ascorbic-acid and Carcinoma--Transitional-Cell

To assess the levels of erythrocyte glutathione peroxidase (GSH-Px), and the serum levels of antioxidant vitamins (A, E and C), selenium and malondialdehyde (MDA) in patients with transitional cell carcinoma (TCC) of the bladder.. The study comprised 91 people (23 healthy controls and 68 patients with TCC). Erythrocyte GSH-Px activity was measured by spectrophotometry, high-performance liquid chromatography to detect serum levels of vitamins and MDA, and fluorometry to detect serum levels of selenium.. The serum levels of vitamin A, E and C, and selenium were significantly lower (P < 0.05) in patients with TCC than in controls. However, erythrocyte GSH-Px activities (P < 0.05) and serum MDA levels (P < 0.01) were significantly higher in patients with TCC than in the controls.. Levels of free oxygen species were higher, and antioxidant vitamin and selenium levels lower, in patients with bladder TCC than in controls. These findings, with the results of previous animal studies, suggest that giving vitamin A, C, E and selenium may be beneficial in preventing and treating human bladder cancer.

Topics: Adult; Aged; Ascorbic Acid; Carcinoma, Transitional Cell; Erythrocytes; Female; Glutathione Peroxidase; Humans; Lipid Peroxidation; Male; Middle Aged; Urinary Bladder Neoplasms; Vitamin A; Vitamin E; Vitamins

The genetic features of primary lymphoepithelioma-like carcinoma (LELC) of the upper urinary tract have not been systematically explored. In this study, tumor mutation profiling was performed using whole-genome sequencing in two patients with LELC of the renal pelvis. Novel candidate variants relevant to known disease genes were selected using rare-variant burden analysis. Subsequently, a population-based study was performed using the Surveillance, Epidemiology, and End Results (SEER), PubMed, MEDLINE, Embase, and Scopus databases to explore clinical features and prognostic risk factors. Immunohistochemical analysis revealed seven positive cytokeratin-associated markers in tumor cells and five positive lymphocyte-associated markers in and around the tumor area. Sub-sequently, we identified KDM6A as the susceptibility gene and LEPR as the driver gene by Sanger sequencing in case 2 of LELC of the renal pelvis. Three mutation sites of the existing targeted drugs were screened: CA9, a therapeutic target for zonisamide; ARVCF, a therapeutic target for bupropion; and PLOD3, a therapeutic target for vitamin C. In a population-based study, patients with primary LELC of the upper urinary tract had clinical outcomes similar to those of patients with primary upper urinary tract urothelial carcinoma (UUT-UC) before and after propensity score matching at 1 : 5. Focal subtype was an independent prognostic factor for the overall survival of patients with LELC of the upper urinary tract. The carcinogenesis of primary LELC may be due to different genetic variations, including single-nucleotide variants, insertion and deletions, structural variations, and repeat regions, which may provide the basis for clinical diagnosis and treatment. The prognosis of LELC in the upper urinary tract is similar to that of UUT-UC. We suggest that the focal subtype can serve as a prognostic factor for LELC of the upper urinary tract; however, further studies are required to confirm this.

Topics: Ascorbic Acid; Bupropion; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Histone Demethylases; Humans; Keratins; Kidney Pelvis; Nucleotides; Prognosis; Urinary Bladder Neoplasms; Zonisamide

The purpose of this study was to establish a 2-stage model of urinary bladder carcinogenesis in male Sprague-Dawley rats to identify tumor promoters. In phase 1 of the study, rats ( n = 170) were administered 100 mg/kg of the tumor initiator, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), twice weekly by oral gavage (po) for a period of 6 weeks. Phase 2 consisted of dividing rats into 4 groups ( n = 40 per group) and administering one of the following for 26 weeks to identify putative tumor promoters: (1) vehicle po, (2) 25 mg/kg/day rosiglitazone po, (3) 5% dietary sodium l-ascorbate, and (4) 3% dietary uracil. Rats were necropsied after 7.5 months, and urinary bladders were evaluated by histopathology. BBN/vehicle treatments induced the development of urothelial hyperplasia (83%) and papillomas (15%) but no transitional cell carcinomas (TCCs). Rosiglitazone increased the incidence and severity of papillomas (93%) and resulted in TCC in 10% of treated rats. Uracil was the most effective tumor promoter in our study and increased the incidence of papillomas (90%) and TCC (74%). Sodium ascorbate decreased the incidence of urothelial hyperplasia (63%) and did not increase the incidence of urothelial papillomas or TCC. These data confirm the capacity of our 2-stage model to identify urinary bladder tumor promoters.

