tretinoin and Urinary-Bladder-Neoplasms

Differentiation is defined as the ability of a cell to acquire full functional behavior. For instance, the function of bladder urothelium is to act as a barrier to the diffusion of solutes into or out of the urine after excretion by the kidney. The urothelium also serves to protect the detrusor muscle from toxins present in stored urine. A major event in the initiation and progression of bladder cancer is loss of urothelial differentiation. This is important because less differentiated urothelial tumors (higher histologic tumor grade) are typically associated with increased biologic and clinical aggressiveness. The differentiation status of urothelial carcinomas can be assessed by histopathologic examination and is reflected in the assignment of a histologic grade (low-grade or high-grade). Although typically limited to morphologic evaluation in most routine diagnostic practices, tumor grade can also be assessed using biochemical markers. Indeed, current pathological analysis of tumor specimens is increasingly reliant on molecular phenotyping. Thus, high priorities for bladder cancer research include identification of (1) biomarkers that will enable the identification of high grade T1 tumors that pose the most threat and require the most aggressive treatment; (2) biomarkers that predict the likelihood that a low grade, American Joint Committee on Cancer stage pTa bladder tumor will progress into an invasive carcinoma with metastatic potential; (3) biomarkers that indicate which pTa tumors are most likely to recur, thus enabling clinicians to prospectively identify patients who require aggressive treatment; and (4) how these markers might contribute to biological processes that underlie tumor progression and metastasis, potentially through loss of terminal differentiation. This review will discuss the proteins associated with urothelial cell differentiation, with a focus on those implicated in bladder cancer, and other proteins that may be involved in neoplastic progression. It is hoped that ongoing discoveries associated with the study of these differentiation-promoting proteins can be translated into the clinic to positively impact patient care.

Topics: Biomarkers, Tumor; Carcinoma; Cell Differentiation; Disease Progression; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 3-alpha; Humans; Muscles; Neoplasm Metastasis; Neoplasm Staging; PPAR gamma; Signal Transduction; Transcription Factors; Tretinoin; Urinary Bladder Neoplasms; Urothelium

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

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; Carcinogens; Cocarcinogenesis; Cyclamates; Cyclophosphamide; Humans; Hyperplasia; Mice; Neoplasms, Experimental; Rats; Saccharin; Schistosomiasis; Time Factors; Tretinoin; Tryptophan; Urinary Bladder; Urinary Bladder Neoplasms; Urinary Calculi; 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

Retinoic acid (RA) is now considered anormal metabolite of vitamin A. It has been established that RA maintains health and supports growth in animals but differs from other forms of vitamin A in that RA does not function in visual or reproductive processes. RA and RA analogs also differ from other forms of vitamin A in: absorption, transport, metabolism, storage, turnover, biochemical functions, excretion, pharmacology, and toxicology.

Topics: Animals; Biological Transport; Female; Intestinal Absorption; Models, Biological; Pregnancy; Reproduction; Stereoisomerism; Structure-Activity Relationship; Teratogens; Tretinoin; Urinary Bladder Neoplasms; Vision, Ocular; Vitamin A

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

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

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; BCG Vaccine; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Humans; Isomerism; Isotretinoin; Methotrexate; Mitomycin; Mitomycins; Neoplasm Recurrence, Local; Random Allocation; Registries; Thiotepa; Tretinoin; Urinary Bladder Neoplasms

The effect of Tigason (etretinate) in the prevention of the recurrence of superficial bladder tumors (Ta-T1, grade 0 papilloma and grade 1 and 2 carcinoma) was studied in 30 patients in a double-blind, placebo-controlled study. Before beginning treatment, the bladder was cleared from all visible tumors by electrocoagulation or TUR. The duration of treatment ranged from 10 to 26 months. The overall preventive effect was significantly better (p less than 0.01) in Tigason-treated patients than in patients given placebo. Tigason was more effective in preventing the recurrence of grade 1 and 2 carcinoma than placebo. On grade 0 papilloma this difference was not so marked. Side effects were common and disturbing at high doses (50 mg/day), but Tigason was well tolerated at the final maintenance dose (25 mg/day). The results obtained from this first clinical study with Tigason in the prevention of recurrence of superficial bladder tumors are promising.

Topics: Aged; Clinical Trials as Topic; Double-Blind Method; Etretinate; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Tretinoin; Urinary Bladder Neoplasms

The authors undertook a double blind study in a group of 20 patients of the possible effectiveness of etretinate in the prevention of recurrences of superficial tumours of the bladder (with the exception of class IV carcinomas). No difference was seen in the course of the two series. These conclusions were not in agreement with those previously published.

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Etretinate; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Random Allocation; Tretinoin; Urinary Bladder Neoplasms

The collaborative group chemotherapy studies of the National Bladder Cancer Project are summarized with regard to intravesical and systemic agents. The necessity for longitudinal observations and data collection in all cases of bladder cancer, and not just those receiving chemotherapy, is also stressed.

Topics: Adult; Aminoacridines; Amsacrine; Antineoplastic Agents; Carcinoma in Situ; Carcinoma, Papillary; Cisplatin; Clinical Trials as Topic; Drug Evaluation; Humans; Isotretinoin; Mitomycin; Mitomycins; Multi-Institutional Systems; Neoplasm Recurrence, Local; Thiotepa; Tretinoin; Urinary Bladder Neoplasms

Acquired chemoresistance is a critical issue for advanced bladder cancer patients during long-term treatment. Recent studies reveal that a fraction of tumor cells with enhanced tumor-initiating potential, or cancer stem-like cells (CSCs), may particularly contribute to acquired chemoresistance and recurrence. Thus, CSC characterization will be the first step towards understanding the mechanisms underlying advanced disease. Here we generated long-term patient-derived cancer cells (PDCs) from bladder cancer patient specimens in spheroid culture, which is favorable for CSC enrichment. Pathological features of bladder cancer PDCs and PDC-dependent patient-derived xenografts (PDXs) were basically similar to those of their corresponding patients' specimens. Notably, CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), a critical enzyme that synthesizes retinoic acid (RA), was abundantly expressed in PDCs. ALDH1A1 inhibitors and shRNAs repressed both PDC proliferation and spheroid formation, whereas all-trans RA could rescue ALDH1A1 shRNA-suppressed spheroid formation. ALDH inhibitor also reduced the in vivo growth of PDC-derived xenografts. ALDH1A1 knockdown study showed that tubulin beta III (TUBB3) was one of the downregulated genes in PDCs. We identified functional RA response elements in TUBB3 promoter, whose transcriptional activities were substantially activated by RA. Clinical survival database reveals that TUBB3 expression may associate with poor prognosis in bladder cancer patients. Moreover, TUBB3 knockdown was sufficient to suppress PDC proliferation and spheroid formation. Taken together, our results indicate that ALDH1A1 and its putative downstream target TUBB3 are overexpressed in bladder cancer, and those molecules could be applied to alternative diagnostic and therapeutic options for advanced disease.

