fenretinide and Urinary-Bladder-Neoplasms
fenretinide has been researched along with Urinary-Bladder-Neoplasms* in 24 studies
Reviews
3 review(s) available for fenretinide and Urinary-Bladder-Neoplasms
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Retinoids in the chemoprevention of bladder cancer.
Bladder cancer is strongly related to tobacco use and is estimated to cause 54,500 new cancer cases and 11,700 deaths in the United States in 1998. Approximately two thirds of new US cases will be superficial tumors, predominantly low-grade papillary. After standard therapeutic resection (with or without intravesical therapy), the superficial bladder tumor recurrence rate is 30% to 70% within 12 months of resection. Morbidity is substantial, with frequent cystoscopy, recurrence, resections, and possible cystectomy for progression to invasive cancers. Therefore, new approaches, including chemoprevention, are needed. Data suggest that bladder carcinogenesis is a multi-step, multifocal (field effect) process, possibly involving the spread of premalignant clones--all of which are prerequisites for effective chemopreventive approaches. To date, retinoids are the best-studied chemopreventive agents in this site, achieving mixed clinical results (with 13-cis-retinoic acid and etretinate) in superficial bladder tumors. This review includes the epidemiology and biology of bladder carcinogenesis in addition to preclinical and clinical retinoid data, and focuses on the most promising avenue of current retinoid chemoprevention in the bladder: the potent apoptosis-inducing retinoid fenretinide (4-HPR), which currently is in three phase III trials. Topics: Anticarcinogenic Agents; Clinical Trials as Topic; Fenretinide; Humans; Retinoids; Urinary Bladder Neoplasms | 1998 |
Retinoids in cancer chemoprevention. Clinical trials with the synthetic analogue fenretinide.
Topics: Anticarcinogenic Agents; Breast Neoplasms; Carcinoma, Basal Cell; Cell Differentiation; Cell Division; Clinical Trials as Topic; Female; Fenretinide; Head and Neck Neoplasms; Humans; Incidence; Leukoplakia, Oral; Models, Biological; Randomized Controlled Trials as Topic; Recurrence; Urinary Bladder Neoplasms | 1995 |
The scientific basis for regarding vitamin A and its analogues as anti-carcinogenic agents.
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 | 1983 |
Trials
11 trial(s) available for fenretinide and Urinary-Bladder-Neoplasms
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Prognostic Significance of VEGF after Twenty-Year Follow-up in a Randomized Trial of Fenretinide in Non-Muscle-Invasive Bladder Cancer.
Non-muscle-invasive bladder cancer (NMIBC) may progress to muscle-invasive disease, but no effective preventive treatments are available. In addition, no reliable prognostic biomarkers have been identified. We assessed the long-term effect of the oral retinoid fenretinide and the prognostic value of circulating VEGF levels. We updated through the Tumor Registry the vital status of 99 patients with resected Ta/T1 bladder tumors who were recruited in a randomized trial of 2 years of fenretinide or no treatment in 1993-1994. Serum VEGF levels measured at baseline and 12 months were available in a subgroup of 62 patients. After a median of 20.5 years, 54 subjects died, 35 of any cancer and 14 of bladder cancer. Neither overall survival (OS), nor cancer survival (CS) or bladder cancer survival (BCS) was affected by fenretinide (log-rank P ≥ 0.2). DNA aneuploidy in bladder washing was associated with shorter OS (P = 0.02), CS (P = 0.05), and BCS (P = 0.09). Subjects with baseline VEGF levels in the top quintile (≥350 pg/mL) had a significantly shorter OS (P = 0.01), CS (P = 0.02), and BCS (P = 0.008). The trend across quintiles of VEGF was significant for BCS (P = 0.007). Multivariate analyses showed that, in addition to smoking status, VEGF level in the top quintile was an independent prognostic factor for OS (HR = 2.7; 95% CI, 1.1-6.5), CS (HR = 3.3; 95% CI, 1.1-9.4) and BCS (HR = 8.9; 95% CI,1.3-61). Fenretinide did not affect the long-term outcome of patients with NMIBC. High serum VEGF level was a significant predictor of overall and cancer death and may help to identify high-risk subjects who may benefit from a preventive therapy. Cancer Prev Res; 9(6); 437-44. ©2016 AACR. Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Transitional Cell; Enzyme-Linked Immunosorbent Assay; Female; Fenretinide; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Muscle, Skeletal; Prognosis; Proportional Hazards Models; Registries; Treatment Outcome; Urinary Bladder Neoplasms; Vascular Endothelial Growth Factor A | 2016 |
Phase III prevention trial of fenretinide in patients with resected non-muscle-invasive bladder cancer.
