ascorbic-acid and Urinary-Bladder-Neoplasms

A dose-response meta-analysis was conducted to assess the association of vitamin C, D, E with risk of bladder cancer. Pertinent studies were identified in PubMed and Embase. The random-effect model was used. The relative risk (95% confidence interval) of bladder cancer was 0.99 (0.95-1.03) for every 100 IU/day increment in vitamin D from diet plus supplement and 0.95 (0.90-1.00) for every 10 nmol/L increment in circulating vitamin D. The effect for every 10 mg/day increment was 0.96 (0.90-1.02) for vitamin E from diet plus supplement, 0.83 (0.72-0.95) from diet and 0.88 (0.67-1.15) from supplement, and the effect was 0.84 (0.76-0.94) for every 1 mg/dL increment in circulating α-Tocopherol and 1.22 (1.00-1.49) for every 0.1 mg/dL increment in circulating γ-Tocopherol. The observed association for vitamin D and vitamin E was significant among smokers but not among non-smokers. No significant association was found between vitamin C and risk of bladder cancer in the dose-response analysis. Based on the dose-response analysis, the risk of bladder cancer might be inversely associated with vitamin D and E (especially α-Tocopherol), but positively associated with γ-Tocopherol.

Topics: alpha-Tocopherol; Ascorbic Acid; Databases, Factual; Diet; Dietary Supplements; Dose-Response Relationship, Drug; gamma-Tocopherol; Humans; Risk; Smoking; Urinary Bladder Neoplasms; Vitamin D; Vitamin E

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Cohort Studies; Cystectomy; Disease-Free Survival; Female; Follow-Up Studies; Garlic; Genetic Therapy; Humans; Immunotherapy, Active; Male; Neoplasm Recurrence, Local; Phytotherapy; Plants, Medicinal; Prospective Studies; Pyridoxine; Randomized Controlled Trials as Topic; Risk Factors; Terminology as Topic; Time Factors; Urinary Bladder; Urinary Bladder Neoplasms; Urinary Diversion; Vitamin A

Topics: Animals; Antioxidants; Ascorbic Acid; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Carcinogens; Colonic Neoplasms; Ethoxyquin; Glutathione Transferase; Mammary Neoplasms, Experimental; Methylnitronitrosoguanidine; Neoplasms, Experimental; Phenobarbital; Propyl Gallate; Rats; Rats, Inbred F344; Saccharin; Stomach Neoplasms; Substrate Specificity; Urinary Bladder Neoplasms

The present studies report on the significance of L-ascorbic acid (AA) and urinary electrolytes for promotion of rat urinary bladder carcinogenesis. Male F344 rats were given an oral administration of 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as an initiator for 4 weeks, and were then subjected to treatment with dietary supplements of test chemicals for 32 weeks. Administration of 5% sodium L-ascorbate (SA), the sodium ion form of AA significantly promoted urinary bladder carcinogenesis, whereas administration of 5% AA did not. The urine of rats given SA but not AA was characterized by an apparent elevation of pH, an increase of sodium ion concentration, and increases in the urinary content of total AA and its metabolite, dehydroascorbic acid. Administration of 3% NaHCO3, which induced elevation of pH and increase of sodium ion concentration in the urine, promoted BBN bladder carcinogenesis. When rats were given 5% AA plus 3% NaHCO3, AA enhanced the promoting activity of NaHCO3. Lowering of pH by 1% NH4Cl clearly reduced the promoting activity of 5% SA when these two compounds were given concurrently. Treatment with 5% AA plus 3% K2CO3 promoted BBN bladder carcinogenesis in rats, whereas addition of 5% CaCO3 or 5% MgCO3 to AA did not. These results strongly indicate the important role of urinary sodium or potassium ion concentration and pH in modulating urinary bladder carcinogenesis by AA.

Topics: Animals; Ascorbic Acid; Bicarbonates; Butylhydroxybutylnitrosamine; Carbonates; Electrolytes; Hydrogen-Ion Concentration; Male; Potassium; Rats; Rats, Inbred F344; Sodium; Sodium Bicarbonate; Urinary Bladder Neoplasms; Urine

Carcinogenicity tests showed that addition of the antioxidant BHA to the diet of F344 rats induced high incidences of papilloma and squamous cell carcinoma of the forestomach of both sexes. Male hamsters given BHA for 24 weeks also developed papilloma showing downward growth into the submucosa of the forestomach. These results indicate that BHA should be classified in the category of "sufficient evidence of carcinogenicity" as judged by IARC criteria. The 3-tert isomer of BHA seemed to be responsible for the carcinogenicity of crude BHA in the forestomach of rats. BHT was not found to be carcinogenic in rats or mice. In two-stage carcinogenesis in rats after appropriate initiation, BHA enhanced carcinogenesis in the forestomach and urinary bladder of rats, but inhibited carcinogenesis in the liver. BHT enhanced the induction of urinary bladder tumors and inhibited that of liver tumors, but had no effect on carcinogenesis in the forestomach. BHT could be a promoter of thyroid carcinogenesis. Sodium L-ascorbate enhanced forestomach and urinary bladder carcinogenesis. Ethoxyquin enhanced kidney and urinary bladder carcinogenesis, but inhibited liver carcinogenesis. Thus, these antioxidants modify two-stage chemical carcinogenesis in the forestomach, liver, kidney, urinary bladder, and thyroid, but show organ-specific differences in effects.

Topics: Animals; Anisoles; Antioxidants; Ascorbic Acid; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Cocarcinogenesis; Drug Synergism; Humans; Kidney Neoplasms; Liver Neoplasms; Methylnitrosourea; Neoplasms; Species Specificity; Stomach Neoplasms; Urinary Bladder Neoplasms

Present knowledge concerning carcinogenesis and the natural history of urothelial tumours precludes firm conclusions relative to nonindustrial prophylaxis. However, a number of measures are consistent with current data and may be instituted for those patients with a demonstrated propensity to urothelial tumours. Their acceptability is based on the lack of associated toxicity for the patient. These measures include the elimination of significant infection, cigarettes, artificial sweeteners, analgesic abuse and coffee, the administration of vitamins C and B(6), and in selected cases, the use of thiotepa. It is emphasized that the merit of these steps in altering the natural history of urothelial tumours is uncertain.

Topics: Analgesics; Ascorbic Acid; Coffee; Female; Humans; Male; Papilloma; Pyridoxine; Sex Factors; Smoking; Sweetening Agents; Thiotepa; Urethral Stricture; Urinary Bladder Neoplasms; Urinary Tract Infections; Urination Disorders

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Common Cold; Depression; Guinea Pigs; Humans; Male; Miliaria; Nutritional Requirements; Scurvy; Sjogren's Syndrome; Skin Manifestations; Urinary Bladder Neoplasms

Topics: Ascorbic Acid; Double-Blind Method; Humans; Transurethral Resection of Bladder; Urinary Bladder; Urinary Bladder Neoplasms; Urinary Catheters

We evaluated the effect of vitamin C administration on postoperative catheter-related bladder discomfort (CRBD).. A double-blind, randomized controlled trial.. University tertiary hospital.. The participants were patients undergoing transurethral resection of bladder tumor.. Patients were randomly assigned to either vitamin C (n = 59) or control (n = 59). The vitamin C group received 1 g of vitamin C intravenously and the control group received normal saline, administered after the induction of anesthesia.. The primary endpoint was moderate or greater CRBD immediately postoperatively. Secondary outcomes included the incidence of moderate or greater CRBD at 1, 2, and 6 h postoperatively. The symptom of CRBD is either a burning sensation with an urge to void or discomfort in the suprapubic area. Moderate CRBD was defined as spontaneously reported by the patient without any behavioral responses, such as attempts to remove the urinary catheter, intense verbal reactions, and flailing limbs. Severe CRBD was spontaneously reported by the patient with behavioral responses. Patient satisfaction scores were also evaluated.. The group that received vitamin C exhibited a significantly lower incidence of moderate or greater CRBD immediately postoperatively compared with the control group (17 [28.8%] vs. 40 [67.8%], p < 0.001, relative risk [95% confidence interval] = 0.426 [0.274-0.656]). The vitamin C group also showed a significantly lower incidence of moderate or greater CRBD at 1 and 2 h postoperatively compared with the control group (10 [16.9%] vs. 25 [42.4%], p = 0.003; and 5 [8.5%] vs. 16 [27.1%], p = 0.008, respectively). However, there was no significant difference in the incidence of moderate or greater CRBD 6 h postoperatively. Patient satisfaction scores were significantly higher in the vitamin C group than in the control group (5.0 ± 1.3 vs. 4.4 ± 1.4, p = 0.009).. Patients who received vitamin C had decreased CRBD and improved patient satisfaction following transurethral resection of bladder tumor.

Topics: Ascorbic Acid; Double-Blind Method; Humans; Pain, Postoperative; Transurethral Resection of Bladder; Urinary Bladder; Urinary Bladder Neoplasms; Urinary Catheters

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

We examined the relation between dietary fruit and vegetables, carotenoids and vitamin intakes and the risk of bladder cancer among male smokers in a prospective cohort study. Over a median of 11 years, we followed 27 111 male smokers aged 50-69 years who were initially enrolled in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. During this period, 344 men developed bladder cancer. All of these men had completed a 276-food item dietary questionnaire at baseline. Cox proportional hazards models were used to estimate the relative risks and 95% confidence intervals and to simultaneously adjust for age, smoking history, energy intake and intervention group. Consumption of fruits and vegetables was not associated with the risk of bladder cancer (relative risk=1.28; 95% confidence intervals CI: 0.89-1.84, for highest vs lowest quintile). Similarly, no associations were observed for groups of fruits or vegetables (berries and cruciferous vegetables), or for specific fruits and vegetables. Dietary intakes of alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin, beta-cryptoxanthin, vitamins A, E, and C, and folate were not related to the risk of bladder cancer. These findings suggest that fruit and vegetable intakes are not likely to be associated with bladder cancer risk. However, these results may not be generalisable to non-smokers.

Topics: Aged; Ascorbic Acid; Cohort Studies; Diet; Eating; Finland; Fruit; Humans; Incidence; Male; Middle Aged; Prospective Studies; Registries; Risk Factors; Smoking; Surveys and Questionnaires; Urinary Bladder Neoplasms; Vegetables; Vitamin A; Vitamin E

There is a growing body of basic science and epidemiologic evidence to support a research thrust to determine whether several natural or synthetic agents, given alone or together, can lower cancer incidence. Candidate agents include analogs of vitamin A and the vitamin A precursor, beta-carotene, vitamins C and E, and the trace metal selenium. Other agents now being studied in the laboratory include phenolic antioxidants, protease inhibitors, prostaglandin synthesis inhibitors, and indoles. Research in chemoprevention involves identifying and characterizing agents with reported activity, efficacy and toxicologic testing to select the most promising agents, and clinical trials to test those with the most potential in humans. Activities are underway in all the above areas, including 24 clinical trials, to evaluate selected compounds in preventing cancer at various cancer sites. Included are studies of individuals at high risk, individuals with precancerous lesions and individuals free of cancer but at risk to second cancers. A number of agents have shown activity in reducing bladder cancer incidence in animal models. The potential applicability of these agents for studies in human cancer risk reduction intervention studies is discussed. Cancer induction is postulated to be a multistage process involving initiation and promotion. Progress in cancer prevention may result from not only reducing exposures to initiators, but also suppressing promotional activity in initiated cells. Newly developed research technologies including cellular, animal, and epidemiologic procedures are being used for identifying, refining, and testing cancer prevention strategies.

Topics: Animals; Ascorbic Acid; beta Carotene; Carotenoids; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation; Epidemiologic Methods; Female; Humans; Male; Mice; Rats; Selenium; United States; Urinary Bladder Neoplasms; Vitamin A; Vitamin E

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

5-Hydroxymethylcytosine (5hmC) is converted from 5-methylcytosine (5mC) by a group of enzymes termed ten-eleven translocation (TET) family dioxygenases. The loss of 5hmC has been identified as a hallmark of most types of cancer and is related to tumorigenesis and progression. However, the role of 5hmC in bladder cancer is seldom investigated. Vitamin C was recently reported to induce the generation of 5hmC by acting as a cofactor for TET dioxygenases. In this study, we explored the role of 5hmC in bladder cancer and the therapeutic efficacy of vitamin C in increasing the 5hmC pattern.. 5hmC was decreased in bladder cancer samples and was related to patient overall survival. Genome-wide mapping of 5hmC in tumor tissues and vitamin C-treated bladder cancer cells revealed that 5hmC loss was enriched in cancer-related genes and that vitamin C treatment increased 5hmC levels correspondingly. Vitamin C treatment shifted the transcriptome and inhibited the malignant phenotypes associated with bladder cancer cells in both in vitro cell lines and in vivo xenografts.. This study provided mechanistic insights regarding the 5hmC loss in bladder cancer and a rationale for exploring the therapeutic use of vitamin C as a potential epigenetic treatment for bladder cancer.

Topics: 5-Methylcytosine; Aged; Animals; Ascorbic Acid; Cell Proliferation; Cell Survival; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Male; Mice; Middle Aged; Prognosis; Sequence Analysis, DNA; Sequence Analysis, RNA; Survival Analysis; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays

Quinone-containing molecules have been developed against cancer mainly for their redox cycling ability leading to reactive oxygen species (ROS) formation. We have previously shown that donor-acceptor phenylaminonaphthoquinones are biologically active against a panel of cancer cells. In this report, we explored the mechanisms involved in cancer cell growth inhibition caused by two phenylaminonaphthoquinones, namely Q7 and Q9, with or without ascorbate (ASC). The results show that Q7 and Q9 are both redox cyclers able to form ROS, which strongly inhibit the proliferation of T24 cells. Q9 was a better redox cycler than Q7 because of marked stabilization of the semiquinone radical species arising from its reduction by ascorbate. Indeed, ASC dramatically enhances the inhibitory effect of Q9 on cell proliferation. Q9 plus ASC impairs the cell cycle, causing a decrease in the number of cells in the G2/M phase without involving other cell cycle regulating key proteins. Moreover, Q9 plus ASC influences the MAPK signaling pathways, provoking the appearance of a senescent cancer cell phenotype and ultimately leading to necrotic-like cell death. Because cellular senescence limits the replicative capacity of cells, our results suggest that induction of senescence may be exploited as a basis for new approaches to cancer therapy.