Topics: Aldehyde Dehydrogenase 1 Family; Animals; Cell Line, Tumor; Disease Progression; Down-Regulation; HEK293 Cells; Heterografts; Humans; Male; Mice; Neoplastic Stem Cells; Retinal Dehydrogenase; Retinoic Acid Receptor alpha; Signal Transduction; Spheroids, Cellular; Tretinoin; Tubulin; Urinary Bladder Neoplasms

Topics: Administration, Cutaneous; Biopsy; Dermatologic Agents; Eyelid Diseases; Hamartoma; Humans; Male; Middle Aged; Remission Induction; Treatment Outcome; Tretinoin; Urinary Bladder Neoplasms

Stra6 is the retinoic acid (RA)-inducible gene encoding the cellular receptor for holo-retinol binding protein. This transmembrane protein mediates the internalization of retinol, which then upregulates RA-responsive genes in target cells. Here, we show that Stra6 can be upregulated by DNA damage in a p53-dependent manner, and it has an important role in cell death responses. Stra6 expression induced significant amounts of apoptosis in normal and cancer cells, and it was also able to influence p53-mediated cell fate decisions by turning an initial arrest response into cell death. Moreover, inhibition of Stra6 severely compromised p53-induced apoptosis. We also found that Stra6 induced mitochondria depolarization and accumulation of reactive oxygen species, and that it was present not only at the cellular membrane but also in the cytosol. Finally, we show that these novel functions of Stra6 did not require downstream activation of RA signalling. Our results present a previously unknown link between the RA and p53 pathways and provide a rationale to use retinoids to upregulate Stra6, and thus enhance the tumour suppressor functions of p53. This may have implications for the role of vitamin A metabolites in cancer prevention and treatment.

Topics: Animals; Apoptosis; Base Sequence; Cell Line, Tumor; Cells, Cultured; Colorectal Neoplasms; Disease Models, Animal; DNA Damage; Fibroblasts; Humans; Membrane Proteins; Mice; Mice, Knockout; Molecular Sequence Data; Reactive Oxygen Species; Signal Transduction; Tretinoin; Tumor Suppressor Protein p53; Urinary Bladder Neoplasms

Previous researches showed that the expression level of E-Cad in most infiltrating cancer cells was reduced or negative. This study explored whether 4HPR restrained the infiltration of bladder cancer cells through regulating the expression of E-Cad. The infiltrating bladder cancer cells T24 were cultured, and then treated by a proper dosage of drug. Their viability was a determined by MTT method. Western blotting and RT-PCR were adopted to detect the changes of E-Cad gene expression at both protein and mRNA levels. Moreover, immunofluorescent staining and confocal fluorescence microscopy were employed for the observation of the expression of E-Cad. The result showed that, at both mRNA and protein levels, the expression level of E-Cad in T24 cells treated by 4HPR was significantly higher than that of control group, while the β-Cat expression was also relocated from the cell nucleus to cytoplasm. Our findings suggested that the regulatory function of 4HPR on infiltration of bladder cancer cells T24 is at least partly achieved by regulating the expression of E-Cad.

Topics: Antineoplastic Agents; Apoptosis; Cadherins; Carcinoma, Transitional Cell; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Tretinoin; Urinary Bladder Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Carcinoma, Transitional Cell; Female; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Neoplasms, Multiple Primary; Oxides; Remission Induction; Tretinoin; Urinary Bladder Neoplasms

Being best-studied superficial bladder cancer (SBC) chemopreventives, retinoids' negative studies and toxicity were stumbling. With proper understanding of retinoid metabolism, we aimed at investigating combined ketoconazole (a strong inhibitor of retinoic acid-catabolizing cytochrome P450s) all-trans retinoic acid (Keto-atRA) SBC treatment. VEGF and TGFalpha levels are end-point pathogenetic biomarkers involved in early SBC.. Keto-atRA treatment significantly improved survival time and decreased recurrence rate compared to control disease group, with tolerable and reversible side-effects. Treatment normalized induced levels of VEGF and TGFalpha with a positive correlation between these cytokines.. Seven days after TURT visible tumor(s), combined atRA 1 mg/kg for five days a week + Keto 200 mg twice daily for five days a week for three months were given to 16 patients with SBC stages Ta and T1 with various grades. Three months follow up/20 months used white light cystoscopy and urinary cytology. Recurrence rate and survival time were compared to a retrospective group of 25 patients of comparable age, stage and grade with TURT as sole treatment for SBC. VEGF and TGFalpha were measured in urine and serum of 12 normal subjects and treated patients. Samples were collected just before TURT, one week after TURT, at the end of one month and at the end of three months of treatment.. The combination and schedule used for Keto-atRA therapy effectively reduced recurrence rate and increased survival time of SBC patients probably through reduction of VEGF and TGFalpha as major mitogenic/angiogenic factors; possibly by eliminating malignant cells that produce them.

Topics: Aged; Biomarkers; Cytochrome P-450 Enzyme System; Drug Therapy, Combination; Humans; Ketoconazole; Middle Aged; Neoplasm Recurrence, Local; Transforming Growth Factor alpha; Tretinoin; Urinary Bladder Neoplasms; Vascular Endothelial Growth Factor A

Topics: Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Drug Therapy, Combination; Humans; Ketoconazole; Neoplasm Recurrence, Local; Tretinoin; Urinary Bladder Neoplasms

Clinical trials have explored the use of natural and synthetic retinoids for the prevention of bladder cancer recurrence. Natural retinoids have been shown to inhibit bladder cancer growth. Here, we compared the effects of natural and synthetic retinoids in bladder cancer cells. Bladder cancer cell lines were treated with all-trans-retinoid acid (ATRA), N-4-hydroxyphenyl-retinamide (4-HPR) and 6-[3-(1-adamantyl)-4 hydroxyphenyl]-2-naphthalene carboxylic acid (CD437). Their effects on cell growth, apoptosis, cell cycle, gene expression, and retinoid acid receptors (RARs) and the JWA-retinoid response gene were assessed. Most of the bladder cancer cells were resistant to ATRA (1 and 10 microM). 4-HPR inhibited cell growth by 90% at 10 microM; however, CD437 showed the same effect at 1 microM. 4-HPR and CD437 increased G1 and decreased S phase. The three retinoids differentially affected p53, RARs, and JWA. Only CD437 increased Caspase 3 expression. The results demonstrated that 4-HPR and CD437 were more potent growth inhibitors and apoptosis inducers than ATRA. However, 4-HPR was effective at a concentration at least 10 microM. The in vitro results suggested the higher dose of 4-HPR in chemoprevention trial be considered.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Proliferation; Fenretinide; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Humans; Receptors, Retinoic Acid; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; Tretinoin; Tumor Cells, Cultured; Urinary Bladder Neoplasms