The study aims to evaluate the efficacy and toxicity of fenretinide in preventing tumor recurrence in patients with transitional cell carcinoma (TCC) of the bladder.. We conducted a multicenter phase III, randomized, placebo-controlled trial of fenretinide (200 mg/day orally for 12 months) in patients with non-muscle-invasive bladder TCC (stages Ta, Tis, or T1) after transurethral resection with or without adjuvant intravesical Bacillus Calmette-Guerin (BCG). Patients received cystoscopic evaluation and bladder cytology every 3 months during the 1-year on study drug and a final evaluation at 15 months. The primary endpoint was time to recurrence.. A total of 149 patients were enrolled; 137 were evaluable for recurrence. The risk of recurrence was considered to be "low" in 72% (no prior BCG) and intermediate or high in 32% (prior BCG) of the evaluable patients. Of the lower-risk group, 68% had solitary tumors and 32% had multifocal, low-grade papillary (Ta, grade 1 or grade 2) tumors. The 1-year recurrence rates by Kaplan-Meier estimate were 32.3% (placebo) versus 31.5% (fenretinide; P = 0.88 log-rank test). Fenretinide was well tolerated and had no unexpected toxic effects; only elevated serum triglyceride levels were significantly more frequent on fenretinide (versus placebo). The Data Safety and Monitoring Board recommended study closure at 149 patients (before reaching the accrual goal of 160 patients) because an interim review of the data showed a low likelihood of detecting a difference between the two arms, even if the original accrual goal was met.. Although well tolerated, fenretinide did not reduce the time-to-recurrence in patients with Ta, T1, or Tis TCC of the bladder. Topics: Administration, Intravesical; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; BCG Vaccine; Carcinoma, Transitional Cell; Female; Fenretinide; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Recurrence, Local; Placebos; Survival Analysis; Urinary Bladder Neoplasms | 2008 |
Effect of the synthetic retinoid fenretinide on circulating free prostate-specific antigen, insulin-like growth factor-I, and insulin-like growth factor binding protein-3 levels in men with superficial bladder cancer.
Fenretinide (4-HPR) is a synthetic retinoid that has shown a preventive activity in prostate cancer animal models.. We measured the changes in total and free prostate-specific antigen (PSA) and its association with insulin-like growth factor I (IGF-I) and IGFBP-3 levels after 1 year of treatment in 24 subjects given 4-HPR and 24 control subjects enrolled in a randomized bladder cancer prevention trial.. No significant effect of 4-HPR was observed on total and free fraction of PSA levels. The median percentage [95 confidence interval (95% CI)] change for % free PSA and total PSA in the 4-HPR and the control group were, respectively, 7.6 (95% CI, -4.0 to 69.3) versus 5.1 (95% CI, -21.4 to 59.8) and -7.8 (95% CI, -18.2 to 52.5) versus -12.3 (95% CI, -44.6 to 9.6). However, in patients ages <60 years, there was a trend to an increase of total free PSA and % free PSA after treatment with 4-HPR that was different from a trend to a decrease in the control group (P = 0.002 and 0.052, respectively). The interaction between age and treatment was statistically significant on free PSA (P = 0.001). A similar pattern was noted with smoking status (P = 0.011 for the interaction on free PSA). No association was observed between PSA levels and IGF-I or IGFBP-3 levels.. We conclude that 4-HPR has no significant effect on circulating PSA, but it increases significantly free PSA levels in subjects younger than 60 years and in nonsmokers. These effects might support an activity in prostate cancer prevention but further studies are required. Topics: Age Factors; Aged; Anticarcinogenic Agents; Fenretinide; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Middle Aged; Prostate-Specific Antigen; Smoking; Urinary Bladder Neoplasms | 2005 |
Time course of fenretinide-induced modulation of circulating insulin-like growth factor (IGF)-i, IGF-II and IGFBP-3 in a bladder cancer chemoprevention trial.