Topics: Aminophenols; Aniline Compounds; Antineoplastic Agents; Ascorbic Acid; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cellular Senescence; Drug Synergism; Humans; Imidazoles; MAP Kinase Signaling System; Naphthoquinones; Necrosis; Oxidation-Reduction; Phenotype; Pyridines; Reactive Oxygen Species; 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

Ascorbate and menadione (Apatone) in a ratio of 100:1 kills tumor cells by autoschizis. In this study, vitamin-induced changes in nucleolar structure were evaluated as markers of autoschizis. Human bladder carcinoma (T24) cells were overlain with vitamins or with culture medium. Supernatants were removed at 1-hr intervals from 1 to 4 hr, and the cells were washed with PBS and prepared for assay. Apatone produced marked alterations in nucleolar structure including redistribution of nucleolar components, formation of ring-shaped nucleoli, condensation and increase of the proportion of perinucleolar chromatin, and the enlargement of nucleolar fibrillar centers. Immunogold labeling of the nucleolar rRNA revealed a granular localization in treated and sham-treated cells, and immunogold labeling of the rDNA revealed a shift from the fibrillar centers to the condensed perinucleolar chromatin. Fibrillarin staining shifted from the fibrillar centers and adjacent regions to a more homogeneous staining of the entire nucleolus and was consistent with the percentage of autoschizic cells detected by flow cytometry. Because autoschizis entails sequential reactivation of DNase I and DNase II, and because the fibrillarin redistribution following DNase I and Apatone treatment is identical, it appears that the nucleolar and fibrillarin changes are markers of autoschizis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Carcinoma; Cell Line, Tumor; Cell Nucleolus; Chromosomal Proteins, Non-Histone; Humans; Urinary Bladder Neoplasms; Vitamin K; Vitamin K 3

Nitrite has been implicated in carcinogenesis, especially under acidic conditions such as in the stomach or in urine, where it forms nitrosating species that can react with secondary amines to form nitrosamines. Recent studies have shown that nitrite and acid form a variety of other nitrogen oxides in vivo including nitric oxide-a compound with documented antitumor activity. Here we tested the effects of nitrite on bladder tumor cells incubated in mildly acidified urine. Nitrite (50 microM) inhibited thymidine incorporation in human T24 bladder cancer cells. This inhibition required slight acidification (pH 5.5-6), and no effect of nitrite could be observed at pH 7. Nitrite effects were further augmented in the presence of ascorbic acid, whereas ascorbic acid alone had no effect. The effects were paralleled by formation of nitric oxide gas. We here demonstrate an inhibitory effect of nitrite on cancer cell replication at concentrations and acidity commonly found in urine and gastric juice. The inhibitory effect is likely caused by nitric oxide and possibly other reactive nitrogen oxides formed from acidified nitrite.

Topics: Antineoplastic Agents; Ascorbic Acid; Cell Line, Tumor; DNA Replication; Drug Synergism; Humans; Hydrogen-Ion Concentration; Luminescent Measurements; Nitric Oxide; Nitrites; Sodium Nitrite; Thymidine; Urinary Bladder Neoplasms; Urine

A human bladder carcinoma cell line RT4 was sham-treated with buffer or treated with ascorbate (VC) alone, menadione alone (VK(3)), or a combination of ascorbate:menadione (VC+VK(3)) for 1, 2, and 4 h. Cytotoxic damage was found to be treatment-dependent in this sequence: VC+VK(3)>VC>VK(3)>sham. The combined treatment induced the greatest oxidative stress, with early tumor cell injury affecting the cytoskeletal architecture and contributing to the self-excisions of pieces of cytoplasm freed from organelles. Additional damage, including a reduction in cell size, organelle alterations, nuclear damage, and nucleic acid degradation as well as compromised lysosome integrity, is caused by reactivation of DNases and the redox cycling of VC or VC+VK(3). In addition, cell death caused by VC+VK(3) treatment as well as by prolonged VC treatment is consistent with cell demise by autoschizis, not apoptosis. This report confirms and complements previous observations about this new mode of tumor cell death. It supports the contention that a combination of VC+VK(3), also named Apatone, could be co-administered as a nontoxic adjuvant with radiation and/or chemotherapies to kill bladder tumor cells and other cancer cells without any supplementary risk or side effects for patients.

Topics: Antineoplastic Agents; Ascorbic Acid; Cell Death; Cell Line, Tumor; Cell Nucleus; Cell Survival; DNA Damage; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Humans; Male; Microscopy, Electron, Transmission; Organelles; Oxidative Stress; Urinary Bladder Neoplasms; Vitamin K 3

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

Benzidine (Bz), a human bladder carcinogen, was strongly mutagenic to Salmonella TA102 tester strain in the Ames Salmonella microsome/mutagenicity assay in the presence of rat liver S9 mix. Various non-mutagenic plant polyphenols were included in the assay to test their inhibitory effects on the Bz-induced mutations. Coumestrol, ellagic acid (EA), (-)-epicatechin (EC), (-)-epichatechingallate (ECG), gallic acid (GA), (-)-gallocatechin (GC), plumbagin, propyl gallate (PG), taxifolin, and 2,2',4'-trihydroxychalcone were found to have a strong inhibitory effect on Bz-induced mutations. (-)-Epigallo-catechingallate (EGCG), fisetin, (-)-gallocatechingallate (GCG), and piceatannol were moderately inhibitory to the mutations; whereas, (-)-catechin, (-)-catechingallate (CG), and reseveratrol were weakly inhibitory to the mutations. (-)-Epigallocatechin (EGC) and 7,3',4'-trihydroxy isoflavon were not inhibitory to the Bz-induced mutations. Isoliquirtigenin, quercetin dihydrate, and rhein were found to be mutagenic in tester strain TA102. Benzidine mediated lipid peroxidation was conducted employing the thiobarbituric acid reactive substances (TBARS) assay using linoleic acid as a substrate. In the presence of rat liver S9 mix, Bz could cause lipid peroxidation as an outcome of production of oxygen free radicals. Incorporation of the above mentioned non-mutagenic plant polyphenols significantly inhibited benzidine mediated lipid peroxidation in a time dependent manner. These polyphenols also effectively reduced the iron mediated lipid peroxidation. Thus, it is concluded that the inhibition of oxidative mutagenicity of Bz by plant polyphenols could be due to an inhibitory effect of plant polyphenols on the bioactivating enzymes such as cytochrome P-450 and peroxidase and the chelation of iron present in the cytochrome P-450 in the S9 mix. Thus, these plant polyphenols play a significant inhibitory role on Bz-induced mutagenicity.

Topics: Animals; Antimutagenic Agents; Ascorbic Acid; Benzidines; Dose-Response Relationship, Drug; Flavonoids; In Vitro Techniques; Lipid Peroxidation; Molecular Weight; Mutagenicity Tests; Mutagens; Phenols; Plants; Polyphenols; Rats; Salmonella; Structure-Activity Relationship; Thiobarbituric Acid Reactive Substances; Urinary Bladder Neoplasms

Feulgen and actin-phalloidin staining as well as gel electrophoresis have been employed in conjunction with cell ultrastructure to describe the effects of 1-, 2-, and 4-hr ascorbate (VC), menadione (VK(3)), and ascorbate:menadione (VC:VK(3)) treatments on the T24 human bladder carcinoma cell line. T24 cells exposed to VC alone display blebs and other superficial membrane defects related to membrane alterations and to superficial cytoskeleton changes. VK(3) treatment damages the cell nucleus and organelles, leads to the redistribution of the organelles in the perikaryon as a consequence of cytoskeletal damage, and results in cytoplasmic self-excisions. After VC:VK(3) treatment, the cells show exaggerated alterations characteristic of each vitamin treatment alone, including damaged mitochondria, self-excision of organelle-free pieces of cytoplasm, and extrusion of the perikaryon containing a nucleus surrounded by the damaged organelles. The nuclear envelope appears intact and contains chromatin that decondenses and dissipates. During the cellular demise that concludes with apparent karyolysis, the cells significantly decrease their size and alter their shape. However, the cisterns of rough endoplasmic reticulum are undamaged, but may become dilated. Since the cellular phenomena leading to cell death differ morphologically from apoptosis and necrosis, but entail self-cutting without nuclear bodies, this new form of cell death was called autoschizis. In addition, gel electrophoresis and Feulgen staining demonstrate that autoschizis is accompanied by random DNA degeneration.

Topics: Ascorbic Acid; Carcinoma; Cell Death; Cell Line, Tumor; Densitometry; DNA Fragmentation; Drug Synergism; Electrophoresis; Histocytochemistry; Humans; Rosaniline Dyes; Urinary Bladder Neoplasms; Vitamin K 3

Early clinical studies showed that high-dose vitamin C, given by intravenous and oral routes, may improve symptoms and prolong life in patients with terminal cancer. Double-blind placebo-controlled studies of oral vitamin C therapy showed no benefit. Recent evidence shows that oral administration of the maximum tolerated dose of vitamin C (18 g/d) produces peak plasma concentrations of only 220 micromol/L, whereas intravenous administration of the same dose produces plasma concentrations about 25-fold higher. Larger doses (50-100 g) given intravenously may result in plasma concentrations of about 14,000 micromol/L. At concentrations above 1000 micromol/L, vitamin C is toxic to some cancer cells but not to normal cells in vitro. We found 3 well-documented cases of advanced cancers, confirmed by histopathologic review, where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy. We examined clinical details of each case in accordance with National Cancer Institute (NCI) Best Case Series guidelines. Tumour pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment. In light of recent clinical pharmacokinetic findings and in vitro evidence of anti-tumour mechanisms, these case reports indicate that the role of high-dose intravenous vitamin C therapy in cancer treatment should be reassessed.

Topics: Aged; Ascorbic Acid; Carcinoma, Renal Cell; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Kidney Neoplasms; Lymphoma, B-Cell; Male; Middle Aged; Survival Analysis; Treatment Outcome; Urinary Bladder Neoplasms; Vitamins

Bladder cancer, the fourth highest incident cancer in men and tenth in women, is associated with a high rate of recurrence, even when treated in situ, and prognosis is poor once the cancer metastasizes to distant sites. Based on anticancer properties, we investigated the effect of a mixture of lysine, proline, arginine, ascorbic acid, and green tea extract on human bladder cancer cells T-24 by measuring: proliferation, matrix metalloproteinase (MMP) expression, and cancer cell invasive potential.. Human bladder cancer cells T-24 (ATCC) were grown in McCoy medium supplemented with 10% fetal bovine serum, penicillin (100 U/mL) and streptomycin (100 mg/mL) in 24-well tissue culture plates. At near confluence, the cells were treated with the nutrient mixture dissolved in media and tested at 0, 10, 50, 100, 500, and 1000 microg/mL in triplicate at each dose. Cells were also treated with PMA 200 ng/mL to study enhanced MMP-9 activity. Cell proliferation was evaluated by MTT assay, MMP activity by gelatinase zymography, and invasion through Matrigel.. Nutrient mixture inhibited the T-24 cell secretion of MMP-2 and -9, with virtual total inhibition of MMP-2 at 500 microg/mL and MMP-9 at 100 microg/mL. The nutrient mixture significantly reduced the invasion of human bladder cancer cells T-24 through Matrigel in a dose-dependent fashion, with 95% inhibition at 500 microg/mL and 100% at 1000 microg/mL nutrient mixture (P < 0.001).. Our results suggest that our nutrient mixture is an excellent candidate for therapeutic use in the treatment of bladder cancer, by inhibiting critical steps in cancer development and spread, such as MMP secretion and invasion.

Topics: Antioxidants; Arginine; Ascorbic Acid; Biomarkers, Tumor; Camellia sinensis; Cell Line, Tumor; Cell Proliferation; Disease Progression; Female; Humans; In Vitro Techniques; Lysine; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Plant Extracts; Proline; Urinary Bladder Neoplasms

We evaluated the antitumor effects of vitamins C and K3 for human urothelial carcinoma and the potential use of the combination of vitamins C plus K3 as a sensitizing agent for conventional chemotherapy for urothelial carcinoma.. The antiproliferative and apoptotic effects of vitamin C alone, vitamin K3 alone, vitamins C plus K3, gemcitabine alone and gemcitabine plus vitamins C plus K3 were assessed in vitro by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, propidium iodide staining and flow cytometry. For in vivo studies we implanted UMUC-14 tumorigenic urothelial carcinoma cells into the subcutis of nude mice. One week later we treated 10 mice each with saline (control), vitamins C plus K3, gemcitabine or gemcitabine plus vitamins C plus K3. Treatment was continued for 4 weeks, followed by necropsy. Tumor volume was measured and tumor kinetics were established. Apoptosis and proliferation were evaluated in tumor sections using immunohistochemistry and TUNEL assay.. Vitamins C plus K3 induced cytostasis and caused apoptosis to a greater degree than either vitamin alone (p < 0.05). Vitamins C plus K3 also substantially augmented the effects of gemcitabine in vitro. There were 32.3% apoptosis with gemcitabine plus vitamins C plus K3, 5.3% with gemcitabine alone and 15.8% with vitamins C plus K3 alone (p < 0.05). In vivo tumor growth was substantially inhibited by gemcitabine plus vitamins C plus K3 compared with that in the control or for either agent alone. Mean tumor weight and growth rate in the gemcitabine plus vitamins C plus K3 group (237 mg and 11.3 mm3 daily) were decreased compared with those in the control (530 mg and 34.3 mm3 daily), and those for vitamins C plus K3 alone (490 mg and 25.2 mm3 daily) and gemcitabine alone (400 mg and 21.3 mm3 daily) (p < 0.05).. Vitamins C and K3 have significant antiproliferative and apoptotic effects when used in combination. This combination enhances the efficacy of gemcitabine against bladder cancer in vivo.