Topics: Animals; Ascorbic Acid; Carcinogens; Carcinoma, Transitional Cell; Disease Models, Animal; Male; Rats; Rats, Sprague-Dawley; Rosiglitazone; Uracil; Urinary Bladder; Urinary Bladder Neoplasms

Published associations between dietary carotenoids and vitamin C and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status.. We investigated the association between plasma carotenoids and vitamin C and risk of urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition.. A total of 856 patients with newly diagnosed UCC were matched with 856 cohort members by sex, age at baseline, study center, date and time of blood collection, and fasting status. Plasma carotenoids (α- and β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin) were measured by using reverse-phase HPLC, and plasma vitamin C was measured by using a colorimetric assay. Incidence rate ratios (IRRs) were estimated by using conditional logistic regression with adjustment for smoking status, duration, and intensity.. UCC risk decreased with higher concentrations of the sum of plasma carotenoids (IRR for the highest compared with the lowest quartile: 0.64; 95% CI: 0.44, 0.93; P-trend = 0.04). Plasma β-carotene was inversely associated with aggressive UCC (IRR: 0.51; 95% CI: 0.30, 0.88; P-trend = 0.02). Plasma lutein was inversely associated with risk of nonaggressive UCC (IRR: 0.56; 95% CI: 0.32, 0.98; P-trend = 0.05). No association was observed between plasma vitamin C and risk of UCC.. Although residual confounding by smoking or other factors cannot be excluded, higher concentrations of plasma carotenoids may reduce risk of UCC, in particular aggressive UCC. Plasma lutein may reduce risk of nonaggressive UCC.

Topics: Ascorbic Acid; Carcinoma, Transitional Cell; Carotenoids; Diet; Female; Humans; Male; Urinary Bladder Neoplasms; Urothelium

Published associations between dietary carotenoids and vitamin C and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status.. We investigated the association between plasma carotenoids and vitamin C and risk of urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition.. A total of 856 patients with newly diagnosed UCC were matched with 856 cohort members by sex, age at baseline, study center, date and time of blood collection, and fasting status. Plasma carotenoids (α- and β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin) were measured by using reverse-phase HPLC, and plasma vitamin C was measured by using a colorimetric assay. Incidence rate ratios (IRRs) were estimated by using conditional logistic regression with adjustment for smoking status, duration, and intensity.. UCC risk decreased with higher concentrations of the sum of plasma carotenoids (IRR for the highest compared with the lowest quartile: 0.64; 95% CI: 0.44, 0.93; P-trend = 0.04). Plasma β-carotene was inversely associated with aggressive UCC (IRR: 0.51; 95% CI: 0.30, 0.88; P-trend = 0.02). Plasma lutein was inversely associated with risk of nonaggressive UCC (IRR: 0.56; 95% CI: 0.32, 0.98; P-trend = 0.05). No association was observed between plasma vitamin C and risk of UCC.. Although residual confounding by smoking or other factors cannot be excluded, higher concentrations of plasma carotenoids may reduce risk of UCC, in particular aggressive UCC. Plasma lutein may reduce risk of nonaggressive UCC.

Topics: Adult; Aged; Ascorbic Acid; Carcinoma, Transitional Cell; Carotenoids; Case-Control Studies; Cohort Studies; Diet; Europe; Female; Follow-Up Studies; Humans; Incidence; Lutein; Male; Middle Aged; Papilloma; Prospective Studies; Urinary Bladder Neoplasms; Urothelium

A range of plausible biological mechanisms support preventive effects of micronutrients in bladder cancer. So far, however, results from the few epidemiological studies on the relation have been inconsistent, with no clear associations found.. To evaluate the association between total, dietary, and supplemental intake of beta-carotene, folate, vitamins C and E, and risk of urothelial carcinoma (UC) and to explore whether the association differs with smoking status.. The association was evaluated in the Danish Diet, Cancer and Health Study, comprising 55,557 men and women aged 50-64 yr at inclusion with no previous cancer diagnosis.. At baseline, all participants completed a detailed food frequency questionnaire including information on consumption of vitamin C, E, folate, and beta-carotene from diet and supplements. Incidence rate ratios (IRRs) of UC were calculated using Cox proportional hazards models.. During a median of 10.6 yr of follow-up, 322 UC cases were diagnosed. Vitamin C, E, and folate showed no association with UC, regardless of source. There was a significantly lower risk of disease with dietary beta-carotene consumption (IRR: 0.82; 95% confidence interval [CI]: 0.69-0.98) and a borderline significant lower risk with total beta-carotene intake (IRR: 0.85; 95% CI: 0.73-1.00) pr. 5000 μg of intake. We found a significant interaction between both dietary (p=0.005) and total (p=0.002) beta-carotene and smoking status, with a significant protective effect of beta-carotene seen among current smokers only.. Our results indicate no preventive effect of vitamin C, E, or folate on UC. We found a protective effect of dietary, but not supplemental, beta-carotene on UC, but further studies are required.

