. We analyzed established human solid tumor-derived cell lines for their RA sensitivity. Growth inhibition by RA in monolayer was examined by [3H]thymidine incorporation and cell proliferation. Here we report that 11 widely used human cell lines were RA resistant. The majority are carcinoma derived (A-431, BT-20, C-41, ACHN, HCT116, 293, A549, and PA-1); two are sarcoma derived (Saos-2 and A673); and one is a melanoma cell line (A-375). Since nuclear retinoid receptors are implicated in the biological effects of RA, we examined the expression of retinoic acid receptors (RARs) RAR alpha, RAR beta, RAR gamma, and the retinoid X receptors (RXRs) RXR alpha, RXR beta, and RXR gamma in the RA-resistant cell lines by northern blotting and by RNase protection analysis for RAR beta. RAR alpha transcripts were constitutively expressed in all cell lines. By contrast, RAR beta was expressed in only seven RA-resistant cell lines (Saos-2, ACHN, 293, A549, A-375, A673, and PA-1), and its level was enhanced by RA in some cases. In most cell lines, RAR gamma expression was low and was not affected by RA. The RXR genes showed a very distinct expression pattern in the group of selected cell lines. In general, RXR alpha was the most abundantly expressed subtype, RXR beta was expressed at low levels, and RXR gamma could not be detected. In none of the RA-resistant cell lines was RXR expression modulated by RA. The results presented here indicate that the resistance of these human tumor cell lines to RA cannot be simply correlated with expression of RAR or RXR or both.

Topics: Blotting, Northern; Cell Division; Cell Transformation, Neoplastic; Cloning, Molecular; Dose-Response Relationship, Drug; Drug Resistance; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Nuclear Proteins; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; RNA; Transcription Factors; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured

Topics: Anticarcinogenic Agents; Cell Differentiation; Humans; Neoplasms; Phenylacetates; Tretinoin; Vitamins

This paper modifies and extends an earlier one on the same subject. It explains why external (but not internal) surface molecules of plasma membrane clusters may be rapidly scattered by any external challenging bioelectrical field. Temporary clusters from challenges may induce mitosis in cells near wounds and in epithelial stem cells. Weak challenges of much longer duration may initiate carcinogenesis by permanent clusters. Basic intracellular ligand/receptors or oncogene products in sufficient concentration at the membrane inner lipid layer may form permanent clusters rapidly. Additive increase of inner surface clusters by initiating agents is equated to promotion; accelerated cluster growth to progression. As a malignant cell grows, its cluster population increases until its membrane becomes permeable enough to stimulate mitosis. A progression mechanism is suggested that is consistent with the known properties of ras p21 proteins. The effect of long term exposure to power transmission line fields on mitosis and carcinogenesis is discussed. An approach to anticancer therapy is suggested, using a hypothesis-based mechanism for the anti-cancer activity of retinoic acid.

Topics: Animals; Anticarcinogenic Agents; Cell Division; Cell Membrane; Cell Transformation, Neoplastic; Humans; Lipid Bilayers; Membrane Lipids; Models, Biological; Neoplasms; Phospholipids; Tretinoin

A novel arotinoid with a morpholine structure in the polar end group Ro 40-8757 (4-[2-[p-[(E)-2(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2- naphthyl)propenyl]phenoxy]ethyl]-morpholine) was tested for its anti-proliferative activity against nine human cancer cell lines in vitro. The lines included two estrogen receptor positive breast cancer lines (MCF-7 and ZR-75-1), two estrogen receptor negative breast cancer lines (MDA-MB-231 and BT-20), one cervix carcinoma line (KB-3-1), two lung adenocarcinoma lines (A549 and HLC-1), one large cell lung cancer line (LXFL 529) and two colorectal lines (CXF 243 and CXF 280). Proliferation of all the lines, except the two lung adenocarcinoma lines, was inhibited by lower concentrations of Ro 40-8757 than those of all-trans retinoic acid (RA) or 13-cis RA giving the same level of inhibition. The degree of inhibition of RO 40-8757 was concentration and time dependent. The arotinoid was not cytotoxic and morphological signs by differentiation were not evident in cultures treated with Ro 40-8757 for up to 2 weeks. Because this compound is active on cells such as KB-3-1 that are not inhibited by all-trans RA and because it does not bind to nuclear retinoic acid receptors, it may represent a novel class of anti-proliferative agents.