Topics: Animals; Antimetabolites, Antineoplastic; Apoptosis; Ascorbic Acid; Carcinoma; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Gemcitabine; Humans; Male; Mice; Mice, Inbred BALB C; Urinary Bladder Neoplasms; Urothelium; Vitamin K 3; Vitamins

Initiation activity of phenylethyl isothiocyanate (PEITC) was examined in a two-stage urinary bladder carcinogenesis model. Male 6-week-old Fischer 344 rats were fed diet containing 0.1% PEITC for 12 or 24 weeks, with or without subsequent administration of 5% sodium l-ascorbate (Na-AsA) in diet until week 48, or for the entire experimental period. After 12 weeks of PEITC-treatment, both simple hyperplasia and papillary or nodular (PN) hyperplasia had developed in all animals, but the majority of these lesions had disappeared at week 48, irrespective of the Na-AsA-treatment. The same lesions after 24 weeks of PEITC-treatment had progressed to dysplasia and carcinoma, in a small number of cases by week 48 (6% in incidence for each lesion), but enhancement by the Na-AsA-treatment was evident only with simple hyperplasias (from 56 to 100% in incidence) and PN hyperplasias (from 19 to 56%). The results suggest a limited initiation activity of PEITC with induction of irreversible lesions by 24 weeks of exposure.

Topics: Animals; Ascorbic Acid; Body Weight; Carcinoma; Diet; Hyperplasia; Isothiocyanates; Male; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

Sodium L-ascorbate (Na-AsA) is widely known to be a tumor promoter of rat bladder carcinogenesis but tests negative in standard 2-year bioassays. In the present study, bladder-cancer-susceptible transgenic rats designated Hras128 were used to further examine the tumorigenicity of Na-AsA. A total of 40 7-week-old male transgenic (Tg) and 42 littermate nontransgenic (Non-tg) rats were divided into 4 groups and given powdered MF diet with or without 5% Na-AsA for 57 weeks. Tg rats showed significantly short survival compared with Non-tg, independent of Na-AsA treatment. Tg rats treated with Na-AsA showed a slightly higher incidence of carcinoma (29.6%) as compared to those without Na-AsA treatment (15.4%), but this was without statistical significance. Moreover, the total bladder tumor incidences, including papillomas, did not differ statistically (with Na-AsA, 37.0%; without Na-AsA, 30.8%). No bladder tumor was detected in Non-tg rats. Various kinds of other lesions in various organs were noted in Tg rats treated with or without Na-AsA treatment, but no intergroup differences were evident. In conclusion, Na-AsA did not show tumorigenicity in highly bladder-cancer-susceptible transgenic Hras128 rats. These results suggest that Na-AsA is a pure promoter but not a complete carcinogen in rats.

Topics: Animals; Animals, Genetically Modified; Ascorbic Acid; Carcinogenicity Tests; Genes, ras; Proto-Oncogene Mas; Rats; Survival Analysis; Urinary Bladder; Urinary Bladder Neoplasms; Vitamins

Exponentially growing cultures of human bladder tumor cells (T24) were treated with Vitamin C (VC) alone, Vitamin K(3) (VK(3)) alone, or with a VC:VK(3) combination for 1, 2, or 4hr. Flow cytometry of T24 cells exposed to the vitamins for 1h revealed a growth arrested population and a population undergoing cell death. Cells in G(1) during vitamin treatment arrested in G(1) while those in S phase progressed through S phase and arrested in G(2)/M. DNA synthesis decreased to 14 to 21% of control levels which agreed with the percent of cells in S phase during treatment. Annexin V labeling demonstrated the majority of the cells died by autoschizis, but necrosis and apoptosis also were observed. Catalase treatment abrogated both cell cycle arrest and cell death which implicated hydrogen peroxide (H(2)O(2)) in these processes. Redox cycling of VC and VK(3) increased H(2)O(2) production and decreased cellular thiol levels and DNA content, while increasing intracellular Ca(2+) levels and lipid peroxidation. Feulgen staining of treated cells revealed a time-dependent decrease in tumor cell DNA, while electrophoresis revealed a spread pattern. These results suggest that Ca(2+) disregulation activates at least one DNase which degrades tumor cell DNA and induces tumor cell death.

Topics: Antioxidants; Ascorbic Acid; Calcium; Cell Cycle; DNA, Neoplasm; Flow Cytometry; Humans; Hydrogen Peroxide; Male; Sulfhydryl Compounds; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Vitamin K 3

Previous epidemiological studies of fruit and vegetable intake and bladder cancer risk have yielded inconsistent results, especially with respect to the role of cigarette smoking as a possible modifier of the diet-bladder cancer association. A population-based case-control study was conducted in nonAsians of Los Angeles, California, which included 1,592 bladder cancer patients and an equal number of neighborhood controls matched to the index cases by sex, date of birth (within 5 years) and race between January 1, 1987 and April 30, 1996. Information on smoking, medical and medication history, and intake frequencies of food groups rich in preformed nitrosamines, vitamins A and C and various carotenoids, were collected through in-person, structured interviews. Beginning in January 1992, all case patients and their matched control subjects were asked for a blood sample donation at the end of the in-person interviews for measurements of 3- and 4-aminobiphenyl (ABP) hemoglobin adducts, and glutathione S-transferases M1/T1/P1 (GSTM1/T1/P1) and N-acetyltransferase-1 (NAT1) genotypes. Seven hundred seventy-one (74%) case patients and 775 (79%) control subjects consented to the blood donation requests. In addition, all case patients and matched control subjects were asked to donate an overnight urine specimen following caffeine consumption for measurements of cytochrome P4501A2 (CYP1A2) and N-acetyltransferase-2 (NAT2) phenotypes. Urine specimens were collected from 724 (69%) case patients and 689 (70%) control subjects. After adjustment for nondietary risk factors including cigarette smoking, there were strong inverse associations between bladder cancer risk and intake of dark-green vegetables [p value for linear trend (p) = 0.01], yellow-orange vegetables (p = 0.01), citrus fruits/juices (p = 0.002) and tomato products (p = 0.03). In terms of nutrients, bladder cancer risk was inversely associated with intake of both total carotenoids (p = 0.004) and vitamin C (p = 0.02). There was a close correlation (r = 0.58, p = 0.0001) between intakes of total carotenoids and vitamin C in study subjects. When both nutrients were included in a multivariate logistic regression model, only total carotenoids exhibited a residual effect that was of borderline statistical significance (p = 0.07 and p = 0.40 for total carotenoids and vitamin C, respectively). Cigarette smoking was a strong modifier of the observed dietary effects; these protective effects were confined largely to

Topics: Acyltransferases; Algorithms; Aminobiphenyl Compounds; Arylamine N-Acetyltransferase; Ascorbic Acid; Carotenoids; Case-Control Studies; Cytochrome P-450 CYP1A2; Diet; Female; Genotype; Glutathione Transferase; Hemoglobins; Humans; Logistic Models; Male; Nutritional Physiological Phenomena; Odds Ratio; Phenotype; Risk; Smoking; Urinary Bladder Neoplasms

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

Some epidemiologic studies suggest that use of vitamin C or vitamin E supplements, both potent antioxidants, may reduce the risk of bladder cancer. The authors examined the association between use of individual vitamin C and vitamin E supplements and bladder cancer mortality among 991,522 US adults in the Cancer Prevention Study II (CPS-II) cohort. CPS-II participants completed a self-administered questionnaire at enrollment in 1982 and were followed regarding mortality through 1998. During follow-up, 1,289 bladder cancer deaths occurred (962 in men and 327 in women). Rate ratios were adjusted for age, sex, cigarette smoking, education, and consumption of citrus fruits and vegetables. Regular vitamin C supplement use (>or=15 times per month) was not associated with bladder cancer mortality, regardless of duration (rate ratio (RR) = 0.91, 95% confidence interval (CI): 0.68, 1.20 for <10 years' use; RR = 1.25, 95% CI: 0.91, 1.72 for >or=10 years' use). Regular vitamin E supplement use for >or=10 years was associated with a reduced risk of bladder cancer mortality (RR = 0.60, 95% CI: 0.37, 0.96), but regular use of shorter duration was not (RR = 1.04, 95% CI: 0.77, 1.40). Results support the hypothesis that long-duration vitamin E supplement use may reduce the risk of bladder cancer mortality.

Topics: Adult; Age Distribution; Aged; Aged, 80 and over; Antioxidants; Ascorbic Acid; Cohort Studies; Confidence Intervals; Death Certificates; Diet; Female; Humans; Male; Middle Aged; Sex Distribution; Surveys and Questionnaires; United States; Urinary Bladder Neoplasms; Vitamin E

In the Netherlands Cohort Study among 120 852 subjects aged 55-69 years at baseline (1986), the association between vitamins and carotenoids intake, vitamin supplement use, and bladder cancer incidence was examined. Exposure status was measured with a food-frequency questionnaire. After 6.3 years of follow-up, data from 569 cases and 3123 subcohort members were available for case-cohort analyses. The age-, sex-, and smoking-adjusted relative risks (RRs) for retinol, vitamin E, folate, a-carotene, b-carotene, lutein and zeaxanthin, and lycopene were 1.04, 0.98, 1.03, 0.99, 1.16, 1.11, and 1.08, respectively, comparing highest to lowest quintile of intake. Only vitamin C (RR: 0.81, 95% CI: 0.61-1.07, P-trend = 0.08), and b-cryptoxanthin intake (RR: 0.74, 95% CI: 0.53-1.03, P-trend < 0.01) were inversely associated with bladder cancer risk. The association with vitamin C disappeared after adjustment for b-cryptoxanthin but not vice versa. The RRs for supplemental use of vitamin A, C or E compared to no use were around unity. We conclude that dietary or supplemental intake of vitamin A, vitamin C, vitamin E, and intake of folate, and most carotenoids are not associated with bladder cancer. In this study, only b-cryptoxanthin intake appeared to be inversely associated.

Topics: Aged; Ascorbic Acid; Carotenoids; Cohort Studies; Diet; Female; Folic Acid; Humans; Incidence; Male; Middle Aged; Netherlands; Risk Factors; Urinary Bladder Neoplasms; Vitamin A; Vitamin E

Scanning and transmission electron microscopy (SEM and TEM) were employed to characterize the cytotoxic effects of vitamin C (VC), Vitamin K3 (VK3) or a VC:VK3 combination on a human bladder carcinoma cell line (T24) following vitamin treatment. T24 cells exposed to VC alone showed membrane defects. VK3-treated cells show greater damage than VC treated cells because they exhibit membrane defects, cytoskeletal damage, excision of cytoplasm, and a substantial decrease in the number of viable cells. VC: VK3 treatment exacerbates the damages, especially intranuclear and nucleolar and induces an extreme reduction of cell size by cytoplasmic self-excision. Conversely, the nuclear envelope remains intact and the rough endoplasmic reticulum (RER) maintains its integrity until karyorrhexis occurs through a new phenomenon of cell death that we have named "autoschizis". From our morphological studies and previous biochemical reports on the topic, we are able to propose that this autoschizic cell death found is induced by oxidative stress.

Topics: Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Carcinoma; Cell Death; Drug Therapy, Combination; Humans; Microscopy, Electron; Oxidative Stress; Treatment Outcome; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Vitamin K 3

Overexpression of ornithine decarboxylase (ODC) has been shown to be characteristic of tumor development and progression in humans and experimental animals. Therefore, we have examined the effects of 1, 3-diaminopropane dihydrochloride (DAP), a potent inhibitor of ODC, on rat two-stage urinary bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). In experiment 1 (36 weeks), 6-week-old F344 male rats were administered 0.05% BBN in drinking water for 4 weeks and then divided into four groups. Animals of groups 1 and 2 received basal diet and drinking water supplemented with or without DAP (2 g/l). Groups 3 and 4 were given diet containing 5% sodium L-ascorbate (NaAsA), a typical urinary bladder tumor promoter, and drinking water with or without DAP. Administration of DAP to group 1 significantly reduced tumor size, multiplicity and incidence, particularly of papillomas, when compared with group 2 values. DAP together with NaAsA (group 3) also decreased tumor size relative to the group 4 case. To determine the effects of DAP on the early stages of bladder carcinogenesis and its mechanisms, a similar protocol was conducted (experiment 2) with death after 20 weeks. DAP treatment caused complete inhibition (0% incidence) of papillary and/or nodular hyperplasia in group 1 but was without influence in group 3, as compared with the respective controls. Moreover, the ODC activity, bromodeoxyuridine labeling indices and mRNA expression levels of cyclin D1 in the urinary bladder mucosa, determined by northern blotting, were markedly lower in group 1 than in group 2, but values were comparable for both groups administered NaAsA. Assessment of mRNA expression levels of the angiogenic vascular endothelial growth factor suggested no involvement in the inhibitory effects of DAP on urinary bladder carcinogenesis. The results indicate that inhibition of ODC could reduce urinary bladder carcinogenesis in rats, particularly in the early stages, through antiproliferative mechanisms.