Topics: Ascorbic Acid; beta Carotene; Carcinoma, Transitional Cell; Denmark; Diet; Diet Records; Female; Folic Acid; Humans; Incidence; Male; Micronutrients; Middle Aged; Nutritional Status; Odds Ratio; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Smoking; Time Factors; Urinary Bladder Neoplasms; Urothelium; Vitamin E

Despite the availability of several therapeutic options, a safer and more effective modality is urgently needed for treatment of bladder cancer. Specific immunotherapy is effective, but severe side effects limit its clinical use and underscore the need for unconventional therapies using less toxic substances. Many natural substances are touted for their medicinal aspects and side effect profiles, and some of these have been well characterized for their biological and medicinal properties. Accordingly, the effects on bladder cancer cells in vitro were investigated. Eight commercially available natural products were tested for possible effects on the growth of human bladder cancer T24 cells. This study demonstrated that two mushroom extracts, GD- and PL-fractions, induced a significant (>90 percent) growth reduction in 72 hours, whereas the remaining six products had no effect. Interestingly, non-toxic concentrations of the GD- or PL-fractions, when combined with a non-toxic concentration of vitamin C, became highly cytotoxic, resulting in >90-percent cell death. Thus, vitamin C appears to act synergistically with these fractions to potentiate their bioactivity (cytotoxicity). No other products tested demonstrated such a synergistic potentiation with vitamin C. The present study indicates that GD- and PL-fractions appear to have the most potent cytotoxic effect on human bladder cancer T24 cells. It is thus plausible that these substances could be used, solely or combined with conventional modalities, for the treatment of superficial bladder cancer.

Topics: Agaricales; Antineoplastic Agents; Ascorbic Acid; Carcinoma, Transitional Cell; Cell Line, Tumor; Complementary Therapies; Fungi; Grifola; Humans; Urinary Bladder Neoplasms; Vitamins

The association between several cancers and selenium status has been investigated in epidemiological studies. However, few results concerning bladder cancer have been reported thus far. The association between toenail selenium status and subsequent bladder cancer incidence was investigated in a prospective cohort study among 120,852 men and women aged 55-69 years at baseline (September 1986). The cohort members completed a questionnaire on risk factors for cancer and provided toenail clippings for determination of baseline selenium status. Follow-up for incident cancer was established by record linkage to cancer registries until December 1992. The multivariable case-cohort analysis was based on 431 bladder cancer cases and 2,459 subcohort members, for whom toenail selenium levels were available. The age-, sex- and smoking-adjusted rate ratios (95% confidence intervals) for increasing quintiles of toenail selenium were 1.00 (reference), 1.09 (0.80-1.48), 0.55 (0.38-0.79), 0.63 (0.43-0.91), and 0.67 (0.46-0.97), respectively (P-trend < 0.01). Analyses with selenium as a continuous variable supported these findings. An inverse association between toenail selenium and bladder cancer risk was most pronounced among ex-smokers (P-trend < 0.01); was similar for subjects with high versus low intakes of beta-carotene, vitamin C, and vitamin E; and was mainly confined to invasive transitional cell carcinomas of the urinary bladder, irrespective of tumor morphology. We conclude that the evidence is in favor of an inverse association between selenium and bladder cancer risk.

Topics: Aged; Antioxidants; Ascorbic Acid; beta Carotene; Carcinoma, Transitional Cell; Cohort Studies; Eating; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Nails; Netherlands; Prospective Studies; Risk Factors; Selenium; Sex Factors; Smoking; Statistics as Topic; Urinary Bladder Neoplasms; Vitamin E