Topics: Adenocarcinoma; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Division; Cell Survival; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Humans; Kinetics; Lung Neoplasms; Morpholines; Neoplasms; Receptors, Estrogen; Retinoids; Tetrazolium Salts; Thiazoles; Tretinoin; Tumor Cells, Cultured

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Humans; Neoplasms; Paclitaxel; Tretinoin

Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Retinoids; Tretinoin

Retinoids such as retinoic acid (RA) are potent anti-arthritic and anti-neoplastic agents. We investigated the mechanism by which RA inhibits induction of collagenase gene transcription by inflammatory mediators, tumor promoters, and proto-oncogenes. We found that the RA receptors (RARs) are potent inhibitors of AP-1 activity generated either by cJun homodimers or cJun/cFos heterodimers. In addition, both cJun and cFos can inhibit RAR activity. In vitro experiments suggested that this inhibition is due to an interaction between RAR and AP-1 proteins that results in mutual loss of DNA-binding activity. The RARs need not bind to the AP-1 site, neither does AP-1 bind to RA response elements. An understanding of this antagonism between the RAR and AP-1 might help to elucidate the anti-neoplastic and anti-arthritic effects of RA as well as its effects on cell differentiation and proliferation.

Topics: Base Sequence; Carrier Proteins; DNA; Gene Expression Regulation, Neoplastic; Genetic Vectors; HeLa Cells; Humans; Inflammation; Microbial Collagenase; Molecular Sequence Data; Neoplasm Proteins; Neoplasms; Plasmids; Promoter Regions, Genetic; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Receptors, Retinoic Acid; Transcription, Genetic; Transfection; Tretinoin

Topics: Brain Neoplasms; Child; Clinical Trials as Topic; Humans; Lymphoma; Neoplasms; Tretinoin

Topics: Cell Differentiation; Humans; Neoplasms; Tretinoin

Topics: Cholecalciferol; Drug Synergism; Eflornithine; Humans; Neoplasms; Somatostatin; Tretinoin; Vitamin A

Topics: Electroretinography; Eye; Fenretinide; Humans; Neoplasms; Night Blindness; Tretinoin

A phase I study was carried out with the new aromatic retinoic acid analogue DCE, all-trans-9-(2,6-dichloro-4-methoxy-m-tolyl)-3,7-dimethyl-2,4,6,8- nonatetraenacetylester. Data from preclinical studies show that DCE has a promising anti-tumor effect. Data from others investigators show that when DCE was given to patients in daily doses, the dose-limiting toxicity. This toxicity was comprising considerable muco-cutaneous toxicity, occurred at 40 mg/day. To avoid this dose-limiting toxicity, a weekly oral treatment schedule was tested for toxicity in this study. The starting dose was 40 mg/m2 body surface, and a modified Fibonacci scheme was used for the dose escalations. A total of 20 patients entered this study, and all were evaluable for toxicity. The highest dose was 300 mg/m2. In three patients, completely reversible WHO grade 1 liver toxicity was observed. In contrast to daily doses, a once-a-week schedule produced no mucocutaneous toxicity. Pharmacokinetic measurements showed that absorption was highly unpredictable and did not increase with dose increments. Given the results of the pharmacokinetic determinations, we concluded that escalating the DCE dose would not lead to a recommendable dose for further phase II studies, and the study was subsequently discontinued.

Topics: Adult; Aged; Antineoplastic Agents; Biological Availability; Chromatography, High Pressure Liquid; Creatinine; Drug Evaluation; Female; Half-Life; Humans; Male; Middle Aged; Molecular Structure; Neoplasms; Tretinoin

Topics: beta Carotene; Carotenoids; Diet; Humans; Leukoplakia, Oral; Neoplasms; Tretinoin

The purpose of the experiments was to establish whether individual cells of a tumor cell population, or clonal lines derived from its express the differentiated phenotype, or respond heterogeneously following treatment with inducers of differentiation or with cytostatic drugs. The human cell lines used in this study were: HL-60 promyelocytic leukemia, K562 erythroleukemia, BHM-97 and A2058 melanoma, and A-1, A-2, A-4 and A-6 clones of A2058 line. Inducers of differentiation were phorbol myristate acetate (PMA), dimethylsulfoxide (DMSO) and retinoic acid (RA); cytostatics: adriamycin (ADM), 5-fluorouracil (5-FU), dacarbazine (DTIC), cis-platin (platidiam, PD) and arabinosyl cytosine (ara-C). Expression of the differentiated phenotype was shown by cell attachment (HL-60), hemoglobin production (K562), dendrit formation (A2058, BHM-97). Individual cells expressed the differentiated phenotype heterogeneously in all types of cell populations. Clone A-4 was the most, and clone A-6 the least sensitive to PMA. The drug sensitivity of the clones was different and drug-dependent. It is concluded that induction of differentiation as another approach to therapy of cancer, similar to anticancer drug therapy, also implies disadvantages due to population heterogeneity. Combinations of cytostatics with differentiation inducers might result in improved therapeutic effects.