Topics: Acetyltransferases; Animals; Anticarcinogenic Agents; Apoptosis; Ascorbic Acid; Butylhydroxybutylnitrosamine; Carcinogens; Carcinoma; Cocarcinogenesis; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Diamines; Endothelial Growth Factors; Hydrogen-Ion Concentration; Hyperplasia; Lymphokines; Male; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Papilloma; Polyamines; Proto-Oncogene Proteins; Rats; Rats, Inbred F344; RNA, Messenger; Urinary Bladder; Urinary Bladder Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Effects of a genotoxic bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and a non-genotoxic bladder promoter, sodium L-ascorbate (Na-AsA), on protein expression, cell proliferation and apoptosis of the bladder epithelium with or without the influence of testicular castration were investigated. Male F344 rats were divided into six groups (groups 1-6). BBN was given with 0.05% drinking water to groups 1 and 4 for 8 weeks, groups 2 and 5 received diet with 5% Na-AsA. Then the animals were treated without any chemicals. Groups 3 and 6 were non-treated controls. Testicular castration was carried out 2 weeks before commencement of chemical treatment on groups 4-6. The total observation period was 18 weeks. Overexpression of cyclin D1 was induced by BBN but not Na-AsA and the degree of overexpression was higher in the order simple hyperplasia, papillary or nodular hyperplasia, papilloma and carcinoma. Metallothionein (MT) was also overexpressed in bladder epithelium treated with BBN but not Na-AsA, but was decreased in papillomas and never found in a carcinoma. Cyclin D1-positive cells were essentially MT-negative. Therefore, it is speculated that MT protects genes from insult by genotoxic carcinogens and its lack is associated with tumor development. Apoptotic cell death occurred during treatment with BBN and Na-AsA and after their withdrawal. Chromatin condensation of many G0/G(1) cells was particularly marked on flow cytometry analysis 1 week after cessation of treatment, this being considered as an early apoptotic change. Although testicular castration had no influence on the above events, it resulted in decreased tumor formation as compared with the case of similarly treated intact animals. Our data demonstrate that overexpression of MT and cyclin D1 is specific for treatment with a genotoxic carcinogen, and suggest that MT overexpression may play an important suppressive role in the early stages of rat urinary bladder carcinogenesis.

Topics: Animals; Apoptosis; Ascorbic Acid; Butylhydroxybutylnitrosamine; Cyclin D1; DNA, Neoplasm; Flow Cytometry; Male; Metallothionein; Microscopy, Electron; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

Sodium saccharin, ascorbate and other sodium salts fed at high doses to rats produce urinary bladder urothelial cytotoxicity with consequent regenerative hyperplasia. For sodium salts that have been tested, tumor activity is enhanced when administered either alone or after a brief exposure to a known genotoxic bladder carcinogen. These sodium salts alter urinary composition of rats resulting in formation of an amorphous precipitate. We examined the precipitate to ascertain its composition and further delineate the basis for its formation in rat urine. Using scanning electron microscopy with attached X-ray energy dispersive spectroscopy, the principal elements present were calcium, phosphorus, minor amounts of silicon and sulfur. Smaller elements are not detectable by this method. Infrared analyses demonstrated that calcium phosphate was in the tribasic form and silicon was most likely in the form of silica. Small amounts of saccharin were present in the precipitate from rats fed sodium saccharin (<5%), but ascorbate was not detectable in the precipitate from rats fed similar doses of sodium ascorbate. Large amounts of urea and mucopolysaccharide, apparently chondroitin sulfate, were detected in the precipitate by infrared analysis. Chemical analyses confirmed the presence of large amounts of calcium phosphate with variably small amounts of magnesium, possibly present as magnesium ammonium phosphate crystals, present in urine even in controls. Small amounts of protein, including albumin and alpha(2u)-globulin, were also detected (<5% of the precipitate). Calcium phosphate is an essential ingredient of the medium for tissue culture of epithelial cells, but when present at high concentrations (>5 mM) it precipitates and becomes cytotoxic. The nature of the precipitate reflects the unique composition of rat urine and helps to explain the basis for the species specificity of the cytotoxic and proliferative effects of high doses of these sodium salts.

Topics: Animals; Ascorbic Acid; Calcium Phosphates; Chemical Precipitation; Dose-Response Relationship, Drug; Female; Male; Osmolar Concentration; Rats; Rats, Inbred F344; Saccharin; Sex Factors; Sodium; Species Specificity; Urinary Bladder Neoplasms

Previous studies have already demonstrated the protective role of vitamin C (ascorbic acid) in certain types of cancer. This study reports on the effects of vitamin C on arylamine N-acetyltransferase (NAT) activity and DNA adduct formation in a human bladder tumor cell (T24) line. The activity of NAT was measured using high-performance liquid chromatography (HPLC), by assaying for the amounts of acetylated 2-aminofluorene (AF) and p-aminobenzoic acid (PABA) and the remaining amounts of AF and PABA. T24 cells were used for examining NAT activity and carcinogen DNA adduct formation. The results demonstrated that NAT activity and 2-aminofluorene DNA adduct formation in T24 cells were inhibited and decreased by vitamin C in a dose-dependent manner. The apparent kinetic parameters (apparent values of Km and Vmax) from T24 cells were also determined with and without vitamin C cotreatment. The data also indicated that vitamin C decreased the apparent values of Km and Vmax from T24 cells.

Topics: 4-Aminobenzoic Acid; Acetylation; Arylamine N-Acetyltransferase; Ascorbic Acid; Chromatography, High Pressure Liquid; DNA Adducts; Dose-Response Relationship, Drug; Fluorenes; Humans; Tumor Cells, Cultured; Urinary Bladder Neoplasms

In our two-stage model of rat urinary bladder carcinogenesis employing N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as the initiator, sodium L-ascorbate (Na-AsA) exhibits dose-dependent promotion. In the present study, in order to assess the possible reversibility of the promoting effects, we investigated how different administration periods of Na-AsA influence its promoting activity. In experiment 1, rats were treated with 5% Na-AsA for different administration periods with or without withdrawal and injected with 5-bromo-2'-deoxyuridine (BrdU) to allow determination of the cell proliferation status. Replicative DNA synthesis in the urinary bladder epithelium was shown to return to normal after removal of the promoting stimulus. In experiment 2, rats were initially given BBN for 4 weeks and subsequently received 16 weeks of Na-AsA, alternating with basal diet, at intervals of 4, 8 or 16 weeks, within a total 32-week period. The longer the continuous exposure to Na-AsA, the greater the yield of papillomas and carcinomas in the urinary bladder. In experiment 3, Na-AsA was given for 4 or 8 weeks after BBN initiation and the animals were killed at weeks 8 and 12. Both promotion of lesion development and increase of DNA synthesis in the urinary bladder epithelium were dependent on the length of exposure to Na-AsA and the total period of exposure. The results indicate that the promoting effects of Na-AsA in urinary bladder carcinogenesis are reversible to a certain extent after its withdrawal, and the existence of a cumulative exposure time threshold seems likely.

Topics: Animals; Ascorbic Acid; Bromodeoxyuridine; Butylhydroxybutylnitrosamine; Carcinogens; Carcinoma; Drug Administration Schedule; Hyperplasia; Male; Papilloma; Rats; Rats, Inbred F344; Time Factors; Urinary Bladder; Urinary Bladder Neoplasms

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

Dimethylarsinic acid (DMA), a main metabolite of arsenicals which are carcinogenic in man, exerts tumor-promoting activity on rat urinary bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Sodium L-ascorbate (Na-AsA) is also a strong tumor promoter in this animal model. In this study, we used (LewisxF344)F, rats to compare molecular alterations in urinary bladder tumors caused by BBN followed by DMA or Na-AsA. Male, 6-week-old rats were given 0.05% BBN in their drinking water for 4 weeks, and then the rats in group 1 were maintained with no further treatment for 40 weeks. The animals of groups 2 and 3 were administered 0.01% DMA in their drinking water (group 2) or 5% Na-AsA in the powder diet (group 3) after the BBN treatment. Group 4 rats were given 0.05% BBN continuously for 36 weeks. At weeks 12, 20, 36 and 44, subgroups of rats were killed. Histopathological examination revealed promoting activity for DMA and, to a greater extent, Na-AsA on urinary bladder carcinogenesis. Loss of heterozygosity (LOH), detected with the polymerase chain reaction using 36 microsatellite markers, was found to be present in 2 of 9 (22%) urinary bladder tumors after treatment with DMA and 3 of 22 (14%) induced by continuous administration with BBN. No LOH was, however, detected in urinary bladder tumors after treatment with Na-AsA. The results thus suggest that the mechanisms of action of these two promoters, DMA and Na-AsA, may differ in rat urinary bladder carcinogenesis.

Topics: Animals; Ascorbic Acid; Butylhydroxybutylnitrosamine; Cacodylic Acid; Carcinogenicity Tests; Carcinoma; Hyperplasia; Loss of Heterozygosity; Male; Microsatellite Repeats; Papilloma; Polymerase Chain Reaction; Rats; Rats, Inbred F344; Rats, Inbred Lew; Urinary Bladder; Urinary Bladder Neoplasms

Sodium L-ascorbate (Na-AsA) has been demonstrated to be a strong promoter of rat urinary bladder tumor development initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). In the present study, we investigated variation in its promoting activity when the same total dose was given with different concentrations and exposure times. After 4 weeks administration of 0.05% BBN, group 1 served as a control without any post-initiation treatment. The rats in groups 2-4 received 1.25% Na-AsA diet for 36 weeks, 2.5% Na-AsA for 18 weeks and 5% Na-AsA for 8 weeks, respectively. Tumor number (papillomas and carcinomas) was greatest in group 3, and area in group 4 (P < 0.05). However, no enhancement was noted in group 2, although preneoplastic lesions were significantly increased. These results suggest that with the same total administration dose, high concentration of Na-AsA has the strongest promoting effects on tumor development in urinary bladder carcinogenesis.

Topics: Animals; Ascorbic Acid; Bromodeoxyuridine; Butylhydroxybutylnitrosamine; Carcinogens; Dose-Response Relationship, Drug; Male; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Carcinoma; Cell Death; Humans; Microscopy, Electron; Microscopy, Electron, Scanning; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Vitamin K 1

Topics: Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Carcinoma; Cell Death; Drug Synergism; Humans; Microscopy, Electron; Microscopy, Electron, Scanning; Time Factors; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Vitamin K 1

Sodium ascorbate, like other sodium salts such as saccharin, glutamate, and bicarbonate, produces urinary alterations when fed at high doses to rats, which results in mild superficial urothelial cytotoxicity and regeneration but not tumors in a standard 2-year bioassay. Sodium saccharin was shown to produce a low incidence of bladder tumors in rats if administered in a two-generation bioassay. In the present study, we evaluated sodium ascorbate in a two-generation bioassay that involved feeding to the male and female parental F344 rats for 4 weeks before mating, feeding the dams during gestation and lactation, and then feeding the weaned (at 28 days of age) male F1 generation rats for the remainder of their lifetime (up to 128 weeks of the experiment). Dietary levels of 1.0, 5.0, and 7.0% sodium ascorbate were tested. At 5.0 and 7.0% sodium ascorbate, there was an increase in urinary bladder urothelial papillary and nodular hyperplasia and the induction of a few papillomas and carcinomas. There was a dose-responsive increase in renal pelvic calcification and hyperplasia and inhibition of the aging nephropathy of rats even at the level of 1% sodium ascorbate. Because the short-term urothelial effects of sodium ascorbate in rats are inhibited by treatments producing urinary acidification to pH < 6.0, we coadministered high doses of long-term NH4Cl to groups of rats with 5.0 or 7.0% sodium ascorbate to evaluate the long-term effects. The combination of 7.0% sodium ascorbate plus 2.78% NH4Cl in the diet was toxic, and the group was terminated early during the course of the experiment. The group fed 5.0% sodium ascorbate plus 2.04% NH4Cl showed complete inhibition of the urothelial effects of sodium ascorbate and significant inhibition of its renal effects. We also demonstrated the presence of a calcium phosphate-containing urinary precipitate in rats fed sodium ascorbate at all doses, in a dose-responsive manner. The formation of the precipitate was inhibited by coadministration with NH4Cl. The proliferative effects of sodium ascorbate on the male rat urinary tract in this study are similar to those seen with sodium saccharin when administered in a two-generation bioassay. Mechanistic information suggests that this is a high-dose, rat-specific phenomenon.

Topics: Ammonium Chloride; Animals; Ascorbic Acid; Carcinogenicity Tests; Drug Interactions; Female; Hyperplasia; Male; Papilloma; Rats; Rats, Inbred F344; Urethral Neoplasms; Urinary Bladder Neoplasms; Urinary Tract

Scanning and transmission electron microscopy and fluorescence light microscopy were employed to characterize the cytotoxic effects of vitamin C (VitC), vitamin K3 (VitK3) or a VitC:VK3 combination on a human bladder carcinoma cell line (T24) following 1-h and 2-h vitamin treatment. T24 cells exposed to VitC alone exhibited membranous damage (blebs and endoplasmic extrusions, elongated microvilli). VitK3-treated cells displayed greater membrane damage and enucleation than those treated with VitC as well as cytoplasmic defects characteristic of cytoskeletal damage. VitC:VitK3-treated cells showed exaggerated membrane damage and an enucleation process in which the perikarya separate from the main cytoplasmic cell body by self-excision. Self-excisions continued for perikarya which contained an intact nucleus surrounded by damaged organelles. After further excisions of cytoplasm, the nuclei exhibited nucleolar segregation and chromatin decondensation followed by nuclear karryorhexis and karyolysis. This process of cell death induced by oxidative stress was named autoschizis because it showed both apoptotic and necrotic morphologic characteristics.

Topics: Adenocarcinoma; Antineoplastic Agents; Ascorbic Acid; Cell Death; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Microscopy, Electron, Scanning; Time Factors; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Vitamin K; Vitamin K 3

Rat strain differences in sensitivity to the promoting effect of sodium L-ascorbate (SA) on the development of urinary bladder tumors were investigated. In experiment 1, WS/Shi (WS), ODS/Shiod/od (ODS), and LEW/Crj (LEW) rats were initiated with 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) in their drinking water and subsequently given basal Oriental MF diet (M) with or without a 5% SA supplement. In LEW rats the SA treatment increased the induction of neoplastic lesions in the urinary bladder, whereas WS and ODS animals proved unresponsive to its promoting effects. In experiment 2, WS and F344 rats were maintained on two kinds of commercial basal diets, M and CLEA CA-1 (C), during administration of SA, since dietary factors can influence promoting effects. Feeding M during the promotion period in F344 rats yielded significantly more neoplastic lesions than feeding C, but in WS rats no such dietary influence was apparent. In experiment 3, strain differences in biosynthesis of alpha-2u-globulin (alpha 1a-g) were assessed because both alpha 2a-g in the urine and administration of sodium salts of organic acids such as SA have been reported to be involved in tumor promotion. Immunohistochemical analysis of renal tubules and Western blotting analysis of urine revealed the presence of alpha 2a-g in all three strains examined. These data suggest that differences in susceptibility to promotion are due to genetic factors rather than dietary factors and the ability to synthesize alpha 2a-g.

