ascorbic-acid and Cocarcinogenesis

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; Cocarcinogenesis; Humans; Neoplasms; Vitamin A; Vitamin A Deficiency; Vitamin E; Vitamin E Deficiency

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

The carcinogen-induced rat mammary carcinoma model, developed a quarter of a century ago by Dr. Charles Brenton Huggins, is today the standard laboratory animal model in the study of human breast cancer. This model has a number of features that make it particularly attractive to the experimental oncologist, e.g., tumor induction ease and reliability, organ site specificity, tumors of ductal origin, tumors of predominantly carcinomatous histopathological characteristics, tumors of varying growth factor and/or hormone responsiveness, and the potential to examine tumor initiation and promotion processes. Since the development of this model, an extensive literature describing the biological behavior and responsiveness of these tumors has been provided. The purpose of this communication is to condense, summarize, and integrate this vast literature into a single review with the intent on facilitating information acquisition and conceptualism by both the new and the established experimental oncologist. In addition, and equally important, this communication is a tribute to Dr. Huggins, whose pioneering efforts in the development of this model and whose scientific contributions and dedication to the oncological sciences in general have made an important and lasting impact on us all.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adrenal Cortex Hormones; Animals; Antioxidants; Ascorbic Acid; Castration; Cocarcinogenesis; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Gonadal Steroid Hormones; Insulin; Male; Mammary Neoplasms, Experimental; Methylcholanthrene; Methylnitrosourea; Neoplasm Transplantation; Nucleotides, Cyclic; Pituitary Hormones, Anterior; Prostaglandins; Rats; Retinoids; Selenium; Thyroid Hormones; Vitamin E

Combined treatment with sodium nitrite (NaNO2) and ascorbic acid (AsA) has already been shown to promote rat forestomach carcinogenesis, possibly due to nitric oxide generation under acidic conditions. We hypothesized that a similar effect might occur in the esophagus when the luminal pH is decreased by acid reflux. To clarify this possibility, reflux esophagitis model rats (F344 male) were coadministered 0.2% NaNO2 in the drinking water and 1% AsA in the diet. After 32 weeks of the combined treatment, a significant increase in the incidence of epithelial hyperplasias of the lower-middle and lowest parts of the esophagus were observed compared with the basal-diet group, along with exacerbation of dysplasia and extension of the lesions. Additionally, one squamous cell papilloma was found only in the combined-treatment group. Subsequently, we confirmed the enhancing effects of NaNO2 and AsA cotreatment in the rat N-bis(2-hydroxypropyl)nitrosamine-initiated esophageal tumorigenesis model. The incidence of hyperplasia was enhanced in all segments, along with the incidence and multiplicity of squamous cell papillomas in the lowest segment of the esophagus. Thus, the data demonstrate that combined treatment with NaNO2 and AsA exerts promoting effects on rat esophageal carcinogenesis under acid reflux conditions, as in the forestomach. These findings suggest that the risk of excessive intake of a combination of nitrite and antioxidants for esophageal carcinogenesis is appreciable, particularly in patients with reflux esophagitis.

Topics: Animals; Antioxidants; Ascorbic Acid; Carcinoma, Squamous Cell; Cocarcinogenesis; Disease Models, Animal; Esophageal Neoplasms; Esophagitis, Peptic; Food Preservatives; Male; Rats; Rats, Inbred F344; Sodium Nitrite