The insulin-like growth factor (IGF) system is widely involved in human carcinogenesis. A significant association between high circulating IGF-I concentrations and an increased risk of lung, colon, prostate and pre-menopausal breast cancer has recently been reported. Lowering plasma IGF-I may thus represent an attractive strategy to be pursued for chemopreventive purposes. We have previously shown that the synthetic retinoid fenretinide (4-HPR) lowers plasma IGF-I in pre-menopausal breast cancer patients. We investigated the effect of fenretinide on circulating IGF-I, IGF-II and IGFBP-3 measured at yearly intervals during the 2-year treatment period and one year after treatment discontinuation in a predominantly male population of patients with superficial bladder cancer. Repeated measures analysis, after adjustment for age, body mass index (BMI) and year of study, showed a significant effect of fenretinide on IGF-I levels, which were further lowered after the second year of treatment and only partially recovered after drug discontinuation. Differently from breast cancer patients, the effect of fenretinide was not modified by age. No significant effect was evident on IGFBP-3, IGF-II and the IGF-I+IGF-II/IGFBP-3 molar ratio, expressing the tissue availability of the mitogenic peptides, although IGF-II and the molar ratio were lowered by treatment by an overall mean of 16% and 15%, respectively. Given the increasingly recognized importance of circulating IGFs in the pathogenesis of different solid tumors, our findings strengthen the rationale for studying fenretinide as a chemopreventive agent. Topics: Age Factors; Anticarcinogenic Agents; Biological Availability; Body Mass Index; Clinical Trials, Phase II as Topic; Female; Fenretinide; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Male; Middle Aged; Randomized Controlled Trials as Topic; Urinary Bladder Neoplasms | 2000 |
Randomized trial of fenretinide in superficial bladder cancer using DNA flow cytometry as an intermediate end point.
Retinoids have shown a potential activity in preventing tumor recurrence in superficial bladder cancer. We assessed the activity of the synthetic retinoid fenretinide in superficial bladder cancer using DNA flow cytometry and conventional cytology as surrogate biomarkers. A total of 99 subjects with resected superficial bladder cancer (pTa, pT1) were randomized to either fenretinide (200 mg day p.o. for 24 months) or no intervention. Cystoscopy and bladder washing for DNA flow cytometry end points (proportion of DNA aneuploid histograms, hyperdiploid fraction, and percentage of apoptotic cells) and proportion of abnormal cytological examinations were repeated every 4 months for up to 36 months. The primary study end point was the proportion of DNA aneuploid histograms after 12 months. This figure was 48.9% in the fenretinide arm and 41.9% in the control arm (odds ratio, 1.16; 95% confidence interval, 0.44-3.07). There was no difference in any other response biomarker between the two groups up to 36 months, nor was any biomarker able to predict recurrence risk. Recurrence-free survival was comparable between the arms (27 events in the fenretinide arm versus 21 in the control arm; P = 0.36). Twelve subjects in the fenretinide arm complained of diminished dark adaptability, and nine subjects in the fenretinide arm versus one control subject had mild dermatological alterations. We conclude that fenretinide showed a lack of effect on the DNA content distribution and the morphology of urothelial cells obtained in serial bladder washings. Recurrence-free survival was comparable between groups. Because our data are hampered by the lack of predictivity of the selected biomarkers, additional studies are necessary to assess the activity of fenretinide in preventing bladder cancer. Topics: Aged; Antineoplastic Agents; Biomarkers, Tumor; Disease-Free Survival; DNA, Neoplasm; Female; Fenretinide; Flow Cytometry; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Treatment Outcome; Urinary Bladder; Urinary Bladder Neoplasms | 2000 |
Ocular effects of fenretinide, a vitamin A analog, in a chemoprevention trial of bladder cancer.
