ascorbic-acid and Hyperplasia

Studies on the relevance of the N-nitrosamines to esophageal cancer in China are reviewed. Esophageal cancer is a complex and multifactorial problem. Although a causal association between nitrosamines exposure and esophageal cancer in China has not yet been rigorously established, exposure of Lin-Xian subjects to nitrosamines either directly or as a result of their in vivo formation has been detected in our study. Several N-nitrosamines (NDMA, NDEA, NMBzA, NPyr, NPip, and NSAR) in gastric juice collected from Lin-Xian inhabitants have been detected. A correlation was found between the lesions of esophageal epithelium and the amount of nitrosamines present. In addition, the amounts of N-nitrosamino acids (N-nitrosoproline, N-nitrosothiazolidine 4-carboxylic acid, NSAR, and nitrates) excreted in 24-hr urine of subjects in Lin-Xian were significantly higher than those in Fan-Xian, indicating a higher exposure to N-nitroso compound and their precursors of the inhabitants in the high-risk area. The effect of nitrosamines on human esophagus has been investigated at the cellular levels. The amounts of O6-MedG in DNA of esophageal or stomach mucosa of patients from Lin-Xian were higher than that from Europe (Lyon and Essen). The presence of O6-MedG in the human fetal esophagus cultured with NMBzA was also detected. These findings indicate that the elevated levels of O6-MedG in esophageal DNA could be the result of a recent exposure to N-nitroso compounds or a genetically determined reduced cellular capacity for repair of O6-MedG from DNA. The hyperplasia was induced in the esophagus of human fetus that cultured with NMBzA for 2 weeks to 2 months. The intervention studies of esophageal cancer in Lin-Xian have been pursued. Intake of moderate doses of ascorbic acids by Lin-Xian subjects effectively reduced the urinary levels of N-nitrosamino acids to those found in un-dosed subjects in the low-risk area. If N-nitroso compounds are formed in vivo and are among the causative factors of esophageal cancer in Lin-Xian, ascorbic acid appears to be effective in lowering the body burden of these carcinogenic compounds. Thus, the plan of chemoprevention is carried out in Lin-Xian.

Topics: Ascorbic Acid; China; DNA; Epidemiologic Methods; Esophageal Neoplasms; Esophagus; Female; Gastric Juice; Guanine; Humans; Hyperplasia; Nitrosamines; Pregnancy; Time Factors

Topics: Adenoma; Ascorbic Acid; Carcinoma; Cytodiagnosis; Glycogen; Glycosaminoglycans; Goiter, Nodular; Histocytochemistry; Humans; Hyperplasia; Karyometry; Precancerous Conditions; Thyroid Gland; Thyroid Neoplasms; Thyroiditis, Autoimmune

We assessed the safety and efficacy of combined intravenous and aerosolized antioxidant administration to attenuate chlorine gas-induced airway alterations when administered after exposure. Adult male Sprague-Dawley rats were exposed to air or 400 parts per million (ppm) chlorine (a concentration likely to be encountered in the vicinity of industrial accidents) in environmental chambers for 30 minutes, and returned to room air, and they then received a single intravenous injection of ascorbic acid and deferoxamine or saline. At 1 hour and 15 hours after chlorine exposure, the rats were treated with aerosolized ascorbate and deferoxamine or vehicle. Lung antioxidant profiles, plasma ascorbate concentrations, airway morphology, and airway reactivity were evaluated at 24 hours and 7 days after chlorine exposure. At 24 hours after exposure, chlorine-exposed rats had significantly lower pulmonary ascorbate and reduced glutathione concentrations. Treatment with antioxidants restored depleted ascorbate in lungs and plasma. At 7 days after exposure, in chlorine-exposed, vehicle-treated rats, the thickness of the proximal airways was 60% greater than in control rats, with twice the amount of mucosubstances. Airway resistance in response to methacholine challenge was also significantly elevated. Combined treatment with intravenous and aerosolized antioxidants restored airway morphology, the amount of airway mucosubstances, and airway reactivity to control levels by 7 days after chlorine exposure. Our results demonstrate for the first time, to the best of our knowledge, that severe injury to major airways in rats exposed to chlorine, as characterized by epithelial hyperplasia, mucus accumulation, and airway hyperreactivity, can be reversed in a safe and efficacious manner by the post-exposure administration of ascorbate and deferoxamine.

