ascorbic-acid and Papilloma

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

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

The present study evaluates the modulatory potential of Phyllanthus niruri on chemically induced skin carcinogenesis, and its influence on oxidative stress and the antioxidant defense system. Oral administration of P. niruri extract (PNE), during peri- (Gr. III), post- (Gr. IV), or peri- and post- (Gr. V) initiational stages of 7,12-dimethylbenz(a) anthracene (DMBA)-croton oil–induced papillomagenesis considerably reduced tumor burden to 4.20, 4.00, and 3.33(positive control value 6.20); cumulative number of papillomas to 21, 16, and 10, respectively, (positive control value 62); and incidence of mice bearing papillomas to 50, 40, and 30%, respectively (positive control value 100%), but significantly increased the average latent period to 10.14, 10.62, and 11.60, and inhibition of tumor multiplicity to 66, 74,and 83%, respectively. Enzyme analysis of skin and liver showed a significant (p ≤ 0.05, ≤ 0.01, ≤ 0.001) elevation in antioxidant parameters such as superoxide dismutase, catalase, glutathione, and vitamin C in PNE-treated groups (Gr. III–V) when compared with the carcinogen-treated control (Gr. II). The elevated level of lipid peroxidation in the carcinogen-treated positive control group was significantly (p ≤ 0.05, ≤ 0.01, ≤ 0.001) inhibited by PNE administration. These results indicate that P. niruri extract has potentiality to reduce skin papillomas by enhancing antioxidant defense system.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antioxidants; Ascorbic Acid; Glutathione; Lipid Peroxidation; Male; Mice; Oxidative Stress; Papilloma; Phyllanthus; Phytotherapy; Plant Extracts; Skin Neoplasms

The annual incidence of all forms of skin cancer, the most common of all human cancers, is increasing yearly. A unique nutrient mixture (NM) was shown to exhibit anticancer activity in vivo and in vitro. We examined the effect of NM on the development of skin cancer induced by 7,12-dimethylbezanthracene (DMBA) in female SENCAR mice by a complete carcinogenesis protocol. Mice (n=55) were divided into four groups and carefully shaved on dorsum. After 2 days, the mice in Groups 1 (n=10), 3 (n=20), and 4 (n=20) were treated topically with 100 nM DMBA in 0.2 ml of acetone twice a week for 4 weeks; Group 2 (n=5), the control group, was treated with acetone 0.2 ml. Groups 1 and 2 were fed the regular diet. Group 3A (n=10) was fed a diet containing 0.5% NM from the day of DMBA treatment and 3B (n=10) the regular diet and received NM (75 mg in 0.4 ml of 1:1 acetone/water) topically to the shaved area 15 min before DMBA application twice a week for 4 weeks. Group 4 mice were fed a diet containing 0.5% NM for 2 weeks prior to the application of DMBA and then divided into two groups: 4A (n=10) was fed the 0.5% NM diet as in 3A, and 4B (n=10) the regular diet as described for 3B. Body weight and diet consumption of the mice were monitored and the skin tumors (papillomas) were counted and recorded. Ten weeks thereafter the mice were euthanized, skinned, and tumors were processed for histology. NM significantly (P<0.0001) inhibited DMBA-induced skin tumor multiplicity by 59, 62, 69, and 86% in NM-treated Groups 3A, 3B, 4A, and 4B, respectively. These results suggest that NM has strong potential as a useful therapeutic regimen for skin cancer by significantly inhibiting the incidence and tumor multiplicity of DMBA-induced skin tumors.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acetylcysteine; Amino Acids; Animals; Arginine; Ascorbic Acid; Camellia sinensis; Carcinogens; Copper; Diet; Female; Keratoacanthoma; Lysine; Manganese; Mice; Mice, Inbred SENCAR; Papilloma; Plant Extracts; Proline; Selenium; Skin; Skin Neoplasms

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

To evaluate the role of vitamins C and E as chemopreventive agents in oral carcinogenesis by optical and ultrastructural studies.. The cheek pouch of male hamsters was treated with the oral carcinogen, dimethylbenz(a)anthracene (DMBA), to induce multiple tumour formation. Vitamins C and E were applied either singly or in combination as a chemopreventive agent. Paraffin and resin-embedded sections of the hamster cheek pouch were studied optically and ultrastructurally.. The epithelium of control hamsters showed hyperorthokeratosis and parakeratosis, but did not develop well differentiated squamous cell carcinoma (WDSCC). Ninety percent of the animals treated with DMBA alone showed WDSCC while 10% of the animals developed papillomas. There was also a marked increase in the number of cells undergoing mitosis in this group. A reduction in the yield (1.1 tumour/animal) and rate 60-80% of squamous cell carcinomas but not of papillomas (2.0 papillomas/animal) was observed in groups VI-VIII treated with DMBA and vitamins C and E singly or in combination as compared to those of DMBA only. In animals treated with DMBA plus vitamins C and E, statistical significant decrease in the number of animals with tumours and mitotic basal cells was observed when compared with the DMBA treated group. Control animals showed normal ultrastructural morphology while tumour-bearing animals showed basal lamina in a discontinuous, fragmented, broken and diffused basement membrane, with diminished lamina densa, fewer hemidesmosomes and invagination of the basal cell cytoplasmic processes in the subepithelium.. These results indicate that vitamin E singly or in combination with vitamin C plays a role in the inhibition of tumour cell growth.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Basement Membrane; Carcinogens; Carcinoma, Squamous Cell; Cheek; Chemoprevention; Chi-Square Distribution; Cricetinae; Cytoplasm; Drug Combinations; Epithelium; Hemidesmosomes; Leukoplakia, Oral; Male; Mesocricetus; Mitosis; Mouth Mucosa; Mouth Neoplasms; Papilloma; Parakeratosis; Vitamin E