Combination treatment with sodium nitrite (NaNO(2)) and ascorbic acid (AsA) is well known to promote forestomach carcinogenesis in rats and weakly enhance esophageal carcinogenesis under acid reflux conditions. Nitric oxide generation and oxidative DNA damage are considered to be related to the enhancement of carcinogenesis. The purpose of the present study was to investigate whether oxidative DNA damage-associated genotoxicity and tumor initiating potential are involved in the carcinogenesis. In the bacterial reverse mutation assay using Escherichia coli deficient in the mutM gene encoding 8-hydroxydeoxyguanosine (8-OHdG) DNA glycosylase, the combination with NaNO(2) and AsA increased the mutation frequency dramatically, slight increase being evident in the parental strain. In vivo, a significant increase in 8-OHdG levels in the rat forestomach epithelium occurred at 24 h after combined treatment. Six-week-old F344 male rats were given drinking water containing 0.2% NaNO(2) and a diet supplemented with 1% AsA in combination, or the chemicals individually or basal diet alone for 12 weeks. After an interval of 2 weeks, they received 1% butylated hydroxyanisole in the diet for promotion until the end of weeks 52 and 78. Although one squamous cell carcinoma was observed in the combined group, there was no significant variation in tumor development among the groups. The study indicated that the combination of NaNO(2) with AsA induces genotoxicity due to oxidative DNA damage in vitro, and elevates 8-OHdG levels in the forestomach epithelium, but lacks initiating activity in the rat two-stage carcinogenesis model.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Ascorbic Acid; Butylated Hydroxyanisole; Carcinogens; Cocarcinogenesis; Deoxyguanosine; Disease Models, Animal; DNA Damage; DNA, Bacterial; Drug Therapy, Combination; Escherichia coli; Gastric Mucosa; Male; Methylnitronitrosoguanidine; Mutagens; Organisms, Genetically Modified; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach Neoplasms

We have shown previously that Vitamin E acts as a tumor promoter in 7,12-dimethylbenz(a)anthracene (DMBA) initiated mouse skin. We now show that high concentrations (80 micromol) of Vitamin E are required for promotion, and that 10-fold lower concentrations do not promote tumor formation. The same high concentration of the water-soluble anti-oxidant Vitamin C did not act as a tumor promoter, but did amplify the promoting effect of high, but not low, concentrations of Vitamin E. Oxidizing free radicals generated by beta-radiation exposure of the skin at the time of Vitamin E treatment also enhanced promotion by high (but not low) concentrations of Vitamin E. The results are consistent with a process whereby tumor promotion by the lipid-soluble Vitamin E occurs as a result of alpha-tocopherol acting as a free radical scavenger, with the formation and subsequent transfer of the alpha-tocopherol free radical center to the surrounding lipids, resulting in lipid oxidations.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Antioxidants; Ascorbic Acid; Beta Particles; Carcinogens; Cocarcinogenesis; Female; Free Radical Scavengers; Mice; Mice, Inbred SENCAR; Oxidation-Reduction; Radiation, Ionizing; Skin; Skin Neoplasms; Vitamin E

Sporadic colorectal cancer (CRC) is characterized by genetic and epigenetic changes such as regional DNA hypermethylation and global DNA hypomethylation. Epidemiological and animal studies suggest that aberrant DNA methylation is associated with low dietary folate intake, which is aggravated by high alcohol intake. The relationship between promoter methylation of genes involved in CRC carcinogenesis and folate and alcohol intake was investigated. Methylation of the APC-1A, p14(ARF), p16(INK4A), hMLH1, O(6)-MGMT, and RASSF1A promoters was studied using methylation-specific PCR in 122 sporadic CRCs, derived from patients with folate and alcohol intake at either the lower or the higher quintiles of the distribution. Overall, promoter hypermethylation frequencies observed were: 39% for APC; 33% for p14(ARF); 31% for p16(INK4A); 29% for hMLH1; 41% for O(6)-MGMT; and 20% for RASSF1A. For each of the tested genes, the prevalence of promoter hypermethylation was higher in CRCs derived from patients with low folate/high alcohol intake (n = 61) when compared with CRCs from patients with high folate/low alcohol intake (n = 61), but the differences were not statistically significant. The number of CRCs with at least one gene methylated was higher (84%) in the low folate intake/high alcohol intake group when compared with the high folate intake/low alcohol intake group (70%; P = 0.085). Despite the size limitations of this study, these data suggest that folate and alcohol intake may be associated with changes in promoter hypermethylation in CRC.