Retinoids modulate the growth and differentiation of normal and malignant epithelial cells in vitro and in vivo. Retinoids and their analogues have been used in animal models and clinical trials of chemoprevention and superficial bladder cancer treatment. Interferons are cytokines that have antiviral, antiproliferative and immunomodulatory function. They are used in many clinical trials for the treatment of different cancers. To identify new effective agents and develop novel approaches for the chemoprevention and treatment of superficial bladder cancer we investigated the effects of a combination of retinoids and interferon alpha-2a (IFN) on growth and apoptosis in bladder cancer cell lines.. The 4 bladder cancer cell lines UM-UC-6, UM-UC-9, UM-UC-10 and UM-UC-13 were treated with 2 retinoids, namely all-trans-retinoic acid (ATRA) and 9-cis retinoic acid (9cRA), as well as with IFN or with combinations of retinoids and IFN. The ability of these agents used alone and in combination to inhibit growth, induce apoptosis and modulate gene expression was investigated. The effects of retinoids on an INF related gene were also examined.. Most bladder cancer cell lines were resistant to growth inhibition and apoptosis induction by ATRA and 9cRA, even at a high concentration. The effects of these retinoids on cell growth and apoptosis were enhanced by IFN. The combination of ATRA and IFN induced retinoic acid receptor beta, and signal transducer and activator of transcription 1 expression in 3 bladder cancer cell lines, as detected by reverse transcriptase-polymerase chain reaction and Western blot analysis. Retinoids increased IFN-related gene expression detected by microarray analysis and real-time reverse transcriptase-polymerase chain reaction.. The results demonstrate that IFN acts synergistically with ATRA and 9cRA in the growth and apoptosis of bladder cancer cells in vitro and suggest that this combination has a potential for the treatment of transitional cell carcinoma of the bladder.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Transitional Cell; Cell Line, Tumor; DNA-Binding Proteins; Drug Therapy, Combination; Humans; Interferon alpha-2; Interferon-alpha; Protein Array Analysis; Recombinant Proteins; STAT1 Transcription Factor; Trans-Activators; Tretinoin; Urinary Bladder Neoplasms

Retinoids, which include vitamin A (retinol; ROL) and its derivatives, have been investigated in the treatment of bladder cancer. We have shown that expression of the enzyme lecithin:ROL acyltransferase (LRAT), which converts ROL to retinyl esters, is reduced in several human cancers. Here we evaluated expression of LRAT protein and mRNA in normal and malignant bladder tissue specimens from human patients. We also examined the effect of retinoids on LRAT expression in bladder cancer cell lines.. We evaluated 49 bladder cancer specimens for LRAT protein expression using immunohistochemistry with affinity-purified antibodies to human LRAT. LRAT mRNA expression was assessed using reverse transcription-PCR in bladder specimens from an additional 16 patients. We examined the effect of retinoic acid and ROL on LRAT mRNA expression in five human bladder cancer cell lines.. LRAT protein was detected throughout the nonneoplastic bladder epithelium in all of the specimens. In bladder tumors, LRAT protein expression was reduced compared with the nonneoplastic epithelium or was completely absent in 7 of 32 (21.9%) superficial tumors versus 16 of 17 (94.1%) invasive tumors (P < 0.001). All of the non-neoplastic bladder specimens tested (11 of 11) showed LRAT mRNA expression, compared with 5 of 8 (62%) superficial tumors and 0 of 5 (0%) invasive tumors (P = 0.001). Three of five human bladder cancer cell lines expressed LRAT mRNA independent of retinoid exposure, whereas in two cell lines LRAT mRNA expression was induced by retinoid treatment.. We report a significant reduction in LRAT expression in bladder cancer. Moreover, we demonstrate an inverse correlation of LRAT mRNA and protein expression with increasing tumor stage. These data suggest that loss of LRAT expression is associated with invasive bladder cancer.

Topics: Acyltransferases; Adult; Aged; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Disease Progression; Esters; Extracellular Matrix; Female; Humans; Immunohistochemistry; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; Prognosis; Proportional Hazards Models; Receptors, Estrogen; Receptors, Progesterone; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; RNA, Messenger; Tretinoin; Urinary Bladder Neoplasms

Urinary bladder epithelial cells play an important role in the host defense against urinary tract infections. Interferon-gamma (IFN-gamma) is a potent cytokine that regulates immune responses by inducing multiple genes in many types of cells including urinary bladder epithelial cells. Retinoic acid-inducible gene-I (RIG-I) is a member of the DExH-box family, which is involved in various reactions related to RNA metabolism, and is induced in leukemic cells by retinoic acid or in endothelial cells by lipopolysaccharide. We have studied the expression of RIG-I in T24 cells, a cell line derived from human urinary bladder epithelial carcinoma cells. IFN-gamma stimulated T24 cells to express RIG-I mRNA and protein in concentration- and time-dependent manners. Immunohistochemical analysis revealed the expression of RIG-I in the urinary bladder epithelium from a patient with chronic urinary tract infection and in a bladder epithelial carcinoma. We conclude that RIG-I may play some role in inflammatory reactions in the urinary tract epithelium.

Topics: Antineoplastic Agents; Blotting, Western; Carcinoma; Cell Line, Tumor; DEAD Box Protein 58; DEAD-box RNA Helicases; Dose-Response Relationship, Drug; Epithelial Cells; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Interferon-gamma; Interleukin-4; Kinetics; Receptors, Immunologic; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA Helicases; RNA, Messenger; Tretinoin; Up-Regulation; Urinary Bladder Neoplasms

Superficial bladder cancer is a major target for chemoprevention. Retinoids are important modulators of epithelial differentiation and proliferation and are effective in the treatment and prevention of several epithelial cancers. One class of compounds, the retinamides, is structurally similar to other retinoids but have the added feature of being potent apoptosis inducers. Among these, fenretinide (N-[4-hydroxyphenyl]retinamide), or 4HPR, has promise for bladder cancer chemoprevention and is currently under Phase III study in this setting. In addition to 4HPR, there are several new structurally related phenylretinamides bearing hydroxyl, carboxyl, or methoxyl residues on carbons 2, 3, and 4 of the terminal phenylamine ring [designated N-(2-hydroxyphenyl)retinamide, N-(3-hydroxyphenyl)retin amide, N-(2-carboxyphenyl)retin- amide, N-(3-carboxyphenyl)retin amide, N-(4-carboxy- phenyl)retinamide, and N-(4-methoxyphenyl)retinamide, respectively]. The objective of this study was to compare the growth inhibitory and apoptotic effects of these phenylretinamides with 4HPR in human bladder transitional cell cancer-derived cell lines of varying histological grade (RT4, grade 1; UM-UC9 and UM-UC10, grade 3; and UM-UC14, grade 4) by cell counting, cell cycle fluorescence-activated cell sorter analysis and a dual stain apoptosis assay. All of the seven phenylretinamides reduced cell number, altered the cell cycle distribution, and induced apoptosis when administered at a concentration of 10 microM, which is within the pharmacologically achievable range. Although the relative potencies of the phenylretinamides varied depending on the cell line, N-(3-hydroxy phenyl)retin- amide was the most active with significantly greater growth inhibition than 4HPR in all of the four cell lines. These in vitro findings warrant further study of these novel phenylretinamides, which may have potential as preventive or therapeutic agents in transitional cell cancer.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Carcinoma, Transitional Cell; Cell Division; Fenretinide; Humans; Retinoids; Tretinoin; Tumor Cells, Cultured; Urinary Bladder Neoplasms