Topics: Animals; Antioxidants; Ascorbic Acid; Bronchi; Bronchial Provocation Tests; Chlorine; Glutathione; Hyperplasia; Inhalation Exposure; Lung; Male; Rats; Rats, Sprague-Dawley; Trachea

Arsenite (As(III)), an inorganic arsenical, is a known human carcinogen, inducing tumors of the skin, urinary bladder and lung. It is metabolized to organic methylated arsenicals. Oxidative stress has been suggested as a mechanism for arsenic-induced carcinogenesis. Reactive oxygen species (ROS) can be important factors for carcinogenesis and tumor progression. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is known to produce intracellular ROS, therefore, we investigated the ability of apocynin (acetovanillone), an NADPH oxidase inhibitor, to inhibit the cytotoxicity and regenerative cell proliferation of arsenic in vitro and in vivo. Apocynin had similar effects in reducing the cytotoxicity of As(III) and dimethylarsinous acid (DMA(III)) in rat urothelial cells in vitro. When tested at the same concentrations as apocynin, other antioxidants, such as l-ascorbate and N-acetylcysteine, did not inhibit As(III)-induced cytotoxicity but they were more effective at inhibiting DMA(III)-induced cytotoxicity compared with apocynin. In vivo, female rats were treated for 3 weeks with 100ppm As(III). Immunohistochemical staining for 8-hydroxy-2'-deoxyguanosine (8-OHdG) showed that apocynin reduced oxidative stress partially induced by As(III) treatment on rat urothelium, and significantly reduced the cytotoxicity of superficial cells detected by scanning electron microscopy (SEM). However, based on the incidence of simple hyperplasia and the bromodeoxyuridine (BrdU) labeling index, apocynin did not inhibit As(III)-induced urothelial cell proliferation. These data suggest that the NADPH oxidase inhibitor, apocynin, may have the ability to partially inhibit arsenic-induced oxidative stress and cytotoxicity of the rat bladder epithelium in vitro and in vivo. However, apocynin did not inhibit the regenerative cell proliferation induced by arsenite in a short-term study.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetophenones; Acetylcysteine; Animals; Antioxidants; Arsenites; Ascorbic Acid; Cacodylic Acid; Carcinogens; Cell Line; Cell Proliferation; Cytoprotection; Deoxyguanosine; Diet; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Hyperplasia; NADPH Oxidases; Oxidative Stress; Rats; Rats, Inbred F344; Sodium Compounds; Urinary Bladder; Urothelium

Coronary hypersensitivity to serotonin promotes platelet aggregation, entailing the progression of the atherosclerotic process. This abnormality is a common finding in cardiac transplant recipients and may be triggered by reactive oxygen species, which plays a main role in the inflammatory process. Hence, this study aimed to determine the influence of intimal hyperplasia on this abnormality and its reversibility after acute supplementation with the superoxide anion scavenger vitamin C. Therefore, intracoronary injections of serotonin (3 microg), bradykinin (600 ng), and nitroglycerin (isosorbide dinitrate 200 microg) were administered to 21 cardiac transplant recipients (1 year after transplantation) with normal coronary angiographic results; the serotonin injections were repeated after intracoronary vitamin C supplementation (40 mg/min for 14 minutes). In the segments in which serotonin effects were the most pronounced, the diameter changes were measured by quantitative angiography, and vessel wall morphology was studied by intravascular ultrasound (IVUS). The IVUS examination revealed moderate to severe intimal thickening (total area - luminal area/total area) in 9 patients (group 1) of 25 +/- 2%, compatible with the early stage of graft vasculopathy. In this group, hypersensitivity to serotonin remained unchanged after intracoronary vitamin C supplementation, from -21 +/- 3% (percentage from baseline) to -25 +/- 3%, whereas in the other 12 patients with mild intimal thickening (9 +/- 1%; group 2), hypersensitivity to serotonin was attenuated from -20 +/- 5% to -4 +/- 6% (p <0.01). In contrast, the responses to bradykinin and isosorbide dinitrate were similar in the 2 groups. In group 1, plasma levels of high-sensitivity C-reactive protein and proinflammatory cytokines (interleukin-6 and -8) were significantly enhanced. For all the patients studied, the effect of vitamin C on the response to serotonin was significantly correlated with the intimal thickening. In conclusion, at 1 year after transplantation, morphologic changes compatible with the early stage of the graft vasculopathy are accompanied by hypersensitivity to serotonin unresponsive to vitamin C, despite a relatively preserved endothelial function (unaltered response to bradykinin).