The cyclin-dependent kinase (CDK) inhibitor p27(KIP1) exerts its growth suppressive effects by targeting the cyclin-CDK complexes. Reduced protein levels of p27(KIP1) have been reported in numerous human cancers and this has been attributed to increased degradation. However, few reports have addressed the significance of p27(KIP1) expression in chemical carcinogenesis of rodents. In a rat two-stage urinary bladder carcinogenesis model, with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) initiation followed by promotion with sodium L-ascorbate (Na-AsA), we evaluated the expression of p27(KIP1) protein using immunohistochemistry during various stages of urinary bladder carcinogenesis. In addition, we evaluated the mRNA expression profiles for p27(KIP1), p21(WAF1/Cip1) and p53 in tumors. Fisher 344 rats were initiated with 0.05% BBN in the drinking water for 4 weeks and then administered 5% Na-AsA in the diet. Immunohistochemical examination revealed p27(KIP1) protein to be constitutively expressed in normal urothelium, simple hyperplasia and in most papillary and nodular (PN) hyperplasias and small papillomas, but diminished or absent in large papillomas and in transitional cell carcinomas. An inverse correlation between expression of p27(KIP1) and cell proliferation was generally observed. Quantitation of mRNA by multiplex reverse transcription-PCR showed a significant downregulaton of p27(KIP1), p21(WAF1/Cip1) and p53 mRNA in tumors. More than 50% reduction in p27(KIP1) mRNA expression was observed in 42 and 47% of tumors at weeks 18 and 24, respectively; similar reduction in p21(WAF1/Cip1) mRNA expression was observed in 58 and 73% of tumors at weeks 18 and 24, and in p53 mRNA expression in 50 and 73% of tumors at weeks 18 and 24, respectively. None of the 25 tumors we examined by PCR-single-strand conformational polymorphism analysis had p53 mutations. These data imply that abnormal down-regulation of p27(KIP1), p21(WAF1/Cip1) and/or p53 in tumor cells may contribute to the malignant progression of tumors during rat two-stage bladder carcinogenesis.

Topics: Animals; Ascorbic Acid; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Cell Cycle Proteins; Cell Division; Cocarcinogenesis; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Disease Progression; Gene Expression Regulation, Neoplastic; Genes, p53; Hyperplasia; Male; Microtubule-Associated Proteins; Neoplasm Proteins; Papilloma; Rats; Rats, Inbred F344; RNA, Messenger; RNA, Neoplasm; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Urinary Bladder Neoplasms; Urothelium

Our previous data showed that F344/DuCrj and LEW/Crj rat strains bearing the type a catalase-1 locus (CS1a) are sensitive to the promoting activity of sodium L-ascorbate (Na-AsA) in 2-stage urinary bladder carcinogenesis, whereas ODS/Shi and WS/ Shi rat strains bearing the type b catalase-1 locus (CS1b) are resistant. In present study, we investigated the susceptibility of F344/Shi rats also bearing the CS1 to the Na-AsA-promoting effects on bladder tumor development. Male rats, 6 weeks old, were given 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in their drinking water for 4 weeks, then fed either basal diet supplemented with 5% Na-AsA or no chemicals for 32 weeks. The rats given BBN alone had a few small carcinomas in the urinary bladder. In contrast, animals administered BBN-Na-AsA had many large carcinomas. Administration of Na-AsA was associated with significant elevation of urinary pH and L-ascorbic acid. The results indicate that F344/Shi rats are sensitive to the promoting effects of Na-AsA on 2-stage urinary bladder carcinogenesis, and thus that the CS1 locus may not influence susceptibility to promotion.

Topics: Alleles; Animals; Ascorbic Acid; Butylhydroxybutylnitrosamine; Carcinogens; Carcinoma, Transitional Cell; Catalase; Disease Susceptibility; Hyperplasia; Male; Neoplasms, Squamous Cell; Papilloma; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

Overexpression of cyclin D1 has been implicated in the malignant transformation of a variety of human cancers, including urinary bladder carcinomas. However, few reports have addressed the significance of cyclin D1 overexpression in chemical carcinogenesis in rodents. In the present study, we evaluated the oncogenic potential of cyclin D1 in experimental rat urinary bladder carcinogenesis and its relationships to the oncogenes cyclin E, K-ras, and H-ras as well as tumor suppressor genes p53 and p21WAF1/Cip1. In addition, proliferation status of preneoplastic lesions and tumors was assessed by proliferating cell nuclear antigen immunohistochemistry. Fisher 344 rats were initiated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 4 weeks and then administered 5% sodium L-ascorbate in diet. Animals were sacrificed at weeks 4, 8, 12, 18, and 24. Preneoplastic lesions such as papillary or nodular hyperplasia and neoplastic lesions of the urinary bladder were observed during carcinogenesis. By immunohistochemical examination, overexpression of cyclin D1 protein was observed in 17% of papillary or nodular hyperplasias, 66% of papillomas, and 69% of transitional cell carcinomas, whereas nuclear accumulation of p53 was observed in none of the preneoplastic lesions and in fewer than 2% of transitional cell carcinomas. Overexpression of cyclin D1 in preneoplastic lesions and tumors was not dependent on the size of the tumors or their proliferation status. Quantitation of mRNA in tumors by multiplex reverse transcription-PCR showed that average mRNA expression of cyclin D1 and cyclin E was increased, whereas average p21WAF1/Cip1 mRNA expression was decreased. More than 2-fold overexpression of cyclin D1 mRNA was observed in 50 and 60% of tumors at weeks 18 and 24, respectively. Localization of cyclin D1 mRNA expression was demonstrated by in situ hybridization, and the results were comparable to immunohistochemistry findings. None of the 25 tumors we examined by PCR-single-strand conformational polymorphism analysis harbored p53 mutations, H-ras mutations, or K-ras mutations. Thus, during the promotion phase of two-stage bladder carcinogenesis, overexpression of cyclin D1 in tumor cells may provide yet another mechanism by which tumors can gain a growth advantage. In contrast, tumors with mutated p53 may not have a growth advantage. Our results suggest that overexpression of cyclin D1 plays a critical role during urinary bladder carcinogenesi