Topics: Animals; Ascorbic Acid; Body Weight; Butylhydroxybutylnitrosamine; Carcinogens; Male; Organ Size; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Species Specificity; Survival Rate; Urinary Bladder; Urinary Bladder Neoplasms; Water Supply

In the two-stage rat bladder carcinogenesis model using N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as an initiator and sodium L-ascorbate (SA) as a promoter, we found a notable strain difference between F344/DuCrj (F344) and WS/Shi (WS) rats in susceptibility to the promoting effect of SA. Twenty each of F344, WS and reciprocal F1 hybrid rats were given 0.05% BBN in their drinking water for 4 weeks and then a basal diet with (BBN-SA group) or without (BBN group) a 5% SA supplement for 32 weeks. In F344 and also in reciprocal F1 hybrids, the number of tumors per rat was significantly higher in the BBN-SA group than in the BBN group (P < 0.0001). In contrast, WS rats were not significantly affected by either treatment (P = 0.8). These findings indicate that F344 rats are highly susceptible to the promoter effect of SA, but WS rats are not. Linkage analysis of 108 WSx (WS x F344) F1 backcrosses revealed that this difference was related to a quantitative trait locus mapped on rat Chr. 17 (maximum LOD score, 3.86) named Bladder Tumor Susceptible-1 and possibly another locus on Chr. 5 (maximum LOD score, 2.39). This study has provided the first evidence that host genes influence the risk of bladder cancer development.

Topics: Animals; Ascorbic Acid; Butylhydroxybutylnitrosamine; Carcinogens; Cocarcinogenesis; Disease Susceptibility; Drug Synergism; Male; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

The study was designed to investigate whether sodium bicarbonate (NaHCO3) and/or L-ascorbic acid (AsA) promote urinary bladder carcinogenesis in male ODS/Shi-od/od (ODS) rats, which, unlike male F344 rats, are resistant to sodium L-ascorbate (Na-AsA)-promoting effects. Whereas F344 rats can synthesize AsA and alpha 2 mu-globulin (A2 mu-G), only A2 mu-G in produced in ODS rats. The two strains were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 2 wk and then were fed basal CA-1 diet supplemented with 3% NaHCO3 plus 5% AsA (NaHCO3 + AsA), 3% NaHCO3, 5% AsA, or no chemicals for 32 wk. ODS rats given BBN-NaHCO3 or BBN-(NaHCO3 + AsA) had only a few small carcinomas in the urinary bladder, like those receiving BBN alone or BBN-AsA. In contrast, F344 rats administered BBN-NaHCO3 or BBN-(NaHCO3 + AsA) had many more, larger, carcinoma than animals of the same strain given BBN alone or BBN-AsA. AsA alone did not have any effect in either strain. Administration of NaHCO3 alone or NaHCO3 + AsA was associated with significant elevation of urinary pH and Na+ concentration to the same extent in both strains but, again, AsA alone was without effect. NaHCO3 + AsA and AsA alone increased the urinary concentration of total ascorbic acid in both strains but the observed levels wer lower in ODS rats. The results indicate that ODS rats are resistant to the modifying effects of NaHCO3 and/or AsA on two-stage urinary bladder carcinogenesis, and thus that the susceptibility to the promotional activity of sodium-salt-type compounds may be regulated by factors other than A2 mu-G-synthesizing ability and urinary levels of pH, Na+ and total ascorbic acid.

Topics: alpha-Macroglobulins; Animals; Ascorbic Acid; Body Weight; Butylhydroxybutylnitrosamine; Carcinogens; Carcinoma; Cocarcinogenesis; Drug Combinations; Eating; Hydrogen-Ion Concentration; Male; Rats; Rats, Inbred F344; Rats, Mutant Strains; Sodium; Sodium Bicarbonate; Urinalysis; 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

The susceptibility to induction of epithelial cell proliferation by three urinary bladder cancer promoters was investigated in NCI-Black-Reiter (NBR) rats, which lack alpha 2u-globulin-synthesizing ability. Six-week-old male NBR and F344 rats were given 5% sodium saccharin (Na-Sac), 5% sodium L-ascorbate (Na-AsA), or 3% uracil in the basal diet for 8 weeks. Administration of uracil evoked a marked cell proliferation response and papillomatosis associated with calculus formation in NBR as well as F344 rats. This result indicates that NBR rats are also susceptible to direct mechanical stimulation. In contrast, both strains of rats given Na-Sac or Na-AsA demonstrated an alkalization of urinary pH and an increase in urinary Na ion concentration, but increase in cell proliferation in the urinary bladder transitional epithelium was only observed in F344 rats. Since previous studies revealed that elevation of urinary pH and Na ion concentration are essential factors for exertion of promotion activity by Na-Sac and Na-AsA, the results of the present investigation suggest that alpha 2u-globulin might also be a necessary component of the mechanisms of their promotion of male rat urinary bladder carcinogenesis.

Topics: Animals; Ascorbic Acid; Body Weight; Carcinogens; Cell Division; DNA; Epithelial Cells; Epithelium; Hydrogen-Ion Concentration; Male; Rats; Rats, Inbred F344; Saccharin; Uracil; Urinary Bladder; Urinary Bladder Neoplasms; Urine

The effects of dietary exposure to sodium L-ascorbate (Na-AsA), butylated hydroxyanisole (BHA), and diphenyl on the development of urinary bladder tumors in a mouse two-stage carcinogenesis model were examined. Male B6C3F1 mice received 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in the drinking water for 4 weeks and were then treated with 5% Na-AsA, 1% BHA, or 1% diphenyl for 32 weeks. None of these chemicals enhanced the development of either preneoplastic or neoplastic lesions in the urinary bladder. Furthermore, DNA synthesis levels of urinary bladder epithelium in mice treated with each substance alone for 8 weeks were not elevated significantly, although Na-AsA was associated with a significant increase in the urinary pH value and Na+ concentration. The results indicate that Na-AsA, BHA, and diphenyl do not exert an enhancing influence on mouse bladder carcinogenesis, in clear contrast to the case in the rat.

Topics: Animals; Ascorbic Acid; Biphenyl Compounds; Butylated Hydroxyanisole; Butylhydroxybutylnitrosamine; Carcinogens; Male; Mice; Rats; Urinary Bladder Neoplasms

The chemopreventive effects of indomethacin (IM) on the enhancement of bladder carcinogenesis and transitional-epithelial-cell proliferation by butylated hydroxyanisole (BHA) or sodium L-ascorbate (Na-AsA) were investigated. All animals were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks. They then received 2% BHA or 5% Na-AsA for 20 weeks, followed by 20 ppm IM in the drinking water or normal tap water without supplement for a further 20 weeks, or BHA or Na-AsA alone or concomitantly with IM for 40 weeks. No differences in bladder-tumor development were found when IM was administered after cessation of BHA or Na-AsA exposure. However, IM in combination with either BHA or Na-AsA significantly reduced both the incidence and the multiplicity of papillomas and carcinomas as compared with the values of groups receiving BHA or Na-AsA alone. This was associated with decreased DNA synthesis and prostaglandin (PG) E2 levels in the existing bladder tumors. Combined treatment with IM did not exert any effects on BHA forestomach carcinogenesis. A separate 8-week combination study demonstrated that IM diminished the increase in expression of proliferation nuclear-cell antigen (PCNA) induced by BHA or Na-AsA alone. The present results suggest that PGE2 may be involved in promotion of rat bladder carcinogenesis and that the PG synthesis blocker IM might exert preventive effects on the development of bladder cancer in humans.

Topics: Animals; Ascorbic Acid; Butylated Hydroxyanisole; Cell Division; Dinoprostone; Drug Screening Assays, Antitumor; Hyperplasia; Indomethacin; Male; Rats; Rats, Inbred F344; Stomach; Urinary Bladder; Urinary Bladder Neoplasms

Topics: Animals; Ascorbic Acid; Cell Division; Cyclic AMP; Dinoprostone; DNA Replication; Epithelial Cells; Epithelium; Hydrogen-Ion Concentration; Hyperplasia; Male; Microscopy, Electron, Scanning; Mitotic Index; Potassium; Rats; Rats, Inbred F344; Sodium; Urinary Bladder; Urinary Bladder Neoplasms; Urine

Five non-genotoxic chemicals previously demonstrated to be bladder cancer promoters in 36-week in vivo assays for carcinogenesis were reevaluated in a 20-week experiment in order to assess the summation influence of dietary uracil, a component of RNA, on the development of (pre)neoplastic lesions. The test chemicals, sodium bicarbonate, sodium L-ascorbate, sodium citrate, butylated hydroxytoluene and ethoxyquin, were mixed into the diet at concentrations of 3%, 5%, 5%, 1% and 0.8%, respectively, and administered to male F344 rats after initiation with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks. The test chemicals were given from the 4th to the 8th and the 11th to 20th experimental weeks, uracil being administered at the level of 3% in the diet during the intervening period. Rats in the control group received only BBN and uracil. All animals were killed at week 20 and the bladders were evaluated for the occurrence of putative preneoplastic papillary or nodular (PN) hyperplasia and tumors. Significant increase in the occurrence of PN hyperplasia was observed in all groups initiated with BBN and fed uracil and test chemicals. Quantitative values for papillomas were also significantly increased except in the ethoxyquin-treated group. The results confirm that uracil given in the middle of the post-initiation stage enhances the promoting activity of chemicals and suggest that the use of this chemical might be useful to reduce the duration of current bioassays for bladder chemical carcinogens.

Topics: Animals; Ascorbic Acid; Body Weight; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butylhydroxybutylnitrosamine; Carcinogens; Epithelium; Ethoxyquin; Male; Mucous Membrane; Organ Size; Papilloma; Precancerous Conditions; Rats; Rats, Inbred F344; Uracil; Urinary Bladder; Urinary Bladder Neoplasms

The proliferation response of rat renal pelvic epithelium, lined by transitional epithelium, to administration of various bladder cancer promoters was investigated. In addition, prostaglandin E2 (PGE2), lipid peroxide (LPO), malondialdehyde (MDA) and cyclic adenosine 3':5'-monophosphate (cyclic AMP) levels were assessed in urine of rats given the non-promoter L-ascorbic acid (AsA) and the promoters sodium L-ascorbate (AsA-Na) or sodium bicarbonate (NaHCO3) for 4 or 8 weeks. DNA synthesis in the renal pelvic epithelium, as assessed by 5-bromo-2'-deoxyuridine (BrdU) incorporation, was increased in the groups given AsA-Na, an extremely high dose of sodium chloride (NaCl), tert-butylhydroquinone (TBHQ) or ethoxyquin (EQ). Moreover, with the exception of AsA-Na, all treatments that induced an elevation of DNA synthesis also caused morphological epithelial alterations as observed by scanning electron microscopy (SEM). Treatment with butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) did not result in any proliferative response of the rat renal pelvis. No treatment-related changes in urinary PGE2 and cyclic AMP were noted, although AsA-Na and AsA but not NaHCO3 reduced levels of LPO and MDA in the urine. The results indicate that while the response of renal pelvic epithelium to certain bladder cancer promoters is similar to that of the bladder itself, none of the urinary cellular growth or free radical biochemical parameters is directly related to urothelial cell proliferation.

Topics: Animals; Ascorbic Acid; Bicarbonates; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Carcinogens; Cyclic AMP; Dinoprostone; DNA; Epithelium; Ethoxyquin; Hydroquinones; Kidney Pelvis; Male; Microscopy, Electron, Scanning; Rats; Rats, Inbred F344; Sodium; Sodium Bicarbonate; Urinary Bladder Neoplasms

A derivative of ascorbic acid, 2-O-octadecylascorbic acid (CV-3611), is a strong scavenger of active oxygen species. We examined the effect of CV-3611 on a short-term test of bladder carcinogenesis, using concanavalin A (Con A)-dependent agglutination of isolated bladder epithelial cells. Rats were given 0.01% N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN) for 1 week, and then 5% sodium saccharin or 2% DL-tryptophan or 0.01% BHBN alone or with 0.002, 0.006 or 0.02% CV-3611 for 3 weeks. Treatment with CV-3611 reduced the effects of the bladder tumor promoters sodium saccharin and DL-tryptophan by 48-86 and 65-87%, respectively. CV-3611 also reduced the number of aggregates of bladder epithelial cells from rats treated with BHBN for 4 weeks. These results suggest that CV-3611 has a suppressive effect on rat bladder carcinogenesis.

Topics: Agglutination Tests; Animals; Ascorbic Acid; Butylhydroxybutylnitrosamine; Cell Aggregation; Concanavalin A; Free Radical Scavengers; Male; Rats; Saccharin; Tryptophan; Urinary Bladder Neoplasms

The promoting effects of sodium L-ascorbate (Na-AsA) on two-stage urinary bladder carcinogenesis were investigated in male ODS/Shi-od/od rats. This strain genetically lacks L-ascorbic acid-synthesizing ability, which is controlled by a single autosomal recessive od gene; heterozygous ODS/Shi(-)+/od, normal ODS/Shi(-)+/+ or F344 rats are able to synthesize L-ascorbic acid. In experiment 1, ODS/Shi-od/od and F344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 2 weeks and then basal CA-1 diet with or without 5% Na-AsA for 32 weeks. F344 rats were sensitive to the promoting effects of Na-AsA, whereas ODS/Shi-od/od rats were resistant. Administration of Na-AsA increased the urinary pH and the urinary concentrations of Na+ and total ascorbic acid in all strains. In experiment 2, DNA synthesis in the urinary bladder epithelium of F344 rats fed MF diet or CA-1 diet was increased by exposure to 5% Na-AsA for 8 weeks, but not in ODS/Shi-od/od rats fed CA-1 diet. In experiment 3, ODS/Shi-od/od, ODS/Shi(-)+/od and ODS/Shi(-)+/+ rats were given 0.05% BBN for 4 weeks and then CA-1 diet with or without 5% Na-AsA for 32 weeks. ODS/Shi-od/od, ODS/Shi(-)+/od and ODS/Shi(-)+/+ rats were resistant to the promoting effects of Na-AsA in two-stage urinary bladder carcinogenesis. The urinary pH and the urinary concentrations of Na+ and total ascorbic acid in ODS/Shi-od/od, ODS/Shi(-)+/od and ODS/Shi(-)+/+ rats were increased by the administration of Na-AsA. These results indicate that ODS/Shi-od/od rats are resistant to the promoting effects of Na-AsA in two-stage urinary bladder carcinogenesis, and that the susceptibilities of ODS/Shi-od/od rats are regulated by genes different from the gene at the od locus.