Topics: Adult; Ascorbic Acid; Bradykinin; Coronary Vessels; Dietary Supplements; Heart Transplantation; Humans; Hyperplasia; Isosorbide Dinitrate; Middle Aged; Nitroglycerin; Oxidative Stress; Serotonin; Time Factors; Tunica Intima; Ultrasonography, Interventional

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

The fomesafen and 2,4-D amine herbicide induce cytotoxic effects at hepatic level in rats, such as: hepatomegaly, hyperplasia and increase in the enzymes activity which participate in the processes of peroxisomal beta-oxidation of fatty acids. In this work, the effect of vitamin E and C was evaluated, as well as, the dexamethasone in the modulation of these hepatotoxic effects. Sprague-Dawley rats were treated with the herbicides and with the agents to be evaluated. The different treatments were given during 15 days orally route. The herbicides combined with the dexamethasone and antioxidant agents were administrated only and simultaneously with the herbicides. Once concluded the different treatment, the rats were weighed and sacrificed. It was evaluated the liver size and liver fragments were obtained to determine the enzymatic activity of Fatty Acyl CoA-oxidase (FACO) and cellular number. The results showed that the hepatomegaly induced by fomesafen was inhibited by the vitamins and by the dexamethasone, while any effect was not observed in the group of rats treated with 2,4-D amine. None of the agents modulated the FACO activity induced by herbicides in treated rats. However, the dexamethasone showed a protective effect in the hyperplasia induced by two herbicides. The hepatotoxic effects induced by the herbicides responded to a different mechanism due to the differences of the effects observed at the antioxidant agents. On the other hand, the inhibition of the cellular proliferation by the dexamethasone does not keep relation with the responsible mechanisms of inducing the oxidant stress into FACO activity. Under experimental conditions of this study, the use of these agents does not guarantee protection against the hepatotoxic effects induced by the herbicides.

Topics: 2,4-Dichlorophenoxyacetic Acid; Acyl-CoA Oxidase; Animals; Antioxidants; Ascorbic Acid; Benzamides; Chemical and Drug Induced Liver Injury; Dexamethasone; Dimethylamines; Hepatomegaly; Herbicides; Hyperplasia; Liver; Male; Oxidoreductases; Rats; Rats, Sprague-Dawley; Vitamin E; Vitamins

In spontaneously hypertensive rats (SHRs) excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes. Vitamin C can increase tissue cysteine and glutathione levels. The aim of the present study was to investigate whether a dietary supplementation of vitamin C can lower tissue aldehydes and blood pressure and normalize associated biochemical and histopathological changes in SHRs. Starting at 12 weeks of age, animals were divided into 3 groups of 6 animals each. Animals in the WKY-control group and SHR-control group were given a normal diet and the SHR-vitamin C group a diet supplemented with vitamin C (1000 mg/kg feed) for the next 9 weeks. After nine weeks, systolic blood pressure, platelet [Ca2+]i, plasma insulin and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared to WKY controls and the SHR-vitamin C group. SHR-controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin C supplementation in SHRs lowered the systolic blood pressure, tissue aldehyde conjugates and attenuated adverse renal vascular changes.

Topics: Aldehydes; Animals; Antioxidants; Ascorbic Acid; Blood Platelets; Blood Pressure; Body Weight; Calcium; Dietary Supplements; Drinking; Eating; Hyperplasia; Hypertension; Liver; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY

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

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

Lipid peroxidation and LDL oxidation have been implicated in intimal hyperplasia and endothelial dysfunction following direct arterial trauma.. The aim of this study was to evaluate the effects of megadose of natural antioxidant vitamin E (VE) combined to vitamin C (VC) on the regenerated endothelial dysfunction.. A first group of rats (VE and C) (n = 10) was pretreated with VE (500 IU/kg/day) and VC (1200 mg/kg/day) for 4 weeks before aortic (thoracic) endothelial denudation with a Fogarty catheter. Rats were then fed with the same vitamin supplemented diet for 2 months. A second group (n = 10) was similarly denuded and treated with soya oil (SO), VE vehicle, for the same period; a third group (n = 10) was denuded only (DN); and a fourth group was maintained on a regular diet (CL) without denudation. Endothelial-dependent and independent relaxation was assessed in organ chambers.. Vascular relaxation to nitric oxide analogue sodium nitroprusside was not affected either by the regenerative process or the vitamin supplementation. However, endothelial-dependent relaxation to acetylcholine, was significantly preserved in VE and C (p < 0.01) treated animals compared to DN group.. These results suggest that, in this model, dietary megadose of antioxidants vitamin initiated 4 weeks before denudation can improve the post-regenerative endothelial dysfunction and could contribute to the prevention of the atherosclerotic process.