Topics: Antineoplastic Agents; Cell Differentiation; Cisplatin; Cytarabine; Dacarbazine; Dimethyl Sulfoxide; Dose-Response Relationship, Drug; Doxorubicin; Fluorouracil; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Promyelocytic, Acute; Melanoma; Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured

Tumor-producing substances that promote lipolysis in vitro may also account for fat mobilization in cachectic cancer patients. Cachexia might improve if this lipolytic action of cancer cells could be halted. This study examined the lipolytic activities of media from four tumor cell lines after treatment with retinoic acid (RA), a cell differentiation inducer. An in vitro adipocyte bioassay measured lipolysis. All four tumor cell lines were intrinsically lipolytic, with elevated baseline lipolytic activities relative to fibroblast-conditioned controls (128% to 287% of control, p less than 0.05). After a 2-week exposure to RA in culture medium followed by 3 days of continued growth in fresh medium, two of four cell lines (both rat prostatic adenocarcinomas) showed significantly reduced lipolytic activities (16% and 61% of corresponding untreated controls, p less than 0.05). These reductions in lipolytic activity after RA treatment were not generalized phenomena; nor were they simply caused by cell differentiation, as the other cell lines (human malignant melanoma and human ovarian teratocarcinoma) showed no reductions despite evidence of cell differentiation. No effect on lipolytic activity was seen after only a 24-hour exposure to RA. We conclude that RA can affect the lipolytic activity of certain tumor cells in vitro, perhaps by influencing tumor-producing lipolytic factor(s).

Topics: Adenocarcinoma; Animals; Cell Line; Cell Transformation, Neoplastic; Female; Fibroblasts; Humans; Lipolysis; Male; Melanoma; Neoplasms; Rats; Teratoma; Time Factors; Tretinoin

Retinoids are natural and synthetic analogues of vitamin A. They have a marked influence on the differentiation of epithelial tissues by modifying membrane glycoconjugates and by acting through cytosolic and nuclear mechanisms like steroid hormones. Their clinical and biological toxic effects are numerous, but they are usually benign and reversible. However the possibility of teratogenic effects requires close monitoring of female patients. Etretinate is particularly effective in disorders of keratinisation (psoriasis, ichthyosis) whereas isotretinoin is the best known therapy of severe acne. Moreover the possible role of retinoids in the prevention and treatment of certain cancers gives hopeful prospects.

Topics: Acne Vulgaris; Chemical Phenomena; Chemistry; Etretinate; Humans; Ichthyosis; Isotretinoin; Neoplasms; Psoriasis; PUVA Therapy; Recurrence; Retinoids; Tretinoin

The effect of topical application of PGE on induction of ODC in mouse epidermis was measured. When direct induction of ODC by TPA was blocked by also applying indomethacin, maximum ODC activity occurred only when PGE was applied simultaneously with TPA 4 1/2 hr before killing of the mice. If either TPA or PGE was applied at other times, ODC activity decreased substantially. Induction of ODC by mezerein was blocked by indomethacin but restored by PGE, as was observed with TPA, but induction by ethyl phenylpropiolate was not affected by indomethacin or PGE. DMBA did not cause a consistent increase in ODC activity, nor was its inductive action affected by indomethacin or PGE. However, another weak inducer, acetic acid, exhibited elevated ODC activity when PGE was also applied. Inhibition by topical retinoic acid of ODC induction by TPA was partially overcome in a dose-response fashion by PGE. The results indicate that at least 2 events, elevation of PGE and another independent event, are required for induction of ODC activity. It appears that TPA causes at least 4 independent events essential for tumor promotion. A model for the events in the 2-stage tumor promotion model is proposed.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Alprostadil; Animals; Diterpenes; Enzyme Induction; Female; Indomethacin; Mice; Mice, Inbred Strains; Models, Biological; Neoplasms; Ornithine Decarboxylase; Phorbols; Terpenes; Tetradecanoylphorbol Acetate; Tretinoin