The aim of this study was to investigate the effect of retinoic acid (RA) and its complexes with transition metals on the bladder cancer cell line EJ. Retinoic acid complexes with transition metals Cu, Co, Zn, and Ni were prepared. Cell proliferation was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in the presence of RA or its complexes with transition metals Cu, Co, Zn, and Ni ¿Cu(RA)2.3H2O, Co(RA)2.3H2O, Zn(RA)2.4H2O, and Ni(RA)2.3H2O¿. Colony formation in soft agar culture, A agglutination reaction, and lactic acid dehydrogenase isoenzyme assay were performed in the cells treated with these drugs to estimate the induced differentiation. p53 or c-Ha-ras expression in drug-treated cells was assayed by ABC immunocytochemistry technique. The results demonstrate that EJ cells treated with the drugs become less confluent and tend to exhibit normal characteristics. Although RA and its complexes showed inhibition to proliferation of EJ cells at the concentrations of 10(-6) mmol/l, the inhibition induced by Ni(RA)2.3H2O was much more marked than that by RA. EJ cells were growth inhibited by RA or Ni(RA)2.3H2O from 48 to 96 h at the concentration of 10(-8) mol/l. The levels of LDH4 and LDH5 in the cells were greatly increased by RA. Nevertheless, Ni(RA)2.3H2O did not affect LDH isoenzyme in EJ cells. The number of colony formations of EJ cells in soft agar culture was decreased by RA or Ni(RA)2.3H2O. The percentage of colony formation in soft agar culture was much lower in EJ cells treated with Ni(RA)2.3H2O than with RA. The required concentration of A agglutination reaction was more increased for EJ cells treated with RA or Ni(RA)2.3H2O than for the control and was further increased in cells treated with Ni(RA)2.3H2O. Mutant p53 expression was more decreased in the EJ cells treated with RA or Ni(RA)2.3H2O than in the control. Although RA at the concentration of 10(-6) mmol/l caused lower p21 expression, Ni(RA)2.3H2O did not affect p21 expression in EJ cells. Therefore, RA and its transition metal complexes have a potential use in the treatment of bladder cancer.

Topics: Agar; Agglutination Tests; Antineoplastic Agents; Carcinoma, Transitional Cell; Cell Differentiation; Cell Division; Cobalt; Copper; Gene Expression Regulation, Neoplastic; Humans; In Vitro Techniques; Isoenzymes; L-Lactate Dehydrogenase; Metals; Mutation; Nickel; Proto-Oncogene Proteins p21(ras); Tretinoin; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Urinary Bladder Neoplasms; Zinc

Retinoids have been shown to have activity in both preclinical and clinical bladder cancer studies but their exact role in its treatment and prevention remains obscure. In this study cytostatic activity of a novel 9-cis-retinoic acid (9-cis-RA) was compared with two other retinoids: tretinoin and isotretinoin, in three different bladder cancer cell lines: RT4 (well differentiated), 5637 (moderately differentiated) and T24 (poorly differentiated). The three retinoids were incubated at concentrations of 0.3, 3 and 30 microg/ml with bladder cancer cells in microtitre plates for 3 and 6 days. The cytostatic effect was estimated by using luminometric measuring of ATP activity of viable cells in suspension. Compared with the older retinoids, tretinoin and isotretinoin, the highest concentration of 9-cis-RA had a cytostatic efficacy in all three bladder cancer cell lines tested. A clear dose response relationship was observed in isotretinoin-treated cultures after 6 days and in all 9-cis-RA-treated cultures. Tretinoin was either ineffective or had a stimulating effect on poorly differentiated tumour cells. To conclude, isotretinoin and 9-cis-RA had a cytostatic effect on human bladder cancer cells in vitro. However, the possibility of stimulating cancer growth at small doses, at least with tretinoin, and toxicity at high doses must be considered when planning clinical trials.

Topics: Alitretinoin; Antineoplastic Agents; Dose-Response Relationship, Drug; Humans; Isotretinoin; Time Factors; Tretinoin; Tumor Cells, Cultured; Urinary Bladder Neoplasms

The present study examined the expression and role of the thiazolidinedione (TZD)-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), in human bladder cancers. In situ hybridization shows that PPARgamma mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's) studied (n=11). PPARgamma was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor alpha (RXRalpha), a 9-cis-retinoic acid stimulated (9-cis-RA) heterodimeric partner of PPARgamma, was also co-expressed in all TCCa tissues and cell lines. Treatment of the T24 bladder cancer cells with the TZD PPARgamma agonist troglitazone, dramatically inhibited 3H-thymidine incorporation and induced cell death. Addition of the RXRalpha ligands, 9-cis-RA or LG100268, sensitized T24 bladder cancer cells to the lethal effect of troglitazone and two other PPAR- activators, ciglitazone and 15-deoxy-delta(12,14)-PGJ2 (15dPGJ(2)). Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, p21(WAF1/CIP1) and p16(INK4), and reduced cyclin D1 expression, consistent with G1 arrest. Troglitazone also induced an endogenous PPARgamma target gene in T24 cells, adipocyte-type fatty acid binding protein (A-FABP), the expression of which correlates with bladder cancer differentiation. In situ hybridization shows that A-FABP expression is localized to normal uroepithelial cells as well as some TCCa's. Taken together, these results demonstrate that PPARgamma is expressed in human TCCa where it may play a role in regulating TCCa differentiation and survival, thereby providing a potential target for therapy of uroepithelial cancers.

Topics: Alitretinoin; Antineoplastic Agents; Apoptosis; Carcinoma, Transitional Cell; Carrier Proteins; Cell Death; Chromans; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; DNA; DNA, Complementary; Dose-Response Relationship, Drug; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; G1 Phase; Humans; Immunoblotting; In Situ Hybridization; Ligands; Luciferases; Myelin P2 Protein; Neoplasm Proteins; Nicotinic Acids; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Ribonucleases; Tetrahydronaphthalenes; Thiazoles; Thiazolidinediones; Transcription Factors; Transcriptional Activation; Transfection; Tretinoin; Troglitazone; Tumor Cells, Cultured; Tumor Suppressor Proteins; Urinary Bladder Neoplasms

Bladder cancer cells have been shown to secrete a variety of factors that are not related to cells of urothelial origin. The histogenesis of these tumour developments is uncertain, and a variety of theories have been previously reported. In the present manuscript, we identify the factors constitutively produced by a human bladder cancer cell line (KU-19-19) that was found to produce beta human chorionic gonadotrophin (beta-hCG), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1alpha (IL-1alpha), interleukin 6 (IL-6) and interleukin 8 (IL-8). The cells were obtained from a case of metastatic carcinoma that was originally diagnosed to be a grade 3 (WHO classification), invasive transitional cell carcinoma of the bladder. On microscopic observation, the cultured cells exhibited an epithelial appearance with vacuole formation in their cytoplasm. Ultrastructural observations revealed relatively marked microvilli and a tight junction. Significant amounts of beta-hCG, G-CSF, GM-CSF, IL-1alpha, IL-6 and IL-8 concentrations in the supernatant from cultured cells were demonstrated by enzyme-linked immunosorbent assays, while the expression of mRNA of these marker proteins in cancer cells was also significantly exhibited by reverse transcription polymerase chain reaction (RT-PCR). In addition, the expression of G-CSF receptor and IL-6 receptor mRNA was also shown by RT-PCR. Xenograft transplantability using nude mice was observed in association with the presence of severe neutrophilia in the peripheral blood. These results indicate that this cell line appears to be an effective model for the study of transitional cell carcinoma of the bladder with multipotent differentiation potentials.