Topics: Animals; Ascorbic Acid; Butylhydroxybutylnitrosamine; Carcinogens; Carcinoma, Transitional Cell; Cell Nucleus; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Hyperplasia; Male; Neoplasm Proteins; Papilloma; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Rats; Rats, Inbred F344; RNA, Messenger; Tumor Suppressor Protein p53; Urinary Bladder; Urinary Bladder Neoplasms

Male F344 rats were fed 0.2% N-[4-(5-nitro-2-furyl)-2-thiazoly]formamide for 6 weeks and then fed 3% or 5% sodium saccharin, 5% sodium ascorbate, 3.12% calcium saccharin, 1.34% sodium chloride, 5.2% calcium saccharin plus 1.34% sodium chloride, or basal diet alone for 72 weeks. Protein and DNA were extracted from 89 bladder tumors [87 transitional cell carcinomas (TCC), 1 papilloma, and 1 sarcoma] from 86 rats p21 expression was examined by Western blotting using a monoclonal antibody against p21 (NCC-RAS-004). H-ras mutations in exons 1 and 2 were examined by direct sequencing of DNA amplified by polymerase chain reaction. Sequencing results demonstrated mutations at codon 61 (CAA to CGA in 15 TCCs; CAA to CTA in 2 TCCs), at codon 12 (GGA to TGG in 1 TCC), and at codon 13 (GGC to GTC in 3 TCCs). Mutations at codon 61 were confirmed by faster mobility of the p21 band in Western blots. The level of p21 expression varied among samples, but many TCCs appeared to express more p21 than controls. The overall incidence of H-ras mutations was 24.4% (21 of 86 rats). The type of chemical used for the promoting phase had essentially no effect on H-ras mutation, suggesting that the effects observed were related to FANFT administration. The frequency of H-ras mutation in each group was negatively related to the incidence of carcinoma (r = -0.85; P less than 0.01). Two groups of tumors (with or without the mutated ras gene) were compared for tumor size (reflected by the bladder weight), histological grading, and the presence of invasion. The size of tumors with mutated ras was significantly smaller than those without mutated ras. There was no difference in the histological grading between the two groups. Although not statistically significant, histological invasion was more frequently observed in tumors with mutated ras (14.3%) than in tumors without mutation (3.1%).

Topics: Animals; Ascorbic Acid; Base Sequence; Blotting, Western; Carcinogens; Carcinoma; Carcinoma, Transitional Cell; DNA, Neoplasm; FANFT; Genes, ras; Male; Mutation; Proto-Oncogene Proteins p21(ras); Rats; Rats, Inbred F344; Saccharin; Urinary Bladder Neoplasms

L-ascorbic acid has been shown to reduce the elevated level of urinary chemiluminescence found in patients with bladder cancer. Thus, it has been suggested that vitamin C might be efficacious in bladder tumor prophylaxis. However, there is no clinical evidence to support this thesis. We evaluated whether L-ascorbic acid given concomitantly with the urinary carcinogen FANFT was capable of reducing the incidence of subsequent bladder tumors. No inhibitory effect was observed. Unless evidence is obtained demonstrating bladder tumor prevention by L-ascorbic acid its routine administration to patients with bladder cancer is not indicated.

Topics: Animals; Ascorbic Acid; Carcinogens; Carcinoma, Transitional Cell; Drug Evaluation; Formamides; Metaplasia; Mice; Mice, Inbred C3H; Nitrofurans; Precancerous Conditions; Thiazoles; Urinary Bladder; Urinary Bladder Neoplasms