Fenretinide is a vitamin A derivative under investigation in cancer prevention trials. Because all available pharmacologic and toxicologic data were obtained from breast cancer patients, we measured plasma drug, metabolite, and vitamin A levels and studied their relationship with visual and ocular symptoms in a cohort formed mostly by male subjects belonging to a bladder cancer prevention trial. After 1 year, the mean plasma retinol levels (+/- standard deviation [SD]) were 168.2 +/- 75.8 ng/ml in 31 subjects treated with fenretinide and 594.5 +/- 168.4 ng/ml in 36 control subjects (P < .001). Plasma retinol levels were correlated inversely to drug and metabolite concentrations, which in turn were correlated inversely to the interval from last drug intake. The decline of plasma vitamin A levels accounted for a 41.7% cumulative incidence of diminished dark adaptability in the retinoid arm as compared to 6.8% in the control arm (odds ratio = 13.8; 95% confidence interval, 2.9-66.1). Although compliance as assessed by capsule count was high, three subjects originally assigned to the treatment group who proved to be noncompliers (8.8%, or 3 of 34) had no detectable plasma drug or metabolite levels. Our data confirm the specific pharmacologic and visual effects of fenretinide also in a male population and strengthen the importance of multiple blood measurements to monitor treatment compliance in prevention trials. Topics: Adult; Aged; Aged, 80 and over; Anticarcinogenic Agents; Carcinoma, Transitional Cell; Chemoprevention; Dark Adaptation; Female; Fenretinide; Follow-Up Studies; Humans; Lacrimal Apparatus; Logistic Models; Male; Middle Aged; Night Blindness; Odds Ratio; Patient Compliance; Urinary Bladder Neoplasms; Vision, Ocular; Vitamin A | 2000 |
Assessment of DNA flow cytometry as a surrogate end point biomarker in a bladder cancer chemoprevention trial.
Although conventional cytology represents the most widely performed cytometric analysis of bladder cancer cells, DNA flow cytometry has, over the past decade, been increasingly used to evaluate cell proliferation and DNA ploidy in cells from bladder washings. We have investigated whether DNA flow cytometry and conventional cytology of epithelial cells obtained from bladder washings provide reliable surrogate endpoint biomarkers in clinical chemoprevention trials. We used cytometric and clinical data from a chemoprevention trial of the synthetic retinoid Fenretinide on 99 patients with superficial bladder cancer. A total of 642 bladder washing specimens obtained from the patients at 4 month intervals was analyzed. Intra-individual agreement and correlation of flow cytometric DNA ploidy (diploid vs. aneuploid), DNA Index, Hyper-Diploid-Fraction (proportion of cells with DNA content higher than 2C), and conventional cytologic examination, as assessed by kappa statistics and Spearman's correlation test, were poor from baseline through 24 months. Moreover, no correlation was found between DNA ploidy and cytology at each time point. The same results were obtained when the analyses were stratified by treatment group. In addition, the association between the results of bladder washing (by either DNA flow cytometry or cytology) and concomitant tumor recurrence was significant only for abnormal cytology, while neither biomarker was predictive of tumor recurrence at the subsequent visit. During the time of this study only four patients progressed to muscle-invasive bladder cancer, indicating the "low-risk" features of the patient population. We conclude that DNA flow cytometry and conventional cytology on epithelial cells obtained from bladder washings do not appear to provide suitable surrogate endpoint biomarkers during the early stages of bladder carcinogenesis. Topics: Antineoplastic Agents; Biomarkers, Tumor; Cell Division; DNA, Neoplasm; Fenretinide; Flow Cytometry; Humans; Neoplasm Recurrence, Local; Ploidies; Urinary Bladder Neoplasms | 1999 |
Pilot study of high dose fenretinide and vitamin A supplementation in bladder cancer.
Topics: Adult; Aged; Dark Adaptation; Female; Fenretinide; Humans; Male; Middle Aged; Pilot Projects; Urinary Bladder Neoplasms; Vitamin A | 1994 |
DNA flow cytometry as a surrogate end-point in patients with superficial bladder cancer treated with 4-HPR.
Topics: Adult; Aged; Aged, 80 and over; Aneuploidy; Diploidy; DNA, Neoplasm; Feasibility Studies; Female; Fenretinide; Flow Cytometry; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Pilot Projects; Urinary Bladder Neoplasms | 1994 |
Phase IIa study of fenretinide in superficial bladder cancer, using DNA flow cytometry as an intermediate end point.