Topics: Animals; Ascorbic Acid; Body Weight; Butylhydroxybutylnitrosamine; Epithelium; Hydrogen-Ion Concentration; Male; Rats; Rats, Inbred F344; Rats, Inbred Strains; Sodium; Urinary Bladder Neoplasms

Sodium saccharin and sodium ascorbate are known to promote urinary bladder carcinogenesis in rats following initiation with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or N-butyl-N-(4-hydroxybutyl) nitrosamine. Sodium salts of other organic acids have also been shown to be bladder tumor promoters. In addition, these substances increase urothelial proliferation in short term assays in rats when fed at high doses. When they have been tested, the acid forms of these salts are without either promoting or cell proliferative inducing activity. The following experiment was designed to compare the tumor promoting activity of various forms of saccharin and to evaluate the role in promotion of urinary sodium, calcium, and pH as well as other factors. Twenty groups of 40 male F344 rats, 5 weeks of age, were fed either FANFT or control diet during a 6-week initiation phase followed by feeding of a test compound for 72 weeks in the second phase. The chemicals were administered to the first 18 groups in Agway Prolab 3200 diet and the last 2 groups were fed NIH-07 diet. The treatments were as follows: (a) FANFT----5% sodium saccharin (NaS); (b) FANFT----3% NaS; (c) FANFT----5.2% calcium saccharin (CaS); (d) FANFT----3.12% CaS; (e) FANFT----4.21% acid saccharin (S); (f) FANFT----2.53% S; (g) FANFT----5% sodium ascorbate; (h) FANFT----4.44% ascorbic acid; (i) FANFT----5% NaS plus 1.15% CaCO3; (j) FANFT----5.2% CaS plus 1.34% NaCl; (k) FANFT----5% NaS plus 1.23% NH4Cl; (l) FANFT----1.15% CaCO3; (m) FANFT----1.34% NaCl; (n) FANFT----control; (o) control----5% NaS; (p) control----5.2% CaS; (q) control----4.21% S; (r) Control----control; (s) FANFT----5% NaS (NIH-07 diet); (t) FANFT----control (NIH-07 diet). NaS, CaS and S without prior FANFT administration were without tumorigenic activity. NaS was found to have tumor promoting activity, showing a positive response at the 5 and 3% dose levels, with significantly greater activity at the higher dose. CaS had slight tumor promoting activity but without a dose response, and S showed no tumor promoting activity. In addition, NaCl showed weak tumor promoting activity, but CaCO3 was without activity. NH4Cl completely inhibited the tumor promoting activity of NaS when concurrently administered with it. NaCl administered with CaS or CaCO3 administered with NaS showed activity similar to that of NaS. Sodium ascorbate was also shown to have tumor promoting activity, with slightly less activity than NaS. Ascorbic acid showed no

Topics: Animals; Ascorbic Acid; Body Weight; Butylhydroxybutylnitrosamine; Calcium Carbonate; Diet; Drinking; Drug Synergism; FANFT; Hydrogen-Ion Concentration; Kidney; Male; Rats; Rats, Inbred F344; Saccharin; Urinary Bladder; Urinary Bladder Neoplasms; Urine

This dietary study was based on 195 male and 66 female cases of lower urinary tract cancer, identified in Hawaii between 1977 and 1986. Each case was matched for sex, age, and ethnic group (Caucasian or Japanese) to 2 population-based controls. There was a decrease in risk with increasing levels of consumption of vitamin C in women (p = 0.03) and dark green vegetables in men (p = 0.02). When examined by quartile, the odds ratios for the highest quartile of intake compared to the lowest quartile were 0.4 for women and 0.6 for men, respectively. Although dark green vegetables are a source of carotenoids, the intake of total carotenoids, retinol and total vitamin A was weakly and inconsistently related to risk in both sexes. Among women only, there was also an inverse association with the consumption of regular ground coffee (p = 0.02) but not with other types of coffee. Finally, there were no statistically significant or consistent differences between cases and controls in the intake of artificial sweeteners and tea.

Topics: Adult; Aged; Aged, 80 and over; Ascorbic Acid; Case-Control Studies; Coffee; Diet; Diet Surveys; Female; Hawaii; Humans; Japan; Male; Middle Aged; Sweetening Agents; Tea; Urinary Bladder Neoplasms; Vitamin A; White People

The dose dependence of K2CO3 promotion of two-stage urinary bladder carcinogenesis and the amplifying effects of additional L-ascorbic acid (AsA) administration were investigated. Male F344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in their drinking water for 4 weeks and then fed basal diet containing K2CO3 at levels of 0, 1, 1.5, 2.2, and 3% with or without 5% AsA or 3% NaHCO3 supplementation from weeks 5 to 8 (4 weeks) and weeks 12 to 20 (9 weeks). During weeks 9 to 11 (3 weeks), the rats were fed 3% uracil in their diet. For controls, rats without N-butyl-N-(4-hydroxybutyl)nitrosamine treatment were given either 3% K2CO3, 5% AsA, or both plus the uracil treatment. The total observation period was 20 weeks. K2CO3 dose dependently increased the numbers of the putative preneoplastic lesion, papillary or nodular hyperplasia, and papillomas in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine. AsA (5%), while itself exerting no promoting effect, amplified the enhancing influence of K2CO3 on the induction of papillary or nodular hyperplasia and papillomas. The dose-dependent elevation of urinary pH and K+ concentration was associated with K2CO3 treatment with or without AsA. Thus, increased urinary pH and K+ concentration appear to play important roles in K2CO3 promotion, and AsA amplifies this promotion.

Topics: Animals; Ascorbic Acid; Body Weight; Carbonates; Carcinoma; Drug Synergism; Hyperplasia; Male; Organ Size; Papilloma; Potassium; Rats; Rats, Inbred F344; Reference Values; 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

Potential second-stage modifying effects of 8 antioxidants on lung tumorigenesis initiated by N-bis(2-hydroxypropyl)nitrosamine (DHPN) were examined in male F344 rats. After an initial 2-week treatment with DHPN (0.1% in drinking water), rats were administered one of the antioxidants supplemented in the diet for 30 weeks. Although the incidences of lung adenomas were not affected, those of carcinomas were lowered by 2% butylated hydroxyanisole (BHA, 2 rats/20 rats), 1% butylated hydroxytoluene (BHT, 1/20), 0.8% ethoxyquin (EQ, 3/20) and 1% a-tocopherol (a-TP, 2/20) treatments as compared to the control level (9/20), while 5% sodium L-ascorbate (SA), 0.8% catechol (CC), 0.8% resorcinol (RN), and 0.8% hydroquinone (HQ) did not exert any significant effect on incidence. Quantitative analysis of adenomas and carcinomas (numbers and areas of lesions per unit area of lung section) revealed obvious inhibitory effects of SA, CC, and RN as well as BHA, BHT, EQ, and a-TP. Among the antioxidants, BHT exerted the strongest inhibitory activity. In contrast, DHPN-induced thyroid tumorigenesis was significantly enhanced by BHT (14/20) and EQ (20/20) treatments (control = 5/20). Thus the antioxidants showed opposite effects on lung and thyroid carcinogenesis in the rat.

Topics: Adenoma; Animals; Antioxidants; Ascorbic Acid; Body Weight; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Carcinoma; Catechols; Ethoxyquin; Hydroquinones; Kidney Neoplasms; Lung Neoplasms; Male; Nitrosamines; Organ Size; Rats; Rats, Inbred F344; Resorcinols; Thyroid Neoplasms; Urinary Bladder Neoplasms; Vitamin E

With a daily intake of 250 ppm total ascorbic acid, ODS and F344 male rats were given 0.0125%, 0.025% or 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water for 12 weeks, and additional groups received 0.05% BBN for 2, 4 or 8 weeks. The experiment was terminated after a total of 36 weeks. A greater response to urinary bladder carcinogenesis was observed in both strains with increasing dose of BBN or longer treatment period. However, the magnitude of urinary bladder carcinogenesis in ODS rats given the higher BBN concentrations and/or long periods of BBN treatment was less than in comparably treated F344 rats, but not with lower concentrations of BBN and/or shorter periods of BBN treatment.

Topics: Animals; Ascorbic Acid; Butylhydroxybutylnitrosamine; Carcinogenicity Tests; Disease Susceptibility; Dose-Response Relationship, Drug; Male; Nitrosamines; Occult Blood; Rats; Rats, Inbred F344; Rats, Mutant Strains; Urinary Bladder Neoplasms

Since both sodium L-ascorbate (Na-AsA) and sodium saccharin (Na-Sac) promote two-stage bladder carcinogenesis in rats, synergism of the two chemicals was investigated with special reference to the role of urinary pH and Na+ concentration. Male F344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 4 wk and then treated with basal diet containing 5% Na-Sac, 5% Na-AsA, 5% Na-Sac plus 5% Na-AsA, 5% L-ascorbic acid (AsA), 5% Na-Sac plus 5% AsA, or no added chemical for 32 wk. Treatment with Na-Sac or Na-AsA alone significantly increased the induction of neoplastic and preneoplastic lesions of the bladder. Na-Sac plus Na-AsA also induced these bladder lesions significantly when compared with the controls, and the number of lesions was greater than the sum of the lesions in the groups treated with Na-Sac alone or Na-AsA alone. In contrast, the induction of carcinomas and papillomas in rats treated with Na-Sac plus AsA was not significantly different from the controls. In addition Na-Sac plus Na-AsA produced an elevation of urinary pH and Na+ concentrations, although the increases were not different from those in rats fed Na-Sac or Na-AsA alone. Na-Sac plus AsA, however, did not cause elevation of urinary pH, although it increased urinary Na+ concentration. Thus, the bladder carcinogenesis promotion by Na-Sac was synergized by Na-AsA and inhibited by AsA. This modulation was associated with changes of urinary pH and Na+ concentration.

Topics: Animals; Ascorbic Acid; Drug Synergism; Male; Precancerous Conditions; Rats; Rats, Inbred F344; Saccharin; Sodium; Urinary Bladder Neoplasms

Rats were treated for 1 week each with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), 0.2% N-bis(2-hydroxypropyl)-nitrosamine (DHPN) and 0.2% N-ethyl-N-hydroxyethylnitrosamine (EHEN) in the drinking water, and then administered diet containing 5% sodium L-ascorbate (Na-AsA), 1% butylated hydroxytoluene (BHT) or 0.05% phenobarbital (PB), or weekly intraperitoneal injections of 2 mg of pepleomycin per kg body weight until week 36. Histopathological examination revealed that all exerted significant modulation effects on tumor development in the various target organs. Na-AsA was found to inhibit liver but promote renal pelvis and bladder carcinogenesis. BHT similarly decreased liver and enhanced bladder lesion development. PB, in contrast promoted hepatocarcinogenesis. However both PB and BHT were associated with increased incidences of adenomas and adenocarcinomas of the thyroid. Thus the wide-spectrum initiation model allowed confirmation of site-specific modification potential and in addition demonstrated potentiation of kidney and bladder carcinogenesis promotion by pepleomycin.

Topics: Animals; Ascorbic Acid; Bleomycin; Body Weight; Butylated Hydroxytoluene; Cocarcinogenesis; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms, Experimental; Peplomycin; Phenobarbital; Rats; Rats, Inbred F344; Thyroid Neoplasms; Urinary Bladder Neoplasms

An investigation of sequential changes in urine composition, levels of DNA synthesis and morphology of bladder epithelium following administration of the tumor promoters sodium ascorbate (AsA-Na) or butylated hydroxyanisole (BHA) and the non-promoter ascorbic acid (AsA) for 36 weeks was performed. In addition, prostaglandin E2 (PGE2), cAMP and AsA content were assessed in bladder tissue after 16 weeks. While AsA-Na caused increase in pH, sodium content and volume, and a decrease in osmolality of the urine throughout the study, these changes were not observed with AsA administration which resulted in a decrease in urinary pH. BHA treatment was not associated with any urinary changes. AsA-Na brought about a significant elevation of DNA synthesis in the bladder epithelium from weeks 2 to 16 and was associated with simple hyperplasia at week 8, which, however, decreased by week 16 and was no longer evident at weeks 24 and 36 when DNA synthesis returned to normal. Under the scanning electron microscope (SEM), morphologic alterations of the urothelial surface in rats given AsA-Na were observed at weeks 8 and 16, but the appearance at week 36 was almost normal. AsA did not cause any changes in these parameters at any time point. BHA induced a significant elevation of DNA synthesis throughout the study, produced simple hyperplasia at week 36 and alterations of the epithelial surface from weeks 4 to 36. Significant increases of PGE2 and AsA in bladder tissue were noted for the AsA-Na or BHA, but not AsA groups. Moreover, cAMP levels in bladder tissue of rats exposed to AsA-Na or BHA were slightly higher than in the controls. The results suggest that changes in PGE2, cAMP and AsA may be involved in promotion of rat bladder carcinogenesis.