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

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

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

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

In experiment I, short-term effects of combined treatment with anti-oxidants, sodium ascorbate (NaAsA) and sodium nitrite (NaNO2) on forestomach cell proliferation were examined in F344 male rats. Groups of 5 animals aged 6 weeks were treated for 4 weeks with 0.8% catechol, 0.8% hydroquinone, 1% tert-butyl-hydroquinone (TBHQ), 2% gallic acid or 2% pyrogallor alone or in combination with 0.3% NaNO2 in the drinking water and/or 1% NaAsA in the diet. The thicknesses of forestomach mucosa in rats treated with anti-oxidants and NaNO2 in combination were greater than those with antioxidant alone and additional NaAsA treatment further enhanced the thickening of mucosa. It was noteworthy that values for mucosae of animals treated with NaNO2 and NaAsA without anti-oxidant were similar to those for anti-oxidants. In experiment 2, effects of combined treatment with NaAsA or ascorbic acid (AsA) and NaNO2 on carcinogenesis were examined in F344 male rats with or without N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) pre-treatment. Groups of 20 or 15 rats, respectively, aged 6 weeks, were given a single intra-gastric administration of 150 mg/kg body weight of MNNG in DMSO:water = 1:1 or the vehicle alone by stomach tube. Starting 1 week later, they received supplements of 1% NaAsA or 1% AsA in the diet and 0.3% NaNO2 in drinking water in combination, each of the individual chemicals alone, or basal diet until the end of week 52. In MNNG-treated animals, incidences of forestomach papillomas and carcinomas were significantly enhanced in the NaNO2 alone group (84 and 47%, respectively) as compared with the basal diet group (30 and 10%), with further significant increase in carcinomas occurring with additional NaAsA (79%, p < 0.05) or AsA (85%, p < 0.05) treatment. In animals without MNNG, all animals in the NaNO2 group demonstrated mild hyperplasia, additional administration of NaAsA or AsA remarkably enhancing the grade of hyperplasia, and resulting in 53% and 20% incidences, respectively, of papillomas. Thus NaNO2 was demonstrated to exert promoter action for forestomach carcinogenesis, with NaAsA and AsA acting as co-promoters. The results strongly indicate that combined treatment with NaAsA or AsA and NaNO2 may induce forestomach carcinomas in the long term.

Topics: Animals; Ascorbic Acid; Body Weight; Carcinoma, Squamous Cell; Drug Interactions; Kidney; Liver; Male; Methylnitronitrosoguanidine; Organ Size; Papilloma; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach Neoplasms

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 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

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

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

Administration to rats of ascorbate with morpholine and nitrite was previously shown to inhibit the liver tumor production and to enhance the induction of forestomach tumors, as compared to treatment with morpholine and nitrite. In a repetition of this experiment, 10 g morpholine/kg in the diet and 2 g sodium nitrite/liter in the drinking water were administered for life to male MRC-Wistar rats without (group 1) or with (group 2) 22.7 g sodium ascorbate/kg in the diet. Group 3 was untreated. Group 2 showed a lower liver tumor incidence with a longer latency than group 1, indicating a 78% inhibition by ascorbate of in vivo N-nitrosomorpholine (NMOR) formation. The incidence of forestomach papillomas was 3% in group 1, 38% in group 2, and 8% in group 3. The difference between groups 1 and 2 was not significant due to the shorter life-span of group 1. Group 1 and especially group 2 had more forestomach hyperplasia and hyperkeratosis than group 3. Ascorbate might have enhanced induction of these lesions because of an action synergistic with that of NMOR. However, it is most likely that the lowered NMOR dose and concomitantly increased survival produced by the ascorbate were solely responsible for the increased incidence of forestomach papillomas and other lesions in group 2.

Topics: Animals; Ascorbic Acid; Diet; Drug Interactions; Esophagus; Hyperplasia; Liver Neoplasms; Male; Morpholines; Nitrites; Nitrosamines; Papilloma; Rats; Sodium Nitrite; Stomach; Stomach Neoplasms; Time Factors

Skin papillomas were observed in the majority of toads when painted with 1 mg of 7,12-dimethyl-benz (alpha) anthracene (DMBA) dialy for 8 weeks. Animals injected with 10 mg/kg/day of ascorbic acid into the dorsal lymph sac showed tumor inhibition when painted with the same dose level of DMBA for 8 weeks. Tumor regression occurred in those animals receiving 10 mg/kg/day of ascorbic acid for 8 weeks.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Ascorbic Acid; Bufonidae; Female; Male; Neoplasms, Experimental; Papilloma; Skin 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