Topics: Adult; Aged; Aged, 80 and over; Dark Adaptation; DNA, Neoplasm; Feasibility Studies; Female; Fenretinide; Flow Cytometry; Humans; Male; Middle Aged; Pilot Projects; Urinary Bladder Neoplasms | 1994 |
Activity of 4-HPR in superficial bladder cancer using DNA flow cytometry as an intermediate endpoint.
The ability of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) to affect the outcome of previously resected superficial bladder cancer was investigated in a pilot study using DNA content flow cytometry and conventional cytology as intermediate endpoints. Twelve patients were treated with oral 4-HPR (200 mg daily) and compared with 17 non-randomized, untreated controls. The median interval between transurethral resection and 4-HPR administration was 5.5 months (range 0-36). The median follow-up period was 12 months (range 3-31) in the 4-HPR group and 9 months (range 2-22) in the control group. The proportion of patients with DNA aneuploid stemlines in bladder-washed cells decreased from 7/12 (58%) to 5/11 (45%) in the 4-HPR group, but increased from 7/17 (41%) to 10/17 (59%) in the control group. In patients with stable diploid profiles, mean (+/- SE) S-phase and G2+M-phase fractions decreased in the course of retinoid treatment from basal levels of 15.2 +/- 4.1% to 7.5 +/- 3.3% and 10.3 +/- 2.2% to 5.2 +/- 0.4%, respectively. The same parameters in the control group changed from basal levels of 14.6 +/- 3.4% to 12.4 +/- 2.7% and 9.8 +/- 1.6% to 12.6 +/- 1.6%, respectively. Positive or suspicious cytologic examinations were present in 3/12 (25%) treated cases prior to 4-HPR administration and all subsequently reverted to normal. The same parameter in the control group increased from 4/17 (24%) to 6/17 (35%) during follow-up. Impaired adaptation to darkness was recorded in 4 patients, and transient dermatologic alterations were observed in one-third of the patients, requiring dose reduction in one case.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Adult; Aged; Aged, 80 and over; DNA, Neoplasm; Female; Fenretinide; Flow Cytometry; Humans; Male; Middle Aged; Neoplasm Invasiveness; Pilot Projects; Ploidies; Urinary Bladder Neoplasms | 1992 |
Other Studies
10 other study(ies) available for fenretinide and Urinary-Bladder-Neoplasms
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Prognostic effect of DNA aneuploidy from bladder washings in superficial bladder cancer.
Superficial (papillary) bladder cancer is associated with progression and death from muscle-invasive bladder cancer, but no reliable predictors of the outcomes have been identified.. We analyzed the long-term prognostic effect of DNA flow cytometry in bladder washings from 93 subjects with previously resected T(a) and T(1) bladder tumors who participated in a chemoprevention trial of the synthetic retinoid fenretinide. Kaplan-Meier analysis and Cox regression were used to determine the prognostic effect of DNA aneuploidy on cancer progression and mortality in conjunction with conventional clinical factors after a median of 11.5 years (interquartile range, 9.5-11.7 years).. Overall, 58 of 93 (62%) specimens were DNA aneuploid at baseline. Progression-free survival was significantly shorter in subjects with stage T(1) [hazard ratio (HR), 31.6; 95% confidence interval (95% CI), 2.6-386.1; P < 0.001] and in subjects with baseline DNA aneuploid washing (HR, 10.5; 95% CI, 1.1-126.1; P = 0.03). The risk of death was also greater for stage T(1) tumors (HR, 2.6; 95% CI, 1.04-6.7; P = 0.04). DNA aneuploidy was a significant prognostic factor also for overall survival (HR, 2.8; 95% CI, 1.0-9.0; P = 0.05). Fenretinide treatment had no significant effect on cancer progression and death.. DNA aneuploidy in washings from endoscopically normal bladder is a significant predictor of progression and death in addition to tumor stage. This biomarker may help to identify and monitor a high-risk group who may benefit from a chemoprevention intervention. Topics: Adult; Aged; Aged, 80 and over; Aneuploidy; Anticarcinogenic Agents; Biomarkers, Tumor; Cohort Studies; Disease Progression; DNA, Neoplasm; Female; Fenretinide; Flow Cytometry; Humans; Male; Middle Aged; Prognosis; Survival Analysis; Urinary Bladder; Urinary Bladder Neoplasms | 2007 |
Comparing the effect of ATRA, 4-HPR, and CD437 in bladder cancer cells.