Topics: Animals; Ascorbic Acid; Body Weight; Butylated Hydroxyanisole; Carcinogens; Dinoprostone; DNA Replication; Epithelial Cells; Epithelium; Hyperplasia; Male; Rats; Rats, Inbred F344; Reference Values; Sodium; Urinary Bladder; Urinary Bladder Neoplasms; Urine

The dose dependence of NaHCO3 promotion of urinary bladder carcinogenesis and the effects of additional L-ascorbic acid (AsA) administration were investigated subsequent to initiation. Male F344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in their drinking water for 4 weeks and then, starting 3 days after cessation of carcinogen treatment, received basal diet containing NaHCO3 at levels of 0, 0.375, 0.75, 1.5, and 3.0% with or without a 5% AsA supplement for 32 weeks. NaHCO3 dose-dependently increased the incidence and numbers of urinary bladder carcinomas in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine. 5% AsA, while itself exerting no promoting effect, amplified the enhancing influence of NaHCO3 on induction of urinary bladder carcinomas. The same dose-dependent elevation of urinary pH and Na+ concentration was associated with NaHCO3 treatment with or without AsA. NaHCO3 significantly increased DNA synthesis in the urinary bladder epithelium and the additional treatment with AsA was associated with a significant further elevation. Thus, increased urinary pH and Na+ concentrations appear to play important roles in NaHCO3 promotion and AsA amplified this promotion. NaHCO3 treatment, with or without AsA, induced cellular proliferation, although it is unclear whether this is an essential factor.

Topics: Animals; Ascorbic Acid; Bicarbonates; Cocarcinogenesis; DNA; Dose-Response Relationship, Drug; Hydrogen-Ion Concentration; Male; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

Assessment of L-ascorbic acid requirement for prolonged survival in ODS (genotype: od/od) rats and their susceptibility to urinary bladder carcinogenesis by N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) were examined. In ODS rats without L-ascorbic acid synthesizing ability, the 50 ppm dietary total ascorbic acid (TAA) was insufficient to survive for 4 weeks, the 250 ppm dietary TAA was sufficient to survive for 36 weeks. In examination of BBN treatment, ODS rats--although showing a lower availability of TAA than the heterozygotes (+/od) and normal (+/+) rats with L-ascorbic acid synthesizing ability--were equally susceptible to bladder carcinogenesis.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Butylhydroxybutylnitrosamine; Male; Rats; Urinary Bladder Neoplasms

L-Ascorbic acid, citric acid or their sodium salts (at levels equivalent to 5% sodium L-ascorbate) were fed in the diet simultaneously with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) or N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) (0.025% BBN or 0.021% EHBN) in the drinking water to male F344 rats for 20 weeks to determine whether urinary pH changes affect the carcinogenicity of BBN or EHBN. In the urine, pH was decreased in rats fed the acidic chemicals and increased in rats fed their corresponding sodium salts. Histopathologically, the incidences and numbers of preneoplastic and neoplastic lesions in groups treated with each test chemical were not different from those in control groups except for sodium citrate-treated groups in which induction of carcinomas was higher, resulting from increased intake of either carcinogen and also from increased urinary excretion of main carcinogenic metabolites. These results show that the test chemicals do not affect the carcinogenicity of BBN or EHBN on the rat urinary bladder when simultaneously administered despite significant differences in urinary pH.

Topics: Animals; Ascorbic Acid; Body Weight; Butylhydroxybutylnitrosamine; Citrates; Citric Acid; Diethylnitrosamine; Drug Interactions; Hydrogen-Ion Concentration; Male; Nitrosamines; Organ Size; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

The potential carcinogenic effect of nitrosamine precursors, DBA (dibutylamine) and nitrite, was clearly demonstrated pathologically in the liver and bladder of male Swiss albino mice. Benign tumours were induced in the bladder with an incidence of 40%, and hepatomas were detected in the liver in 27% of the cases. The protective effect of soybean and ascorbic acid, added separately to the diet or to the drinking water respectively, was demonstrated by a marked reduction in dysplastic features and absence of tumour in both the liver and the urinary bladder.

Topics: Animals; Ascorbic Acid; Butylamines; Glycine max; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred Strains; Nitrites; Sodium Nitrite; Urinary Bladder; Urinary Bladder Neoplasms

The influences of strain and diet on the promoting effects of sodium L-ascorbate (SA) on two-stage urinary bladder carcinogenesis was investigated in male F344 and Lewis rats. Two kinds of commercial basal diets, Oriental MF and Clea CA-1, were used. Rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in their drinking water for 4 weeks and then basal diet with 5% SA or without SA for 32 weeks. Treatment with SA increased the induction of neoplastic lesions of the urinary bladder in rats initiated by 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine. The promoting effect of SA for urinary bladder carcinogenesis was: F344 strain-Oriental MF diet greater than Lewis strain-Clea CA-1 diet greater than F344 strain-Clea CA-1 diet = Lewis stain-Oriental MF diet. In both strains or with both diets, SA-treatment increased the urinary pH and the concentrations of sodium ion and total ascorbic acid. These results demonstrate that strain and diet strongly influence susceptibility to the SA-promoting effects in rat urinary bladder carcinogenesis.

Topics: Animals; Ascorbic Acid; Butylhydroxybutylnitrosamine; Carcinoma; Cocarcinogenesis; Diet; Hydrogen-Ion Concentration; Rats; Rats, Inbred F344; Rats, Inbred Lew; Sodium; Urinary Bladder Neoplasms

The effects of treatment with calcium L-ascorbate, L-ascorbic dipalmitate, L-ascorbic stearate and erythorbic acid on two-stage urinary bladder carcinogenesis in F344 rats after initiation with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were examined. Carcinogen was administered at a dose of 0.05% in drinking water for 4 weeks and thereafter the test chemicals were given as a 5% supplement in the diet for the following 32 weeks. No increase in the induction of preneoplastic lesions, papillomas or carcinomas was apparent and it was concluded that none of the test chemicals possess promoting activity for urinary bladder carcinogenesis.

Topics: Animals; Ascorbic Acid; Cocarcinogenesis; Male; Palmitates; Palmitic Acids; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

Dietary administration of 5% L-ascorbic acid plus 3% K2CO3 to male F344 rats clearly enhanced the development of preneoplastic and neoplastic lesions of the urinary bladder initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine. Promotion of carcinogenesis by L-ascorbic acid and K2CO3 was associated with changes in urinary parameters: elevation of pH, increased K+ concentration, and increase in total ascorbic acid.

Topics: Animals; Ascorbic Acid; Body Weight; Butylhydroxybutylnitrosamine; Hydrogen-Ion Concentration; Male; Organ Size; Potassium; Rats; Rats, Inbred F344; Sodium; Urinary Bladder Neoplasms

Since the sodium salt of ascorbic acid (AA) promoted two-stage urinary bladder carcinogenesis in rats, whereas AA itself did not, the roles of the urinary sodium ion concentration and pH on urinary bladder carcinogenesis were investigated. Male F344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in their drinking water for 4 weeks and then treated with basal diet containing 5% AA plus 3% sodium bicarbonate (NaHCO3), 5% AA, 3% NaHCO3 or 5% sodium L-ascorbate (SA), 5% SA plus 1% ammonium chloride (NH4Cl) or 1% NH4Cl, or no added chemical for 32 weeks. NaHCO3 significantly increased the induction of neoplastic and preneoplastic lesions of the urinary bladder. Like SA, AA plus NaHCO3 induced high incidences of neoplastic and preneoplastic lesions of the urinary bladder, whereas AA alone did not. NH4Cl reduced the promoting activity of SA in urinary bladder carcinogenesis. These results suggest important roles for urinary sodium ion concentration and pH in modulating urinary bladder carcinogenesis. Moreover, AA was found to act as a copromoter under conditions of increased urinary pH and sodium ion concentration.

Topics: Animals; Ascorbic Acid; Bicarbonates; Body Weight; Butylhydroxybutylnitrosamine; Dehydroascorbic Acid; Hydrogen-Ion Concentration; Male; Rats; Rats, Inbred F344; Sodium; Urinary Bladder; Urinary Bladder Neoplasms

This report presents preliminary findings from 3 case-control studies in Hawaii in which we are examining the relationship of dietary vitamin A and ascorbic acid intake to the risk for cancers of the lung, bladder, and prostate. All 3 studies involved home interviews of cancer patients and neighborhood controls and use of quantitative dietary history method. In the lung cancer study, we found an inverse dose-response effect for total vitamin A intake in males only, with an odds ratio of 1.8 (P less than .05) for the lowest intake quartile relative to the highest; we found no association for ascorbic acid. In the bladder cancer study, we found lower (but not statistically significant) mean intakes of both vitamins in patients compared with controls, with the effect stronger for ascorbic acid. In the prostate cancer study, no effect was detected for total vitamin A or ascorbic acid in men less than 70 years old, but a direct association of vitamin A only with a dose-response gradient was found for men 70 years or older (odds ratio = 1.87; P less than .05, for the highest relative to the lowest intake quartile). Our findings at present indicate that vitamin A has a protective effect against lung and bladder cancers but not against prostate cancer and that ascorbic acid has a protective effect against bladder cancer as well. In our later analyses, we will examine the possibility that the effects of vitamin A vary with histologic type and that this may account for the lack of an association with lung cancer in women.

Topics: Ascorbic Acid; Diet; Ethnicity; Female; Hawaii; Humans; Japan; Lung Neoplasms; Male; Prostatic Neoplasms; Registries; Risk; Urinary Bladder Neoplasms; Vitamin A; White People

Using ascorbic acid as a model, this paper proposes that the concept of the RDA should be broadened to take into account the effects of ubiquitous pollutants on human health, a factor not specifically incorporated in RDA derivations. It is now widely accepted that ascorbic acid nutritional status markedly affects the toxicity and/or carcinogenicity of greater than 50 pollutants, many of which are ubiquitous in the air, water, and food environments. At the present time, the data do not warrant changing the ascorbic acid RDA in light of the knowledge of pollutant interactions.

Topics: Air Pollutants, Occupational; Animals; Ascorbic Acid; Carcinogens, Environmental; Diet; Environmental Health; Environmental Pollutants; Female; Guinea Pigs; Humans; Male; Mice; Models, Theoretical; Nitrosamines; Nutritional Physiological Phenomena; Nutritional Requirements; Occupational Diseases; Occupational Health Services; Rats; Smoking; Sodium Nitrite; Urinary Bladder Neoplasms

The modifying effects of 3 antioxidants, sodium L-ascorbate (SA), ascorbic acid (AA) and sodium erythorbate (SE) on two-stage gastric carcinogenesis in F344 rats initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated. Administration of 5% SE in the diet significantly decreased the incidence of dysplasia of the pylorus and, more marginally the incidence of papilloma of the forestomach, whereas administration of 5% and 1% SA and 5% AA in the diet was not associated with effect. These results suggest that SE exerts a weak inhibitory effect on gastric carcinogenesis.

Topics: Animals; Ascorbic Acid; Body Weight; Cocarcinogenesis; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred F344; Stomach Neoplasms; Urinary Bladder Neoplasms

The influence of external abdominal irradiation and cytostatic therapy on the vitamin status was studied in patients with cancer of the uterus, bladder or prostate and in patients with malignant lymphoma. It was found that the vitamin status of these patients at the beginning of therapy in general was adequate, though vitamin A and vitamin D levels were reduced. During radiotherapy decreases of vitamin E, vitamin C, vitamin B12 and folic acid levels were observed. Chemotherapy caused a decrease of the folic acid levels after a few months. No clinical symptoms of vitamin deficiency were observed.

Topics: Ascorbic Acid; Calcifediol; Female; Humans; Lymphoma; Male; Neoplasms; Prostatic Neoplasms; Urinary Bladder Neoplasms; Uterine Neoplasms; Vitamin A; Vitamin B 12; Vitamin E; Vitamins

The promoting effects of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and sodium L-ascorbate on two-stage carcinogenesis initiated with methylnitrosourea (MNU) in F344 male rats were investigated. Animals were given injections of MNU (20 mg/kg ip) twice a week for 4 weeks, and then basal diet containing 2% BHA, 1% BHT or 5% sodium L-ascorbate for the next 32 weeks. Administration of BHA, BHT or sodium L-ascorbate in the diet significantly increased the incidences per group and numbers per rat of papilloma and papillary or nodular hyperplasia of the urinary bladder, and BHA and BHT also increased the number of cancers per rat. Furthermore BHA significantly increased the incidences of cancer and papilloma in the forestomach of rats initiated with MNU, whereas treatment with BHA alone was associated with papilloma but no carcinoma development in the rat forestomach. The incidence of adenoma, but not adenocarcinoma, of the thyroid was significantly increased by treatment with MNU plus BHT. These results show that BHA, BHT and sodium L-ascorbate have promoting activities on urinary bladder carcinogenesis in rats initiated with MNU, and that BHA also has a promoting effect on forestomach carcinogenesis after initiation with MNU.

Topics: Animals; Anisoles; Ascorbic Acid; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Hyperplasia; Male; Methylnitrosourea; Papilloma; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms; Urinary Bladder Neoplasms

Summation and synergism in the effects of three tumor promoters on urinary bladder carcinogenesis initiated by a 4-week treatment with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male F344 rats were examined. In experiment 1, the sequential administration of sodium saccharin (SS, 5.0%), DL-tryptophan (Tr, 2.0%) and sodium L-ascorbate (SA, 5.0%) in the diet, each for 10 weeks, significantly increased the incidence and the number of bladder tumors over that observed after SS alone or SS followed by Tr. In experiment 2, the simultaneous dietary administration of 2.5% SA, 1.0% butylated hydroxyanisole and 0.01% allopurinol for 32 weeks significantly increased the yield of bladder tumors. Paired combinations of promoters or each of the promoters administered alone were associated with a less pronounced promotive effect than when all three were combined. Thus, it is evident from the results of the present investigation that whatever the mechanisms underlying promotion by the different agents, they are capable of working in an additive fashion, under conditions of summation (consecutive administration) or synergism (simultaneous administration).