Topics: Aged; Animals; Carcinoma, Transitional Cell; Cell Differentiation; Chorionic Gonadotropin, beta Subunit, Human; Cytokines; DNA Primers; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron; Neoplasm Transplantation; Polymerase Chain Reaction; RNA, Messenger; Tretinoin; Tumor Cells, Cultured; Urinary Bladder Neoplasms

To study the effect of tretinoin (Tre) or retinol (Ret) on the proliferation of lymphokine-activated killer (LAK) cells in patients with transitional cell cancer of bladder and their cytolysis to bladder tumor cells.. LAK cell proliferation was assayed in the presence of either Tre or Ret by cell counting. Human transitional bladder cancer cell lines BIU-87, EJ, or bladder tumor cells (BTC) from patients with bladder cancer were used as target cells and cytotoxicity of LAK cells was determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.. The proliferation of LAK cells induced by interleukin-2 (IL-2) was stimulated by Tre or Ret (10-100 nmol.L-1). The cytotoxicity of LAK cells against BIU-87, EJ cells, or BTC was enhanced by pretreatment of LAK cells with Tre or Ret 10-100 nmol.L-1.. Tre or Ret enhances the proliferation and cytotoxicity of LAK cells from patients with bladder cancer. Retinoids are potential in adoptive immunotherapy of bladder cancer.

Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Cell Division; Cytotoxicity, Immunologic; Humans; Immunotherapy, Adoptive; Killer Cells, Lymphokine-Activated; Tretinoin; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Vitamin A

The aim was to establish a model of reversible radiosensitization in human tumor cell lines by all-trans retinoic acid without influencing cell cycle or differentiation.. Three human carcinoma cell lines (one bladder and two lung lines) were incubated in medium containing delipidized serum with or without varying concentrations of all-trans retinoic acid for a range of time periods, and their acute response to radiation measured by clonogenic assay. Cell phenotype was monitored using growth rates, morphology, and intermediate filament expression.. Two of the three cell lines (those in which cell kill was predominantly through reparable damage beta in control cultures) showed an increase in radiosensitivity with retinoic acid, at a concentration with no discernable effect on phenotype (10(-7) M). No significant change in alpha values was observed. The values for beta increased from 0.057 to 0.109 and from 0.039 to 0.075, corresponding to dose modification factors of 1.59 and 1.67. When retinoic acid was removed prior to irradiation, cell survival returned to control levels by 48 h.. Radiosensitization occurred at retinoic acid concentrations that did not otherwise perturb the cells; the effect may be due to inhibition of DNA repair in cells usually competent at repair. The model provides a method of altering radiosensitivity in selected cell lines without genetic mutation, which may enable investigation of DNA repair mechanisms.

Topics: Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Transitional Cell; Cell Cycle; Cell Survival; Humans; Lung Neoplasms; Phenotype; Radiation Tolerance; Time Factors; Tretinoin; Tumor Cells, Cultured; Urinary Bladder Neoplasms

The model of precancerous lesions of the bladder in rats was induced by N-butyl-(4-hydroxybutyl) nitrosamide (BBN). The animals were randomly divided into the following 3 groups: 1) given Antitumor-B (Chinese herbs); 2) given 4-ethoxycarbophenylretinamide (Retinamide); and 3) control. After treatment for 13 months the rats were killed for pathomorphological examination of the bladder. The results showed that the incidence of bladder cancer in group 1 and 2 was reduced by 90.7% (P < 0.01) and 75.0% (P < 0.01) respectively after treatment as compared with the control group. Our results provide a useful reference for clinical trial in the prevention of bladder cancer recurrence by using antitumor-B and Retinamide.

Topics: Animals; Antineoplastic Agents, Phytogenic; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Drugs, Chinese Herbal; Precancerous Conditions; Rats; Rats, Wistar; Tretinoin; Urinary Bladder Neoplasms

Glutathione S-transferases (GSTs) are a group of enzymes which play an important role in the detoxication of xenobiotics. It is shown that the expression of human glutathione S-transferase P1-1 (GSTP1-1) is suppressed by retinoic acid (RA) as the result of decreased transcription from its gene, GSTP1. Chloramphenicol acetyltransferase (CAT) assays indicate that the effect of RA on the transcription of a GSTP1 promoter-CAT fusion gene is mediated by the region -99 to +72 of GSTP1. A consensus activator protein 1-binding site, located at nucleotide position -59 to -65 of GSTP1, is suggested to be responsible for RA repression. This effect of RA on GSTP1 expression is mediated by the human beta-type RA receptor, hRAR beta, but not the chicken retinoid X receptor, cRXR. The retinoid X receptor does not augment the action of hRAR beta on GSTP1. In addition, it is shown that GSTP1-1 expression is enhanced by insulin as a result of increased transcription of GSTP1. Assay of CAT activity indicates that the effect of insulin on the transcription of GSTP1 is also mediated by the region -99 to +72 of GSTP1. Comparison with sequences of other insulin-responsive genes, suggests that insulin enhancement of GSTP1 expression is effected by an eight-base-pair sequence, 'CCCGCGTC', located at +48 to +55 in intron 1 of the gene. These results are discussed in relation to the increased expression of GSTP1-1 in many tumour cells.

Topics: Animals; Base Sequence; Carrier Proteins; Chickens; Chloramphenicol O-Acetyltransferase; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutathione Transferase; Humans; Insulin; Kinetics; Promoter Regions, Genetic; Receptors, Cell Surface; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoid X Receptors; Transcription Factors; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured; Urinary Bladder Neoplasms

The effects and interactions were investigated of the two growth regulatory molecules alltrans retinoic acid (RA), and epidermal growth factor (EGF) on the in vitro expression by bladder cancer cell lines of the transformed phenotype (anchorage-independent growth in soft agar). When tested individually, the two molecules had opposite effects: RA (10(-11) to 10(-5) M) caused a dose-related reduction in anchorage-independent growth, whereas EGF (0.1 to 50 ng/ml) caused a dose-dependent increase. These effects were observed with both cell lines tested: RT112, a human papillary, non-metastatic bladder cancer cell line and RU-CL2, a rat metastatic bladder carcinoma cell line. When the effect of EGF (2.5 ng/ml) was tested against the growth inhibition produced by a range of doses of RA, EGF stimulated growth and reduced the degree of inhibition produced by RA at all dose levels. Conversely, a single dose of 10(-8) M RA tested against a range of EGF concentrations reduced the dose-related EGF-induced increase in anchorage-independent growth. The two cell lines responded similarly to those combinations of RA and EGF in vitro, regardless of their different biological potentials in vivo. These experiments provide no evidence that RA potentiates EGF-induced growth, as has been observed by others using mesenchymal cells. RA could, therefore, theoretically be used to inhibit or delay bladder tumour recurrences. Trials would show whether oral doses of RA, or of synthetic retinoids metabolized to RA, would reach therapeutic levels and be chemopreventive in bladder cancer patients.

Topics: Animals; Cell Division; Cell Line, Transformed; Dose-Response Relationship, Drug; Down-Regulation; Epidermal Growth Factor; ErbB Receptors; Humans; Phenotype; Rats; Receptors, Cell Surface; Tretinoin; Urinary Bladder Neoplasms

The ability of the retinoid compounds, all-trans and 13-cis, to inhibit the growth of bladder tumour cells was investigated in primary tissue culture. A significant decrease in tumour growth was evident in 9 human bladder cancer patients. Since retinoid compounds are able to delay the progression or induction of tumours in primary tissue culture, their trial use as intravesical agents may be warranted.