Topics: Adult; Drug Administration Schedule; Female; Headache; Humans; Isotretinoin; Male; Menstruation Disturbances; Middle Aged; Neoplasms; Pain; Risk; Tretinoin

Topics: Humans; Indomethacin; Isotretinoin; Neoplasms; Ornithine Decarboxylase; Research Design; Tretinoin

In an attempt to increase the peak plasma levels of 13-cis-retinoic acid (13-cis-RA) and its efficacy in vivo, a Phase I study and pharmacokinetics of weekly high-dose, oral 13-cis-RA was conducted in 23 cancer patients who were refractory to conventional treatments. At 200 mg/sq m, the mean peak plasma level of 13-cis-RA was 1.5 +/- 0.1 (SE) micrograms/ml; at 400 mg/sq m, the mean peak plasma level increased to 3.8 +/- 0.7 micrograms/ml. Further increases of the 13-cis-RA dose up to 1800 mg/sq m did not lead to proportional increases in either the mean peak plasma levels or area under the curve, indicating a saturable absorption phenomenon. The terminal half-life was highly variable (range, 2.8 to 101.3 h) and was not related to the dose given. A secondary peak plasma concentration was seen in five patients, suggesting enterohepatic circulation. The toxicities such as headache, cheilitis, dry skin, and dry eyes were frequent on the weekly schedule but were not dose-limiting. One patient had an elevation of the triglycerides of 2 to 5 times the upper limit of normal; five patients had an elevation of 1.1 to 2 times normal. No objective responses were observed to treatment with 13-cis-RA. Of 20 patients receiving an adequate trial of the drug, 18 showed progression of their cancer, and two had stable disease.

Topics: Adult; Aged; Drug Evaluation; Female; Humans; Kinetics; Male; Middle Aged; Neoplasms; Tretinoin

Treatment of several tumor cell lines, including the murine melanomas B16 and S91 and the human sarcoma Hs791 and Hs705, with retinoic acid resulted in an increased sialylation of specific cell surface membrane sialoglycoproteins. This treatment also augmented the sensitivity of these cells to the cytopathic effects of a sialic acid-specific toxin from Entamoeba histolytica. In contrast, a similar treatment with retinoic acid of a retinoic acid-resistant mutant clone S91-C154, which does not increase sialylation of cell surface glycoproteins, failed to alter the susceptibility of the cells to the E. histolytica toxin. These results imply that cell surface sialoglycoproteins serve as receptors for the amoebic toxin.

Topics: Animals; Cell Line; Drug Synergism; Entamoeba histolytica; Glycoproteins; Humans; Lectins; Mice; N-Acetylneuraminic Acid; Neoplasms; Sialic Acids; Sialoglycoproteins; Toxins, Biological; Tretinoin; Wheat Germ Agglutinins

Topics: Alkaline Phosphatase; Calcitriol; Cells, Cultured; Cyclic AMP; Enzyme Induction; Fatty Acids; Glucocorticoids; Humans; Hydrocortisone; Isoenzymes; Neoplasms; Nucleosides; Osmolar Concentration; RNA, Neoplasm; Tretinoin

Several 13-cis-retinamides were synthesized from 13-cis-retinoic acid via either 13-cis-retinoyl chloride or 13-cis-1-retinoylimidazole. All-trans-retinoylglycine was prepared from all-trans-retinoyl chloride and ethyl glycinate. Detailed procedures were developed for the preparation of other all-trans-retinamides on a large scale for studies of the chemoprevention of cancer.

Topics: Animals; Cricetinae; Drug Stability; Drug Storage; Male; Mice; Neoplasms; Organ Culture Techniques; Tretinoin

Topics: Chemical Phenomena; Chemistry; Humans; Isotretinoin; Neoplasms; Precancerous Conditions; Retinaldehyde; Skin Diseases; Tretinoin; Vitamin A; Vitamin A Deficiency