Topics: Acetylcholine; Animals; Antioxidants; Aorta, Thoracic; Arteriosclerosis; Ascorbic Acid; Catheterization; Cholesterol, LDL; Endothelium, Vascular; Hyperplasia; Lipid Peroxidation; Nitroprusside; Rats; Rats, Sprague-Dawley; Regeneration; Soybean Oil; Tunica Intima; Vasodilation; Vasodilator Agents; Vitamin E

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 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

A total of 391 gastric juice samples was collected from Ji Yuan and An Shi counties, high and medium risk areas of esophageal carcinoma in Henan province. NDMA, NDEA, NMBzA, NPip and unknown compounds were assayed in the fasting gastric juice. Among these nitrosamines, NMBzA, NPyr and NPip were specific in inducing esophageal cancer in animals. The amount of nitrosamines in the gastric juice collected from Ji Yuan county was higher than that from An Shi county. The exposure level of nitrosamines of subjects from these two localities were significantly different (P < 0.001). There was a positive relationship between the nitrosamines exposure level and esophageal cancer mortality rate. The amount of gastric N-nitrosamines from An Shi subjects as treated with vitamin C was reduced. It is evident that vitamin C can inhibit N-nitrosamine formation in the stomach, thereby, reducing the N-nitrosamines exposure level.

Topics: Adult; Aged; Ascorbic Acid; Dimethylnitrosamine; Esophageal Neoplasms; Esophagus; Female; Gastric Juice; Humans; Hyperplasia; Male; Middle Aged; N-Nitrosopyrrolidine; Nitrosamines; Precancerous Conditions

The effects of indomethacin (IM) or L-ascorbic acid (AsA) on cell proliferation induced by bladder tumor promoters such as butylated hydroxyanisole (BHA), sodium L-ascorbate (Na-AsA), sodium citrate (Na-Cit), and diphenyl (DP) in rat bladder and forestomach epithelium were investigated. Treatment with IM in combination with BHA or Na-AsA diminished DNA synthesis levels of bladder epithelium as compared to the BHA or Na-AsA alone values. On the other hand, AsA further amplified the increase of bladder epithelial DNA synthesis caused by Na-Cit treatment. Histopathologically, administration of Na-AsA in combination with IM reduced the incidence of simple hyperplasia. In contrast, simultaneous treatment with Na-Cit and AsA caused an increase of the hyperplasia development. No apparent combination effects were observed in the DP-treated groups. In forestomach epithelium, AsA enhanced the BHA-induced increase in DNA synthesis and epithelial hyperplasia, characterized by marked basal cell proliferation. The present results thus suggested that IM may exert inhibitory effects on promotion of bladder carcinogenesis by certain tumor promoter types, and AsA may enhance BHA forestomach carcinogenesis.

Topics: Animals; Ascorbic Acid; Butylated Hydroxyanisole; Carcinogens; Cell Division; Citrates; Citric Acid; Drug Interactions; Epithelium; Gastric Mucosa; Hyperplasia; Indomethacin; Male; Rats; Rats, Inbred F344; Urinary Bladder

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

Vitamin C is an essential nutrient whose protective influence in carcinogenesis has been reported frequently. In general, evidence suggests that vitamin C inhibits the formation of some carcinogens and decreases the incidence and delays the onset of neoplastic lesions but the mechanisms by which this occurs are not known. In 1973, Wallenius and Lekholm induced intra-oral palatal squamous cell carcinomas by the use of the water soluble carcinogen 4-nitroquinoline-1-oxide (4NQO) applied thrice weekly to the palatal mucosa of rats. The aim of this study was to determine if in rats topically applied vitamin C had an effect on the process of carcinogenesis caused by the application of 4NQO. The results of this study showed that in the 4NQO treated animals a progression through mild, moderate and severe dysplasia occurred prior to neoplastic changes at 24 weeks and that this progression was delayed in the animals treated topically with vitamin C. It can be concluded that topically applied vitamin C has a modulating effect on the neoplastic process induced by 4NQO in the palatal mucosa of rats.