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 | 2006 |
Intravesical N-(4-hydroxyphenyl) retinamide and adriamycin induces apoptosis in bladder cancer.
The objective of this study was to evaluate the intravesical application of N-(4-hydroxyphenyl) retinamide (4-HPR) and adriamycin (ADM), as a treatment modality in a an animal model of chemically-induced bladder cancer. Bladder cancer developed in 50.0% of female Wistar rats, 4-6 weeks after intravesical application of the chemical carcinogen, N-methyl-N-nitrosourea (MNU). There was no significant difference in side effects induced by local versus systemic 4-HPR. Although tumor growth was inhibited by 4-HPR and ADM alone, tumor size was lower when both agents were used together. Apoptosis occurred at a higher rate in the combination group than when 4-HPR or ADM was used alone. The results suggest that intravesical use of 4-HPR and ADM may increase their efficacy in treatment of bladder cancer. Topics: Administration, Intravesical; Alkylating Agents; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Apoptosis; Cell Cycle; Disease Models, Animal; Doxorubicin; Female; Fenretinide; Flow Cytometry; In Situ Nick-End Labeling; Methylnitrosourea; Rats; Rats, Wistar; Urinary Bladder Neoplasms | 2006 |
[The role of reactive oxygen species in N-[4-hydroxyphenyl] retinamide induced apoptosis in bladder cancer cell lineT24].
To study the mechanism of the apoptosis induced by N-[4-hydroxyphenyl] retinamide (4-HPR) in bladder cancer cell line T24, and the involvement of DNA damage and repair.. T24 cells were treated with 4-HPR at the concentration of 2.5, 5.0 and 10.0 micromol/L, and the cell grow inhibition was measured by cell counting assay. The fluorescent intensity of reactive oxygen species (ROS) was determined by spectrofluorometer. The apoptosis was measured by flow cytometry and DNA fragment assay. The expression of XRCC1 protein and activation of caspase-3 were detected by Western blot.. 4-HPR induced apoptosis in T24 cell. A dose-dependent increase in the percentage of apoptosis cells was observed (1.8%, 4.0% and 10.5% respectively at 2.5, 5.0, 10.0 micromol/L 4HPR). In the meantime, ROS level in the cell was increased (peaked at 3 fold). It also caused down-regulation of the expression of XRCC1, and activation of caspase-3. Vitamin C effectively inhibited ROS rise induced by 4-HPR, and also partially inhibited cell growth, apoptosis, and down-regulation of the expression of XRCC1.. The generation of ROS and DNA damage may be the major mechanism of the apoptosis of bladder cancer cell line T24 induced by 4-HPR. Topics: Antineoplastic Agents; Cell Line, Tumor; DNA Damage; DNA Repair; DNA-Binding Proteins; Fenretinide; Humans; Reactive Oxygen Species; Urinary Bladder Neoplasms; X-ray Repair Cross Complementing Protein 1 | 2005 |
N-(4-hydroxyphenyl)retinamide (4-HPR) modulates GADD45 expression in radiosensitive bladder cancer cell lines.
We previously demonstrated that N-(4-hydroxyphenyl)retinamide (4-HPR) and gamma-irradiation, when used in combination, had a synergistic effect in inducing apoptosis in bladder cancer cells, suggesting that 4-HPR may increase radiosensitivity in bladder cancer cells. To unravel molecular correlates in this radiosensitizing effect of 4-HPR, we examined the baseline and 4-HPR-induced expression of GADD45 to elucidate possible mechanisms by which 4-HPR enhanced the effect of gamma-irradiation in three bladder cancer cell lines. To investigate the role of p53 in mediating the radiosensitizing effect of 4-HPR, we also examined mutations in exons 5-9 by using direct sequencing and the levels of p53 expression by using RT-PCR and Western blot, before and after treatment with 4-HPR in these bladder cancer cell lines. Two cell lines had low expression of GADD45, and a dose-dependent increase in GADD45 expression induced by 4-HPR was found in bladder cancer cell lines without p53 mutations in exons 5-9. A combination of gamma-irradiation and 4-HPR showed a significantly greater effect in enhancing GADD45 expression than either agent used alone. The results indicate that the combined treatment with 4-HPR and gamma-irradiation has a stronger effect on GADD45 expression than the treatment with either agent alone, which suggests that the two agents may have an additive/synergistic effect. However, a normal p53 function appears to be necessary for the dose-dependent induction of GADD45 by 4-HPR. Once our results are verified and replicated by other investigators, 4-HPR may have a potential clinical implication in effectively treating bladder cancer in combination with low-gamma-irradiation therapy. Topics: Antineoplastic Agents; Fenretinide; GADD45 Proteins; Gamma Rays; Gene Expression Regulation, Neoplastic; Genes, p53; Humans; Intracellular Signaling Peptides and Proteins; Mutation; Proteins; Radiation Tolerance; Tumor Cells, Cultured; Urinary Bladder Neoplasms | 2002 |
Effects of novel phenylretinamides on cell growth and apoptosis in bladder cancer.