Topics: Cell Division; Humans; Isomerism; Tretinoin; Tumor Cells, Cultured; Urinary Bladder Neoplasms

RII, a new analog of retinoic acid, is an effective anticarcinogenic drug. The pharmacokinetic characteristics of RII were studied by HPLC in thirteen cancer patients after oral administration. The sensitivity to detect RII was greater than 3 ng and CV values of duplicate samples were 1.88-6.62. The results showed that peak concentration of RII in plasma appeared at 8 hrs after oral administration of 200 mg of the drug, and the mean peak concentration in serum was 3.612 +/- 1.099 micrograms/ml. Half life time (T1/2) was 6.62 +/- 0.81 hrs. The area under the drug-time curve (AUC) was 35.70 +/- 14.46 micrograms hr/ml. The results indicate that it is advisable to take RII twice a day.

Topics: Administration, Oral; Antineoplastic Agents; Chromatography, High Pressure Liquid; Female; Humans; Lung Neoplasms; Male; Tretinoin; Urinary Bladder Neoplasms

An in vitro clonogenic assay was used to study the activity of 3 established cytotoxic drugs and 3 experimental agents against a series of 33 human transitional cell carcinomas. Strict adherence to rigid colony size criteria gave very reproducible results with the 3 cytotoxic drugs (adriamycin, mitomycin C and thiotepa) and our sensitivity curves are of the form expected on the basis of past experience with tumour cell lines. The unexplained plateau form curves which have previously led to criticism of the assay were not seen. Resistant subpopulations were found only in poorly differentiated tumours. This modified assay was then used to test 3 experimental agents for activity against transitional cell carcinoma. Sulphopentosan, DMSO and retinoic acid all proved inactive in this system.

Topics: Carcinoma, Transitional Cell; Clone Cells; Colony-Forming Units Assay; Culture Techniques; Dimethyl Sulfoxide; Doxorubicin; Drug Resistance; Humans; Methods; Mitomycin; Mitomycins; Thiotepa; Tretinoin; Urinary Bladder Neoplasms

The effects of HER upon early and late stages of BBN-induced bladder cancer in rats were examined. Female Fischer 344 rats were administered HER in the diet either before and during or continuously after BBN administration and were monitored periodically for up to 2 years. The total dose of BBN was 600 mg administered over a 6-week period. In a separate experiment, the effects of HER administration to syngeneic recipients of a transplanted primary bladder cancer were examined. No effects on neoplastic development were observed as the result of HER treatment before and during carcinogen administration. However, at the 1-year sacrifice, there was a significant increase in bladder tumor incidence in the animals receiving BBN followed by continuous retinoid treatment versus animals receiving BBN only. At the 2-year sacrifice, there was a significant increase in tumor progression in the continuous retinoid group versus the animals receiving BBN alone, based upon grading and staging of tumors, although tumor incidences were not significantly different. In the transplantation experiment, more recipients (9/20 versus 2/20) receiving continuous HER had large, anaplastic tumors following 9 months of observation than did control animals. This study supports the view that retinoids should not be considered as only inhibitors of carcinogenesis, but rather as modifiers which vary in their effects depending upon factors yet to be understood.

Topics: Animals; Butylhydroxybutylnitrosamine; Female; Neoplasm Transplantation; Rats; Rats, Inbred F344; Time Factors; Tretinoin; Urinary Bladder Neoplasms

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

The effects of an aromatic retinoic acid analog (Ro 10-9359), its metabolite (Ro 10-1670) and mitomycin C (MMC) on the in vitro growth of rat bladder carcinoma cells, BC50-TC were examined. The growth of the cells treated with 10(-4) M of either of the retinoids for 1 hour was not inhibited. The growth of the cells was inhibited by 37% and 93%, respectively, by the 3-day treatment with Ro 10-9359 and Ro 10-1670, at the concentration of 5 X 10(-5) M. The retinoids given in combination with MMC produced additive effects. Slight synergism was suggested at high concentrations of the retinoid. The fact that the retinoids exhibited anti-tumor activity in vitro might preclude indirect effects from being the only factor in the inhibition of the tumor growth in vivo, but the fact that antagonism with MMC did not occur in vitro whereas it did in vivo suggests that the indirect effects of the retinoid might be more important in mediating the anti-tumor effects. Regardless of the mechanism of action, care should be taken when prescribing retinoids with MMC or other cytotoxic agents.

Topics: Acitretin; Animals; Cell Division; Cell Line; Cells, Cultured; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Etretinate; Mitomycin; Mitomycins; Rats; Tretinoin; Urinary Bladder Neoplasms

Several multivariate statistical methods are available which can alleviate the problems of analysing the large volumes of data generated from toxicological experiments. One such technique, principal components analysis, provides a method for exploring the relationships between a number of variables (such as blood parameters) and for eliminating redundant data if strong correlations exist between the characters. It also provides a method for clustering individuals, which may reveal similarities between animals in a treatment group or highlight individual 'outliers'. The application of principal components analysis to a set of haematological data from a trial evaluating the efficacy of a synthetic retinoid against carcinogen-induced bladder cancer in the rat has clearly shown, in two bivariate plots, that while some animals in the carcinogen-treated groups were normal, others were anaemic and that animals fed the synthetic retinoid and killed at 1 year had a microcytic anaemia. A full exploration of the data using conventional univariate statistical analysis would have involved at least 28 graphic representations of the data, as well as the interpretation of more than 130 means and SDs. Principal components analysis provides a valuable additional tool for the statistical analysis and exploration of toxicological data, but it must be used in conjunction with univariate or other multivariate methods if hypothesis testing is required. The use of multivariate techniques in toxicology may best be assessed by their practical application to toxicological data, and this paper presents such an evaluation with the aim of encouraging further exploration of the usefulness of principal components analysis. The raw data on which most analyses have been carried out are given.

Topics: Analysis of Variance; Animals; Antineoplastic Agents; Blood; Blood Cell Count; Blood Cells; Butylhydroxybutylnitrosamine; Drug Evaluation, Preclinical; Erythrocytes; Female; Hemoglobins; Rats; Rats, Inbred F344; Time Factors; Tretinoin; Urinary Bladder Neoplasms

The prophylactic effect of 2 retinoids (Ro 4-3780 and Ro 10-9359), either alone or in combination with Bacillus Calmette Guérin (BCG), was studied in an experimental murine bladder tumor model. The incidence of tumor takes in all treatment groups was lower than in the control group. Both BCG and Ro 10-9359 were effective in decreasing the percentage of tumor takes and the simultaneous use of these agents was more effective than either one alone. Ro 10-9359 was found to possess more antitumor activity than Ro 4-3780 in this tumor model. Treatment of mice with a combination of Ro 10-9359 and BCG resulted in an 83.3 per cent incidence of complete tumor regression within 80 days. Results suggest that vitamin A derivatives may be useful in the prevention and treatment of bladder cancer and that the activity is likely potentiated by nonspecific stimulation.

Topics: Animals; BCG Vaccine; Etretinate; Female; Isotretinoin; Mice; Mice, Inbred C3H; Neoplasms, Experimental; Tretinoin; Urinary Bladder Neoplasms

N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid, and MVE-2, a maleic anhydride-divinyl ether copolymer, were both effective inhibitors of mammary carcinogenesis induced in Sprague-Dawley rats by N-methyl-N-nitrosourea and of urinary bladder carcinogenesis induced in C57BL/6 x DBA/2F1 mice by N-butyl-N-(4-hydroxybutyl)-nitrosamine. However, combined administration of 4-HPR and MVE-2 was no more effective in cancer inhibition than was either agent alone. Retinoids and maleic anhydridedivinyl ethers may exhibit a mechanistic or metabolic antagonism which precludes an additive or synergistic interaction in inhibiting chemical carcinogenesis.