Topics: 4-Nitroquinoline-1-oxide; Administration, Topical; Animals; Ascorbic Acid; Carcinoma, Squamous Cell; Epithelium; Hyperplasia; Leukoplakia, Oral; Male; Mouth Mucosa; Mouth Neoplasms; Palate; Rats; Rats, Inbred Strains; Time Factors

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

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

Male Syrian golden hamsters receiving 12 weekly subcutaneous injections of diethylnitrosamine (DEN) were subjected to cigarette smoke-inhalation and fed a diet or without 1% vitamin C supplement for a period of 58 weeks. Another group was a sham-smoked control and was not fed vitamin C. Tissues of the oral cavity and costal cartilage were examined by light and/or scanning electron microscopy. Oral leukoplakia and costochondral hyperplasia occurred with high frequency in all groups treated with DEN. Leukoplakic lesions were found in the palate, tongue, and pharynx; the early change was focal erosion with mild epithelial hyperplasia and inflammatory cell infiltration. Advanced lesions had marked mucosal thickening due to acanthosis, parakeratosis, hyperkeratosis, and submucosal infiltration of lymphocytes and plasma cells. Precancerous lesions were noted in tongue and pharynx. Scanning electron microscopy of tongues revealed destruction of filiform papillae. The incidence of leukoplakic lesions were higher in smoke-exposed hamsters than in controls, but the incidence in vitamin C-supplemented hamsters was low when compared with the smoke-exposed hamsters without vitamin C. Costochondral hyperplasia was initiated by thickening of the perichondrium followed by proliferation of chondrocytes. Costochondral hyperplasia appeared earlier, and the incidence was higher in the vitamin C-supplemented hamsters. It could not be determined whether costochondral hyperplasia was the primary lesion induced by DEN or secondary change.

Topics: Animals; Ascorbic Acid; Cartilage; Cartilage Diseases; Cricetinae; Diethylnitrosamine; Hyperplasia; Leukoplakia, Oral; Male; Mesocricetus; Microscopy, Electron, Scanning; Palate; Pharynx; Ribs; Smoking; Tongue

Synergistic effects of butylated hydroxyanisole (BHA) and other antioxidants on induction of rat forestomach lesions were investigated. Groups of F344 male rats were treated with 1% BHA plus 0.7% butylated hydroxytoluene (BHT), 1% BHA plus 1% propyl gallate (PG), 1% BHA plus 1% sodium L-ascorbate (SA), 1% BHA plus 1% DL-alpha-tocopherol (alpha-TP), 0.4% BHT plus 0.4% BHA plus 0.4% PG plus 0.4% SA plus 0.4% alpha-TP, 1% BHA or 2% BHA. Further groups of 10 rats each received antioxidants without BHA as controls. Histological examination revealed significantly increased incidences of hyperplasia in the groups given BHA together with SA or PG at the prefundic region or at the mid region respectively. The forestomach changes induced by BHA together with SA were equal to those induced by 2% BHA. On the other hand, simultaneous treatment with BHA and PG or alpha-TP reduced the incidence of hyperplasia at the prefundic region. It is concluded that mixed treatment with BHA and other antioxidants exerted enhancing or inhibitory effects on the induction of hyperplasia at different sites of the forestomach epithelium.

Topics: Animals; Antioxidants; Ascorbic Acid; Butylated Hydroxyanisole; Cell Division; Drug Synergism; Hyperplasia; Male; Propyl Gallate; Rats; Rats, Inbred F344; Stomach; Vitamin E

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

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

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

Topics: 17-Hydroxycorticosteroids; Adrenal Glands; Alkaline Phosphatase; Animals; Ascorbic Acid; Burns; Cholesterol; Histocytochemistry; Hyperplasia; Lipid Metabolism; Organ Size; Rabbits; Shock, Traumatic

Topics: Aged; Anemia, Sideroblastic; Ascorbic Acid; Autopsy; Blood Cell Count; Blood Transfusion; Bone Marrow; Bone Marrow Cells; Bone Marrow Examination; Erythrocytes; Erythropoiesis; Folic Acid; Follow-Up Studies; Humans; Hyperplasia; Iron; Leukemia, Myeloid; Male; Middle Aged; Monocytes; Muramidase; Precancerous Conditions; Pyridoxine; Vitamin B 12

Topics: Animals; Ascorbic Acid; Azo Compounds; Body Weight; Chemical and Drug Induced Liver Injury; Female; Food Additives; Food Preferences; Hyperplasia; Leukocyte Count; Liver; Liver Diseases; Lymphocytes; Male; Naphthalenes; Organ Size; Rats; Sulfonic Acids

Topics: Ascorbic Acid; Hyperplasia; Liver Diseases; Liver Regeneration; Metabolism; Rabbits; Research

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Ascorbic Acid; Histology; Hyperplasia; Hypertrophy; Lipid Metabolism; Metyrapone; Mineralocorticoid Receptor Antagonists; Pharmacology; Pituitary Diseases; Pituitary Gland; Research; Rodentia