Topics: Aged; Alcohol Drinking; Ascorbic Acid; Cocarcinogenesis; Cohort Studies; Colorectal Neoplasms; Diet; Dietary Fiber; DNA Methylation; DNA, Neoplasm; Dose-Response Relationship, Drug; Energy Intake; Ethanol; Feeding Behavior; Female; Folic Acid; Folic Acid Deficiency; Gene Silencing; Humans; Iron, Dietary; Male; Middle Aged; Netherlands; Pilot Projects; Promoter Regions, Genetic; Risk Factors

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

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

Procyanidins present in grape seeds are known to exert anti-inflammatory, anti-arthritic and anti-allergic activities, prevent skin aging, scavenge oxygen free radicals and inhibit UV radiation-induced peroxidation activity. Since most of these events are associated with the tumor promotion stage of carcinogenesis, these studies suggest that grape seed polyphenols and the procyanidins present therein could be anticarcinogenic and/or anti-tumor-promoting agents. Therefore, we assessed the anti-tumor-promoting effect of a polyphenolic fraction isolated from grape seeds (GSP) employing the 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol 13-acetate (TPA)-promoted SENCAR mouse skin two-stage carcinogenesis protocol as a model system. Following tumor initiation with DMBA, topical application of GSP at doses of 0.5 and 1.5 mg/mouse/application to the dorsal initiated mouse skin resulted in a highly significant inhibition of TPA tumor promotion. The observed anti-tumor-promoting effects of GSP were dose dependent and were evident in terms of a reduction in tumor incidence (35 and 60% inhibition), tumor multiplicity (61 and 83% inhibition) and tumor volume (67 and 87% inhibition) at both 0.5 and 1.5 mg GSP, respectively. Based on these results, we directed our efforts to separate and identify the individual polyphenols present in GSP and assess their antioxidant activity in terms of inhibition of epidermal lipid peroxidation. Employing HPLC followed by comparison with authentic standards for retention times in HPLC profiles, physiochemical properties and spectral analysis, nine individual polyphenols were identified as catechin, epicatechin, procyanidins B1-B5 and C1 and procyanidin B5-3'-gallate. Five of these individual polyphenols with evident structural differences, namely catechin, procyanidin B2, procyanidin B5, procyanidin C1 and procyanidin B5-3'-gallate, were assessed for antioxidant activity. All of them significantly inhibited epidermal lipid peroxidation, albeit to different levels. A structure-activity relationship study showed that with an increase in the degree of polymerization in polyphenol structure, the inhibitory potential towards lipid peroxidation increased. In addition, the position of linkage between inter-flavan units also influences lipid peroxidation activity; procyanidin isomers with a 4-6 linkage showed stronger inhibitory activity than isomers with a 4-8 linkage. A sharp increase in the inhibition of epid

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acetone; Administration, Cutaneous; Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Biflavonoids; Catechin; Cocarcinogenesis; Epidermis; Female; Flavonoids; Lipid Peroxidation; Mice; Mice, Inbred SENCAR; Microsomes; Molecular Structure; Phenols; Plant Extracts; Polymers; Proanthocyanidins; Rosales; Seeds; Skin Neoplasms; Tetradecanoylphorbol Acetate; Vitamin E

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

Forty young adult male Syrian hamsters (Mesocricetus auratus) were divided into four groups of 10 animals. The animals in group 1 (tumor control) had the right buccal pouches painted three times a week with a 0.5% solution of 7,12 dimethylbenz(a)anthracene in heavy mineral oil USP with the use of a number 4 sable brush. The animals in group 2 (experimental group) had the right buccal pouches painted with the same solution as group 1. In addition, they received 1 mg ascorbic acid in 0.5 ml mineral oil three times a week on days alternating with the other application. The ascorbic acid was administered by mouth with the use of a pipette. The animals in group 3 received 1 mg ascorbic acid in 0.5 ml mineral oil three times weekly, and the animals in group 4 were untreated controls. The animals were killed after 14 weeks. Tumors were counted and measured. Both right and left (control) pouches were photographed, excised, fixed in formalin, sectioned in paraffin, and studied histologically. The animals that received the ascorbic acid (vitamin C) had significantly larger tumors in the right buccal pouch, although actual numbers of gross tumors were only slightly increased. The figures for tumor burden in the animals in groups 1 and 2 were 364 versus 648 mm3. Histologic study revealed that the animals in group 2 had more anaplastic tumors and a significantly greater number of areas of dysplastic leukoplakia than the animals in group 1.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Ascorbic Acid; Carcinogens; Carcinoma, Squamous Cell; Cheek; Cocarcinogenesis; Cricetinae; Drug Synergism; Leukoplakia, Oral; Male; Mesocricetus; Mouth Neoplasms