Topics: Allopurinol; Animals; Ascorbic Acid; Butylated Hydroxyanisole; Butylhydroxybutylnitrosamine; Drug Synergism; Hyperplasia; Male; Nitrosamines; Rats; Rats, Inbred F344; Saccharin; Tryptophan; Urinary Bladder; Urinary Bladder Neoplasms

The promoting effects of various chemicals on urinary bladder carcinogenesis in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were studied. Male Fischer 344 rats were given BBN at 0.01% or 0.05% in their drinking-water for four weeks. One of the following chemicals was then administered in the diet for 32 or 34 weeks: acetazolamide, allopurinol, phenobarbital, phenacetin, ortho-phenylphenol, sodium ortho-phenylphenate, diphenyl, sodium L-ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, sodium saccharin, aspartame, sodium cyclamate, stevioside, DL-tryptophan, quercetin, caffeine, nicotine and hippuric acid. Phenacetin, sodium ortho-phenylphenate, sodium L-ascorbate and butylated hydroxyanisole were significant promoters of urinary bladder neoplasia in rats initiated with BBN. Sodium saccharin, diphenyl, butylated hydroxytoluene, allopurinol, and DL-tryptophan caused moderate or slight promotion of neoplastic changes in the experimental animals. No change in tumour yield was observed after administration of the other chemicals.

Topics: Animals; Ascorbic Acid; Biphenyl Compounds; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butylhydroxybutylnitrosamine; Carcinogens; Food Additives; Hyperplasia; Male; Rats; Rats, Inbred F344; Urinary Bladder; Urinary Bladder Neoplasms

The promoting effects of ascorbic acid, sodium erythorbate and ethoxyquin on two-stage urinary bladder carcinogenesis in F344 rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) at a dose of 0.05% in the drinking water were examined. Administration of 5% sodium erythorbate in the diet significantly increased the incidences of preneoplastic lesions, papilloma and cancer of the urinary bladder, whereas administration of 5% ascorbic acid in the diet did not. Administration of 0.8% ethoxyquin also increased the incidence of neoplastic lesions. Administrations of 5% sodium L-ascorbate and 5% sodium erythorbate caused increases in the pH, the sodium content and crystals of MgNH4PO4 in the urine. These results show that sodium erythorbate and ethoxyquin promote urinary bladder carcinogenesis, while ascorbic acid does not.

Topics: Animals; Ascorbic Acid; Body Weight; Butylhydroxybutylnitrosamine; Carcinogens; Cocarcinogenesis; Electrolytes; Ethoxyquin; Hydrogen-Ion Concentration; Hyperplasia; Male; Nitrosamines; Organ Size; Osmolar Concentration; Papilloma; Quinolines; Rats; Urinary Bladder; Urinary Bladder Neoplasms

The effects of the antioxidants, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethoxyquin (EQ), and sodium L-ascorbate (SA) on two stage chemical carcinogenesis were investigated in male F344 rats initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), N-ethyl-N-hydroxyethylnitrosamine (EHEN), N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) or N-methylnitrosourea (MNU). BHA was given in diet at a dose level of 0.5 or 2.0%, BHT at 1.0%, SA at 5.0% and EQ at 0.8% for 29-51 weeks. Complete autopsy was performed at sacrifice and organs were examined histologically for the presence of preneoplastic and neoplastic lesions. All of the antioxidants tested exerted a positive influence on the development of BBN- or MNU-initiated bladder carcinogenesis. Similarly, these chemicals tended to enhance the appearance of forestomach tumors although the data gained after BHT administration were not significant. In clear contrast, no effect was observed on glandular stomach carcinogenesis and, with the exception of SA, the antioxidants all showed inhibition of the development of preneoplastic and neoplastic lesions in the liver. EQ increased the occurrence of renal adenoma in EHEN-treated rats. Clear differences were observed with respect to the modification of thyroid carcinogenesis after MNU initiation, BHT demonstrating strong promotion activity whereas BHA and SA had no effect. Thus organ specificity, with regard to both direction of modification and to the effects of individual antioxidants was apparent, this intriguing finding offering hope for the development of future experimental approaches for elucidation of the mechanisms underlying chemical carcinogenesis.

Topics: Animals; Antioxidants; Ascorbic Acid; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Ethoxyquin; Kidney Neoplasms; Liver Neoplasms; Methylnitrosourea; Neoplasms, Experimental; Rats; Rats, Inbred F344; Stomach Neoplasms; Urinary Bladder Neoplasms

We studied the capacity of various chemicals to promote urinary bladder cancer in male F344 rats after initiation by N-nitroso-n-butyl-(4-hydroxybutyl)amine (BBN). The rats were given initially 0.01% BBN in the drinking-water for 4 wk and then the test compound in the diet for 34 wk. Effects were judged by measuring the formation of preneoplastic lesions papillary or nodular hyperplasia (PN hyperplasia) of the urinary bladder. Administration of 5%, but not 0.5% (w/w) sodium saccharin in the diet significantly increased the incidence and extent of PN hyperplasia. This finding could be related to the induction of cancers in the rat urinary bladder by high levels of saccharin. Sodium ascorbate (5%). DL-tryptophan (5%) and allopurinol (0.02%) also significantly increased the extent of PN hyperplasia in the affected animals, but other test chemicals, such as acetazolamide (0.35%) and quercetin (5%) did not. The results with sodium saccharin and DL-tryptophan were consistent with previous findings and suggest that sodium ascorbate and allopurinol have promoting activities in urinary bladder carcinogenesis in rats. No correlation was found between the extent of crystalluria and promotion of preneoplastic lesions.

Topics: Acetazolamide; Allopurinol; Animals; Ascorbic Acid; Body Weight; Butylhydroxybutylnitrosamine; Carcinogens; Hyperplasia; Male; Neoplasms, Experimental; Nitrosamines; Quercetin; Rats; Rats, Inbred F344; Saccharin; Tryptophan; Urinary Bladder; Urinary Bladder Neoplasms

The promoting effect of sodium L-ascorbate on two-stage urinary bladder carcinogenesis in F344 rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine at levels of 0.01 and 0.05% in drinking water was studied. Administration of 5.0% but not of 1.0% sodium L-ascorbate in the diet significantly increased the incidence and number of preneoplastic lesions, papillary or nodular hyperplasia, papilloma, and cancer of the urinary bladder. In groups given 5.0% sodium L-ascorbate, the urine was characterized by an apparent elevation of pH, a decrease of osmolality, and an increase of MgNH4PO4 crystalline. Addition of sodium L-ascorbate to the diet also resulted in increase in the content of ascorbic acid and its metabolite, dehydroascorbic acid, in the urine. These results show that an extremely high dose of sodium L-ascorbate (5.0%) promotes urinary bladder carcinogenesis under the present experimental conditions, while a high dose (1.0%) does not.

Topics: Animals; Ascorbic Acid; Body Weight; Carcinogens; Male; Neoplasms, Experimental; Rats; Rats, Inbred F344; Urinary Bladder Neoplasms

A systematic study of vitamin C blood levels in patients with cancer and an evaluation of their modifications when the patients were orally treated with daily large doses of ascorbic acid (5g/day) have been carried out. For excluding any interference on intestinal vitamin C absorption, all patients with digestive tract cancer have been excluded. Our first results concern 24 lung cancer and 35 bladder cancer patients, operable or not, of different sex and age. The study has shown hypovitaminosis C subclinic conditions for the greater part of subjects: in fact the average haematic rate of ascorbic acid approaches to lower level of physiologic range, appearing very low particularly for the younger patients. Periodic haematic dosages of vitamin C of unoperable and operated patients treated with large doses of ascorbic acid, have shown a rapid increase of its blood concentration which frequently has been very over 1500 micrograms%, the higher level of normal range. These high vitamin haematic levels, generally constant during the time, appear usefull in increasing the defence reactions of the cancerous patient.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Ascorbic Acid; Ascorbic Acid Deficiency; Carcinoma; Carcinoma, Squamous Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Urinary Bladder Neoplasms

The dominant role of the physical and chemical environment in the development of cancer is challenged. Analyses of the etiology of skin, bladder, respiratory and gastric cancers are presented which demonstrate the considerable extent to which one's health status may modify the initiation and promotion of environmentally associated cancers. It is concluded that although environmental factors may initiate and/or promote 85 to 90 percent of all cancers this is misleading since it neglects the critical role of the individual's health status as a factor modifying carcinogenesis.

Topics: Ascorbic Acid; Benzopyrenes; Carcinogens, Environmental; Carcinoma, Bronchogenic; Diet; Humans; Hydrocarbons; Neoplasms; Neoplasms, Radiation-Induced; Racial Groups; Riboflavin; Skin Neoplasms; Smoking; Stomach Neoplasms; Ultraviolet Rays; Urinary Bladder Neoplasms; Vitamin A

Topics: Adult; Ascorbic Acid; Breast Neoplasms; Child; Female; Humans; Leukocytes; Lung Neoplasms; Mouth Neoplasms; Neoplasms; Rectal Neoplasms; Skin Neoplasms; Urinary Bladder Neoplasms; Uterine Cervical Neoplasms

Ascorbic acid metabolism is associated with a number of mechanisms known to be involved in host resistance to malignant disease. Cancer patients are significantly depleted of ascorbic acid, and in our opinion this demonstrable biochemical characteristic indicates a substantially increased requirement and utilization of this substance to potentiate these various host resistance factors. The results of a clinical trial are presented in which 100 terminal cancer patients were given supplemental ascorbate as part of their routine management. Their progress is compared to that of 1000 similar patients treated identically, but who received no supplemental ascorbate. The mean survival time is more than 4.2 times as great for the ascorbate subjects (more than 210 days) as for the controls (50 days). Analysis of the survival-time curves indicates that deaths occur for about 90% of the ascorbate-treated patients at one-third the rate for the controls and that the other 10% have a much greater survival time, averaging more than 20 times that for the controls. The results clearly indicate that this simple and safe form of medication is of definite value in the treatment of patients with advanced cancer.

Topics: Adult; Aged; Ascorbic Acid; Breast Neoplasms; Bronchial Neoplasms; Colonic Neoplasms; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Rectal Neoplasms; Stomach Neoplasms; Terminal Care; Urinary Bladder Neoplasms

Topics: Animals; Ascorbic Acid; Dogs; FANFT; Mice; Thiazoles; Urinary Bladder Neoplasms

Topics: 2-Naphthylamine; 3-Hydroxyanthranilic Acid; Animals; Ascorbic Acid; Carcinoma; Dogs; Humans; Smoking; 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

Topics: Administration, Oral; Ascorbic Acid; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Evaluation; Drug Stability; Female; Fibrosarcoma; Humans; Injections, Intravenous; Neoplasms; Papilloma; Rectal Neoplasms; Stomach Neoplasms; Time Factors; Urinary Bladder Neoplasms

Topics: Ascorbic Acid; Blood; Cellophane; Creatinine; Cystoscopy; Dialysis; Humans; Hydrogen-Ion Concentration; Luminescent Measurements; Smoking; Specific Gravity; Temperature; Urinary Bladder Neoplasms; Urine

Topics: Animals; Ascorbic Acid; Carcinogens; Depression, Chemical; Dogs; Female; Male; Naphthalenes; Rabbits; Tritium; Urinary Bladder; Urinary Bladder Neoplasms

Topics: Ascorbic Acid; Candida; Humans; Kidney; Male; Neoplasm Recurrence, Local; Pacemaker, Artificial; Smoking; Ureteral Neoplasms; Urethra; Urinary Bladder Neoplasms

Topics: Animals; Ascorbic Acid; Biopsy; Cattle; Cattle Diseases; Cystoscopy; Humans; Naphthalenes; Occupational Diseases; Smoking; Sweden; Urinary Bladder Neoplasms; Urinary Diversion; Urine; Urography; Yugoslavia

Topics: Animals; Ascorbic Acid; Carcinogens; Carcinoma, Squamous Cell; Humans; Mice; Neoplasms, Experimental; ortho-Aminobenzoates; Oxidation-Reduction; Precancerous Conditions; Urinary Bladder Neoplasms

Topics: Age Factors; Animals; Ascorbic Acid; Carcinogens; Female; Humans; Mice; Middle Aged; ortho-Aminobenzoates; Oxidation-Reduction; Sex Factors; Smoking; Urinary Bladder Neoplasms

Topics: Animals; Ascorbic Acid; Carcinogens; Free Radicals; Humans; Luminescent Measurements; Mice; ortho-Aminobenzoates; Oxidation-Reduction; Smoking; Urinary Bladder Neoplasms

Topics: Ascorbic Acid; Carcinogens; Chromatography; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Methods; ortho-Aminobenzoates; Oxazines; Smoking; Spectrophotometry; Ultraviolet Rays; Urinary Bladder Neoplasms; Urine

Topics: Amines; Ascorbic Acid; Carcinogens; Humans; Luminescent Measurements; Oxidation-Reduction; Smoking; Spectrum Analysis; Tryptophan; Urinary Bladder Neoplasms

Topics: Animals; Ascorbic Acid; Female; Methods; Mice; Neoplasms, Experimental; ortho-Aminobenzoates; Urinary Bladder Neoplasms

A method is described for the estimation of adrenaline and noradrenaline in a 5 to 10 ml plasma sample.A batch technique of adsorption and elution from alumina is used and the final estimation is carried out using an automated fluorimetric technique based on the trihydroxyindole method. Fluorescence is stabilized first by thioglycollic acid to give noradrenaline concentrations only and then by ascorbic acid to give the total catecholamine concentration. The results of a number of catecholamine analyses are given.

Topics: Adsorption; Adult; Aluminum; Ascorbic Acid; Autoanalysis; Epinephrine; Fluorometry; Humans; Male; Methods; Norepinephrine; Pheochromocytoma; Thioglycolates; Urinary Bladder Neoplasms

Topics: Ascorbic Acid; Carcinogens; Free Radicals; Humans; Kynurenine; Luminescent Measurements; ortho-Aminobenzoates; Oxidation-Reduction; Smoking; Tryptophan; Ultraviolet Rays; Urinary Bladder Neoplasms

Topics: Antineoplastic Agents; Ascorbic Acid; Carcinogens; Hemorrhage; Humans; Lymph Node Excision; Urinary Bladder; Urinary Bladder Neoplasms; Urinary Tract Infections