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

Syrian hamsters were treated with either a low (10 mg/kg body weight) or high (40 mg/kg body weight) single dose of bis(2-oxopropyl)nitrosamine (BOP) and beginning 1 week later fed either low (0.2 mmol/kg diet) or high (0.4-1.0 mmol/kg diet) levels of one of four retinoids [13 cis retinoic acid (13-cis-RA), N-ethylretinamide (ERA), N-(2-hydroxyethyl)retinamide (OHERA) or N-(phenyl)retinamide (PRA)] for periods of 40 or 50 weeks. The high retinoid levels (0.4-1.0 mmol/kg diet) fed following the highest BOP treatment enhanced pancreatic carcinoma yields (average number/effective animal) in males fed all four retinoids, and in females fed ERA and 13-cis-RA. Enhanced adenoma yields were also seen in all groups when high retinoid levels were fed following 40 mg BOP/kg body weight. However, these retinoid levels caused an increased adenoma yield in male hamsters only and did not modify carcinoma yields when fed following 10 mg BOP/kg body weight. Similarly, tumor yields at extra-pancreatic sites were elevated in retinoid-fed hamsters of both sexes after 40 mg BOP/kg body weight and in males fed ERA and 13-cis-RA after 10 mg BOP/kg body weight when retinoids were given at the high levels (0.4-1.0 mmol/kg diet). Increased incidences of bile duct and liver tumors in particular were found in hamsters given 40 mg BOP/kg body weight. Consumption of retinoid levels of 0.4 mmol/kg diet and above was also associated with a high incidence of liver cell necrosis, ovarian cysts and ovarian hemorrhage. Retinoids (ERA, OHERA, and PRA) fed at the low level (0.2 mmol/kg diet) following the low BOP dose did not enhance carcinogenesis in the pancreas or at other sites and did not cause alterations in morphologic observations.

Topics: Animals; Body Weight; Cricetinae; Dose-Response Relationship, Drug; Female; Isomerism; Isotretinoin; Male; Mesocricetus; Neoplasms; Nitrosamines; Pancreatic Neoplasms; Sex Factors; Tretinoin

We investigated the effect of the synthetic vitamin A derivative isotretinoin (13-cis-retinoic acid) on advanced cancers in 103 patients and on preneoplastic lesions in five patients. Six of 14 patients with squamous cell epithelial cancers had objective regressions of skin or subcutaneous metastases. Three of five patients with preneoplastic lesions had objective responses. The major dose-limiting toxic effects were reversible dermatitis, emotional lability, and headaches. We conclude that the growth of some squamous cell epithelial malignancies can be inhibited by isotretinoin and suggest that other retinoids should be evaluated as antitumor agents.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Eruptions; Drug Evaluation; Emotions; Headache; Humans; Isotretinoin; Neoplasms; Precancerous Conditions; Tretinoin

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

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

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

Topics: Animals; Cell Adhesion; Cell Division; Cell Line; Clone Cells; Female; Fibrinolysis; Fibrosarcoma; HeLa Cells; Humans; Melanoma; Mice; Neoplasms; Osteosarcoma; Plasminogen Activators; Tretinoin; Vulvar Neoplasms

In some squamous cell carcinomas of the otorhinolaryngologic region with different grades of differentiation, a protein was found that specifically binds vitamin A acid. In 28 of 37 tumors, the retinoic acid-binding sites were found in significant amounts, according to the authors' data. Areas with metastases showed a lower incidence of retinoic acid-binding, whereas in all normal epiglottis and vocal cord tissue specimens the binding was present. The possible significance of the protein-binding for the biologic effect of the vitamin A acid is discussed.

Topics: Binding Sites; Binding, Competitive; Carcinoma, Squamous Cell; Centrifugation, Density Gradient; Etretinate; Head and Neck Neoplasms; Humans; Neoplasms; Otorhinolaryngologic Diseases; Protein Binding; Tretinoin; Vitamin A

Topics: Adolescent; Adult; Aged; Amniocentesis; Amniotic Fluid; Arteriosclerosis; Ascorbic Acid; Child; Child, Preschool; Chromosome Aberrations; Dementia; Female; Folic Acid; Glutathione; Humans; Infant; Middle Aged; Mutagens; Neoplasms; Pregnancy; Tretinoin

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

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

Topics: Dose-Response Relationship, Drug; Humans; Neoplasms; Tretinoin

Topics: Antineoplastic Agents; Breast Neoplasms; Humans; Interferons; Neoplasms; Prognosis; Time Factors; Tretinoin

Topics: Animals; Carrier Proteins; Cell Membrane; Glycoproteins; Humans; Intestinal Absorption; Liver; Neoplasms; Prealbumin; Retinol-Binding Proteins; Tretinoin; Vitamin A

The effects of retinoic acid on cultured human cells derived from normal and neoplastic tissues were studied. Retinoic acid consistently induced plasminogen activator synthesis by cells of mesenchymal origin (with the exception of adult skin fibroblasts) but not by cells of epithelial origin. The effect of retinoic acid was more pronounced than that of equimolar concentrations of retinol or retinyl acetate. Dexamethasone inhibited the retinoid-induced increase in plasminogen activator in lung- and foreskin-derived fibroblasts. Cells derived from normal or neoplastic tissues showed no consistent differences either in baseline rates of plasminogen activator release or in the magnitude of the retinoid effect.