Topics: Animals; Diet; Female; Fenretinide; Mammary Neoplasms, Experimental; Mice; Neoplasms, Experimental; Polymers; Pyran Copolymer; Rats; Rats, Inbred Strains; Time Factors; Tretinoin; Urinary Bladder Neoplasms

An aromatic retinoic acid analog (Ro 10-9359) was given orally in combination with intraperitoneal administration of mitomycin C (MMC), in an attempt to reduce the toxicity and enhance the therapeutic effect. Male ACI/N rats were inoculated subcutaneously with BC50-TC cells, an established bladder carcinoma cell line of ACI/N rats. The chemotherapy was initiated at 16 days after the inoculation and continued for 4 weeks thereafter. Tumor growth was significantly inhibited in the rats given 100 mg/kg/week Ro 10-9359 or 0.3 mg/kg/twice a week MMC. Neither additive nor synergistic effect was apparent when these two drugs were given simultaneously. No effect was seen when 0.1 mg/kg/twice a week MMC was given alone or in combination with Ro 10-9359. MMC may suppress Ro 10-9359 activity directly or indirectly by affecting the responding cells. Therefore care should be taken when prescribing retinoids with MMC or possibly with other cytotoxic agents.

Topics: Animals; Antineoplastic Agents; Carrier Proteins; Drug Therapy, Combination; Etretinate; Male; Mitomycin; Mitomycins; Neoplasms, Experimental; Rats; Rats, Inbred ACI; Receptors, Retinoic Acid; Tretinoin; Urinary Bladder Neoplasms; Vitamin A

Topics: Carrier Proteins; Electrophoresis, Agar Gel; Humans; Neoplasm Proteins; Receptors, Retinoic Acid; Tretinoin; Urinary Bladder Neoplasms

A series of experiments was conducted to determine the efficacy of 15 synthetic retinoic acid amides (retinamides) as inhibitors of chemical carcinogenesis of the urinary bladder in C57BL/6 x DBA/2F1 mice. Eight of the retinamides tested had significant protective activity when administered at nontoxic levels in the diet. Minor structural alterations, such as the addition of a methyl or hydroxyl group to the terminal amide moiety had a major influence on the anticarcinogenic activity of the retinamides. Although 13-cis retinamides generally were less toxic on a molar basis than were their all-trans isomers, no consistent pattern of differential anticarcinogenic activity was noted among the six pairs of all-trans and 13-cis isomers tested. All-trans-4-hydroxyphenyl retinamide was among the most active and least toxic of the retinoids tested, and appears to be the compound of choice for further study.

Topics: Animals; Butylhydroxybutylnitrosamine; Carcinogens; Diet; Mice; Molecular Conformation; Neoplasms, Experimental; Tretinoin; Urinary Bladder Neoplasms

Topics: Cell Division; Female; Humans; Melanoma; Ovarian Neoplasms; Structure-Activity Relationship; Tretinoin; Urinary Bladder Neoplasms

The failure of 13-cis-retinoic acid to inhibit either the incidence or severity of bladder carcinoma in female Fischer rate initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) suggests that inhibition of bladder carcinogenesis by natural and synthetic retinoids is carcinogen-class specific, and adds an element of complexity to approaches in chemoprevention.

Topics: Animals; Butylated Hydroxytoluene; Carcinogens; FANFT; Female; Isomerism; Isotretinoin; Neoplasms, Experimental; Rats; Rats, Inbred F344; Thiazoles; Tretinoin; Urinary Bladder Neoplasms

The failure of N-ethylretinamide and N-(2-hydroxyethyl)retinamide to inhibit the incidence or severity of bladder carcinoma in female Fischer rats initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide supports the concept that the inhibition of bladder carcinogenesis by natural and synthetic retinoids is carcinogen-class specific.

Topics: Animals; Body Weight; FANFT; Female; Neoplasms, Experimental; Rats; Rats, Inbred F344; Thiazoles; Tretinoin; Urinary Bladder Neoplasms

Highly invasive carcinomas of the urinary bladder were induced in male C57BL/6 X DBA/2 F1 (hereafter called B6D2F1) mice by gastric intubation of N-butyl-(4-hydroxybutyl)nitrosamine (OH-BBN) using a quantitative dosing schedule. Animals received either 5 or 10 mg OH-BBN per intubation, two times each week, for 9 weeks for a total dose of either 90 or 180 mg, and they were killed 6 months after the first carcinogen intubation. Seven days after the final intubation of OH-BBN, animals were fed either a placebo diet or diet supplemented with either 150 or 200 mg 13-cis-retinoic acid per kg of diet. A 41 and 43% incidence of urinary bladder cancer was observed in mice given the low and high dose of carcinogen, respectively, and fed a placebo diet. Sixty-seven % of the carcinomas induced in these animals invaded either into or through the urinary bladder wall. Varying degrees of transitional and either squamous or glandular or both squamous and glandular differentiation were observed in the carcinomas. Feeding of diet supplemented with 13-cis-retinoic acid reduced cancer incidence; the degree of reduction was proportional to the dose of retinoid administered. The highly invasive nature of the carcinomas induced by quantitative administration of OH-BBN in B6D2F1, mice provides a useful animal model of the highly invasive variant of human transitional cell urinary bladder cancer in which to study chemoprevention by retinoids as well as other compounds.

Topics: Animals; Butylhydroxybutylnitrosamine; Disease Models, Animal; Male; Mice; Microscopy, Electron; Neoplasms, Experimental; Nitrosamines; Tretinoin; Urinary Bladder Neoplasms

The chemopreventive activity of two synthetic retinamides of relatively low toxicity against N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder cancer was studied in F344 rats and C57BL/6 X DBA/2 F1 mice. Female and male rats were given a total dose of either 1800 or 3200 mg OH-BBN over a period of 6 or 8 weeks, respectively. Male mice were given a total dose of either 90 or 180 mg OH-BBN over a period of 9 weeks. Seven days after the final intubation of a period of 9 weeks. Seven days after the final intubation of OH-BBN, animals were fed either a placebo diet or a diet supplemented with the following retinoids: for rats, 0.8 mmol 13-cis-retinoic acid, 2 mmol N-(ethyl)-all-trans-retinamide, or 2 mmol N-(2-hydroxyethyl)-all-trans-retinamide per kg diet; and for mice, either 0.5 or 1.0 mmol of N-(ethyl)-all-trans-retinamide or N-(2-hydroxyethyl)-all-trans-retinamide per kg diet. Animals were killed 6 months after the initial gastric intubation. In comparison to male and female rats fed placebo diets, all three retinoids reduced the incidence, number, and severity of the low-grade papillary transitional cell carcinomas of the urinary bladder. Similarly, treatment of mice with either of the two retinamides reduced the incidence of highly invasive urinary bladder carcinomas. The chemopreventive effect of the less toxic retinamides was equal to or greater than that of 13-cis-retinoic acid.