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 | 2001 |
Combined effect of chemopreventive agent N-(4-hydroxyphenyl) retinamide (4-HPR) and gamma-radiation on bladder cancer cell lines.
The incidence of bladder cancer has increased in the United States during the past 50 years, consistent with increased exposure to bladder carcinogens in the environment and tobacco use. Although N-(4-hydroxyphenyl) retinamide (4-HPR), a retinoid derivative, has been used as a chemopreventive agent of bladder cancer in clinical trials, little is known about its mechanisms of action against bladder cancer cells. Previous studies suggest this chemopreventive agent may inhibit tumor growth by inducing apoptosis. To further investigate this putative effect, we examined the effect of 4-HPR and gamma-radiation and their combined effects in three selected bladder cancer cell lines. Indeed, 4-HPR induced apoptosis in these cell lines in a dose-dependent manner. A 2.5 microM dose of 4-HPR and 50 rad of gamma-irradiation induced about 10% increase in apoptotic cells, respectively. However, this low dose 4-HPR combined with low dose gamma-irradiation had a synergistic effect on apoptosis, in which apoptotic cells increased by more than 30%. The findings have potential clinical implications and warrant further investigations both in vitro and in vivo in bladder cancer. Topics: Antineoplastic Agents; Apoptosis; Cell Division; Cells, Cultured; Chemoprevention; Chromatids; Chromosome Aberrations; Combined Modality Therapy; Fenretinide; Gamma Rays; Humans; Tumor Cells, Cultured; Urinary Bladder Neoplasms | 1998 |
Clinical development plan: N-(4-hydroxyphenyl)retinamide.
Topics: Animals; Clinical Trials as Topic; Cricetinae; Dogs; Drug Approval; Drug Evaluation, Preclinical; Fenretinide; Humans; Mice; Rats; Urinary Bladder Neoplasms | 1994 |
Chemoprevention of OH-BBN-induced bladder cancer in mice by piroxicam.
Piroxicam inhibited induction of transitional cell carcinoma in mouse urinary bladder by N-butyl-N-(4-hydroxybutyl)-nitrosamine. At 15 mg piroxicam/kg diet, tumor incidence was reduced 82% (P < 0.0001) compared with carcinogen controls. At 30 mg piroxicam/kg diet, tumor incidence was reduced 70% (P < 0.001). Results at the higher dose level suggested that piroxicam also may have inhibited invasion slightly. Combination treatment with 2-difluoromethyl-ornithine (DFMO) or all-trans-N-(4-hydroxyphenyl)retinamide (4-HPR) or both agents did not improve the chemopreventive potential of piroxicam. However, the three-agent combination of 30 mg piroxicam/kg, 1200 mg DFMO/kg and 313 mg 4-HPR/kg diet was highly effective. Tumor incidence was reduced 91% (P < 0.0001) compared with carcinogen controls. Unfortunately, the high efficacy was somewhat compromised by a significant decrease in survival and body weight gain in mice receiving the combination of agents compared with the carcinogen control. Topics: Animals; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Drug Synergism; Eflornithine; Fenretinide; Male; Mice; Piroxicam; Urinary Bladder Neoplasms | 1993 |
Inhibition of mammary and urinary bladder carcinogenesis by a retinoid and a maleic anhydride-divinyl ether copolymer (MVE-2).
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 | 1982 |