Topics: Cells, Cultured; Epithelium; Humans; Neoplasms; Plasminogen Activators; Tretinoin; Vitamin A

Topics: Animals; Binding, Competitive; Mice; Neoplasms; Phospholipases; Phospholipases A; Phospholipases A2; Prostaglandins E; Receptors, Prostaglandin; Stereoisomerism; Tetradecanoylphorbol Acetate; Tretinoin

The tumour-promoting agents 12-0-tetradecanoylphorbol-13-acetate (TPA) and phorbol-12, 13-dibutyrate (PDB) I are potent mitogens for human peripheral blood lymphocytes. In contrast, the non-cocarcinogenic substance phorbol lacks lymphocyte-activating properties. Non-toxic levels of retinoic acid (RA) or retinyl acetate (RAt) inhibit the phorbol-ester-stimulated lymphocyte blastogenesis required the near-concurrent addition of retinoids. Differences in the sensitivity of phorbol-ester-stimulated lymphocyte subpopulations to the antagonistic action of RA or RAt, respectively, suggest that the inhibitory effect of retinoids may not be due to a common mode of action. Lymphocyte cultures may provide a useful model system for studies of the mechanisms of action of both phorbol esters and retinoids.

Topics: Carrier Proteins; Cell Division; Humans; Lymphocyte Activation; Lymphocytes; Mitogens; Neoplasms; Phorbol Esters; Phorbols; Tretinoin

Following the well established prevention of chemical carcinogenesis by vitamin A in several species of laboratory animals, we performed in vitro studies with human diploid fibroblasts in culture. Vitamin A-palmitate, alltransretinoic acid and the analogue compound Ro 10-9359 were found to reduce the formation of active intermediates following the administration of G3H Benzo(a)pyrene to the cells. This effect which lead to a considerable decrease of alkylated DNA is not based on a direct inhibition of Benzpyrene metabolizing enzymes by the retinoids but by a preferential inhibition of the de novo synthesis of these enzymes. This caused the well known substrate mediated enzyme induction of benzpyrene metabolizing enzymes to cease. From our data we conclude that the mechanism of the cancer protective effect of vitamin A with respect to certain carcinogens is based on an inhibited activation of procarcinogens. This effect can also be expected in human tissues.

Topics: Benzopyrenes; Biotransformation; Cell Transformation, Neoplastic; Cells, Cultured; DNA; Fibroblasts; Humans; Neoplasms; Tretinoin; Vitamin A

Two intracellular proteins that bind compounds with vitamin A activity have been discovered in animal tissues. One, called cellular retinol-binding protein (CRBP), binds retinol with high specificity and affinity, but not retinal or retinoic acid. The other protein, called cellular retinoic acid-binding protein (CRABP), has high affinity for retinoic acid but does not bind retinol or retinal. CRBP is different from the well-known serum retinol binding protein. The proteins are present in many fetal tissues, whereas their tissue distribution in the adult rat differs. The levels of these proteins change differently during perinatal development, suggesting that they are regulated in a nonsynchronous manner. Some malignant tumors contain these proteins. The presence of these proteins could be an indication of whether the tumor might be inhibited by or might require vitamin A for growth. It appears that the cell nucleus is a target for retinol action, as CRBP allows specific interaction of retinol with the nucleus, showing the presence of specific binding sites for retinol. The number of these sites is dependent on the vitamin A status of the animal.

Topics: Animals; Binding Sites; Cell Differentiation; Cell Nucleus; Neoplasms; Rats; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Tretinoin; Vitamin A

Topics: Animals; Fetus; Humans; Male; Neoplasms; Rats; Retinol-Binding Proteins; Tretinoin; Vitamin A

Topics: Animals; Cricetinae; Drug Evaluation, Preclinical; Humans; Neoplasms; Rats; Research Design; Tretinoin; United States; Vitamin A

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