Topics: Animals; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Female; Male; Mice; Neoplasms, Experimental; Nitrosamines; Rats; Tretinoin; Urinary Bladder Neoplasms

The responses of mouse urinary bladder ornithine decarboxylase (EC 4.1.1.17) and S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50) activities were studied following topical intravesical administration of N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) or 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT), potent rodent bladder carcinogens. A single bladder topical application of ANFT or FANFT resulted in a significant increase over controls of ornithine decarboxylase activity within 5 hr, with a return to control levels by 10 hr. S-Adenosyl-L-methionine decarboxylase activity demonstrated a lesser response to topical ANFT or FANFT, achieving a level 2 or 3 times that of controls at 5 to 8 hr, followed by a gradual decline to control levels. Stimulation of activities of both enzymes was dose dependent over a range of 4.6 to 460 nmol of ANFT. ANFT-induced ornithine decarboxylase activity was principally localized in the bladder epithelium and was inhibited in a linear dose-response relationship by the synthetic retinoid, 13-cis-retinoic acid. Mice given FANFT p.o. demonstrated a significant increase over controls in ornithine decarboxylase activity within 12 hr, followed by a gradual decline to control levels by 72 hr.

Topics: Adenosylmethionine Decarboxylase; Animals; Carboxy-Lyases; Carcinogens; Enzyme Induction; Epithelium; FANFT; Female; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Thiazoles; Tretinoin; Urinary Bladder; Urinary Bladder Neoplasms

The inhibitory effect of an aromatic retinoic acid analog, ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate, on bladder carcinogenesis in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was evaluated. Administration of 50 ppm of aromatic retinoid in the diet before BBN in the drinking water reduced the incidence of papillary or nodular hyperplasia as a preneoplastic lesion of the bladder epithelium (P < 0.05). When given before, during or after BBN, it also greatly reduced the incidence of papilloma (P < 0.001 before BBN, P < 0.01 during or after BBN treatment), and slightly inhibited the development of cancer. Administration of 100 ppm of aromatic retinoid before or during BBN administration also reduced the incidences of papillary or nodular hyperplasia (P < 0.01 before BBN, P < 0.05 during BBN treatment), and its administration before, during or after BBN treatment greatly reduced the incidences of papilloma (P < 0.001), and cancer (P < 0.01 before or after BBN, P < 0.001 during BBN treatment). Similar results were obtained by assessing the effect of the retinoid on the average numbers of various epithelial lesions per 10 cm length of basement membrane of the bladder in tissue slices. These results show that the aromatic retinoid inhibits both the initiation and promotion of bladder carcinogenesis induced in rats by BBN, and that its effect is dose-dependent.

Topics: Animals; Butylhydroxybutylnitrosamine; Cricetinae; Etretinate; Hyperplasia; Male; Mice; Nitrosamines; Papilloma; Precancerous Conditions; Rats; Tretinoin; Urinary Bladder; Urinary Bladder Neoplasms

Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Humans; Neoplasm Recurrence, Local; Thiotepa; Tretinoin; Urinary Bladder Neoplasms

The effect of a delay in starting 13-cis-retinoic acid treatment on the inhibition of urinary bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine was studied in male Fischer 344 rats. Animals received a total p.o. dose of either 1200, 1800 or 2400 mg N-butyl-N-(4-hydroxybutyl)nitrosamine over a period of six weeks. At either one, five, and nine weeks after the last N-butyl-N-(4-hydroxybutyl)nitrosamine intubation, animals were started on a diet supplemented with 13-cis-retinoic acid (240 mg/kg of laboratory chow) or continued on laboratory chow. Animals were killed at one year after the first carcinogen intubation for histological evaluation of the bladder. Feeding of 13-cis-retinoic acid reduced the incidence, average number, and severity of transitional cell carcinomas as well as hyperplasia and cellular atypia. Furthermore, even a nine-week delay in starting the retinoid feeding did not diminish the ability of 13-cis-retinoic acid to inhibit bladder carcinogenesis.

Topics: Animals; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Dose-Response Relationship, Drug; Male; Neoplasms, Experimental; Rats; Rats, Inbred F344; Time Factors; Tretinoin; Urinary Bladder Neoplasms; Vitamin A

Topics: Animals; Cell Membrane; Female; Isomerism; Methylnitrosourea; Microscopy, Electron; Microscopy, Electron, Scanning; Nitrosourea Compounds; Rats; Structure-Activity Relationship; Tretinoin; Urinary Bladder Neoplasms

Topics: Antineoplastic Agents; Female; Hospitals, University; Humans; Male; Platinum; Tretinoin; Urinary Bladder Neoplasms

Topics: Animals; Cell Differentiation; Humans; Rats; Risk; Time Factors; Tretinoin; Urinary Bladder Neoplasms; Vitamin A

The effect of 13-cis-retinoic acid on the induction of urinary bladder carcinoma by N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) was studied in male C57BL/6 mice. Animals received a total dose of either 90 or 140 mg of OH-BBN via gastric intubations of 7.5 or 10.0 mg of OH-BBN 2 times each week for 6 or 7 weeks, respectively. Seven days after the last OH-BBN intubation, animals were fed laboratory chow diet supplemented with either 200 mg of 13-cis-retinoic acid per kg or its placebo. Animals were killed at 6 months after the first carcinogen intubation. Highly invasive squamous and transitional cell carcinomas of the urothelium were found at autopsy. In the majority of these carcinomas, invasion of the bladder muscle wall by tumor cells had occurred. At the two dose levels of OH-BBN, feeding of 13-cis-retinoic acid reduced the incidence of both carcinomas and noninvasive papillomas, as well as the extent of neoplastic development in the urinary bladder. In mice receiving the lower dose of OH-BBN, the feeding of 13-cis-retinoic acid prevented the appearance of both squamous and transitional cell carcinomas with a reduction in incidence from 33 to 0% (p less than 0.01). The results of this study indicate that 13-cis-retinoic acid reduced not only the severity of highly invasive urinary bladder carcinomas but also the incidence of such cancers.

Topics: Animals; Butylhydroxybutylnitrosamine; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Male; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Nitrosamines; Tretinoin; Urinary Bladder Neoplasms; Vitamin A

Transitional cell and squamous cell cancer of the bladder was induced in Wistar/Lewis female rats by direct instillation of N-methyl-N-nitrosourea into the bladder. Feeding of the synthetic retinoid, 13-cis-retinoid acid, inhibited the incidence and extent of bladder cancer in these rats, even when 13-cis-retinoic acid administration was begun after completion of the carcinogen treatment.

Topics: Animals; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Female; Methylnitrosourea; Neoplasms, Experimental; Rats; Tretinoin; Urinary Bladder Neoplasms; 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

An objective system for histopathological and statistical evaluation of rat bladder lesions induced by the carcinogen, N-methyl-N-nitrosourea, is described. This system has been used to measure the inhibitory effects of 13-cis-retinoic acid on the development of bladder cancer in female Wistar/Lewis rats. 13-cis-Retinoic acid caused significant inhibition of development of both preneoplastic and neoplastic lesions in bladder epithelium.

Topics: Animals; Epithelium; Female; Methylnitrosourea; Neoplasms, Experimental; Precancerous Conditions; Rats; Statistics as Topic; Tretinoin; Urinary Bladder Neoplasms; Vitamin A

Transitional cell carcinoma was induced in the bladders of male Fischer rats by 12 oral doses of the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine. Feeding of 13-cis-retinoic acid after completion of carcinogen treatment diminished the number and severity of cancers and other proliferative lesions of the bladder.

Topics: Animals; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Male; Neoplasms, Experimental; Nitrosamines; Rats; Rats, Inbred F344; Tretinoin; Urinary Bladder Neoplasms; Vitamin A