The effects of the synthetic antioxidant butylated hydroxyanisole (BHA) and naturally occurring antioxidants such as L-ascorbic acid (AsA; vitamin C), citric acid, benzoic acid or gallic acid in combination, on the development of rat forestomach epithelial lesions were investigated. A dietary level of 2.0% was selected for all antioxidants and the experimental period was 1 year. As compared with BHA alone, treatment with AsA in combination with BHA increased the severity of the hyperplasia in the mid-region, but not in the prefundic region of the forestomach epithelium, as well as the multiplicity of forestomach tumors. Furthermore, incidences of squamous cell carcinomas (SCCs) in the forestomach were significantly elevated in this group, while papilloma development only showed a tendency to increase. In addition, SCC invasion into the muscle layer of the forestomach was observed only in the BHA + AsA group. Treatment with the other antioxidants did not affect BHA-induced forestomach lesion development. The present study demonstrated that AsA can clearly enhance BHA forestomach carcinogenesis.

Topics: Animals; Ascorbic Acid; Butylated Hydroxyanisole; Cocarcinogenesis; Drug Synergism; Epithelium; Food Additives; Male; Rats; Rats, Inbred F344; Stomach; Stomach 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

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

It was shown in experiments on 186 mice that formation of tumors of the lung and fore-stomach induced by injection of sodium nitrite in combination with aminopyrine or methylurea is inhibited following treatment with ascorbic acid, hexamethylenetetramine or sodium metabisulfite.

Topics: Aminopyrine; Animals; Ascorbic Acid; Cocarcinogenesis; Female; Lung Neoplasms; Male; Methenamine; Methylurea Compounds; Mice; Mice, Inbred Strains; Nitrites; Sodium Nitrite; Stomach Neoplasms; Sulfites

Administration of ascorbic acid (0.3% in drinking water) inhibited the promoting effect of estradiol dipropionate on the 1,2-dimethylhydrazine-induced uterine sarcomogenesis in CBA mice. However administration of sodium ascorbate intensified the promoting effect of estradiol on the uterine sarcomogenesis, as evidenced by the shortening of the periods of tumour incidence.

Topics: 1,2-Dimethylhydrazine; Animals; Ascorbic Acid; Cocarcinogenesis; Dimethylhydrazines; Drug Synergism; Female; Methylhydrazines; Mice; Mice, Inbred CBA; Sarcoma, Experimental; Uterine 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

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 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 biological mode of action of tumor promoters, exemplified by the phorbol esters, is a subject of intensive study in a number of laboratories. A few investigators have recently begun to examine the role of dietary nutrients in tumor promotion, but the available data are sparse and interpretation difficult. A few examples are provided to indicate that some nutrients may be important in the promotion of cancer. However, the fine dividing line between effects on initiation or on promotion, so clearly shown in the mouse two-stage skin cancer model, is not so clear as yet in models used for studies in nutritional carcinogenesis. The animal models for these studies have been primarily rats, mice and hamsters. These have shown that nutrients which appear to have promotion activity are zinc deficiency and 13-cis-retinoic acid for the esophagus; vitamin A deficiency and lipotrope deficiency for the forestomach, unsaturated fat and vitamin A deficiency for liver and colon, lipotrope deficiency for the liver; selenium for the liver. It is probably more correct at this early stage of investigation to consider the effects of nutrients acting either during the time of exposure to the carcinogen, or, after such exposure and when no detectable carcinogen is found in the animals tissues, rather than as promoters in the strict sense.

Topics: Animals; Ascorbic Acid; Carcinogens; Cocarcinogenesis; Colonic Neoplasms; Cricetinae; Diet; Disease Models, Animal; Esophageal Neoplasms; Gastrointestinal Neoplasms; Liver Neoplasms; Mice; Neoplasms, Experimental; Pancreatic Neoplasms; Rats; Stomach Neoplasms; Zinc

Topics: Aflatoxins; Amaranth Dye; Animals; Ascorbic Acid; Azo Compounds; Cocarcinogenesis; Liver Neoplasms; Male; Rats; Vitamin A