sodium-nitrite and Carcinoma--Squamous-Cell

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

To study farm compost polluted water that may induce pharyngo-esophageal, gastric and liver carcinoma in chickens.. 280 chickens were randomized into 4 groups: experiment group 100 chickens fed with compost water + NaNO(2) by stomach tube. The other 180 were evenly randomized into 3 control groups (60 each), fed with compost water, NaNO(2) and tap water in the same way. The farm compost was prepared with corn stalks, rice straws, excreta of men and livestock. The compost water, after being nitrosified and acidified, was fed through stomach tube 5 - 7.5 ml/session, twice a week. Besides, a solution consisting of the respective formula of each group added with 3 - 4 L water with pH adjusted to 3 - 4 by 1N HCL was given ad lib to all chickens in each group for 26.5 months.. In the experiment group, there were pharyngo-esophageal carcinoma 16 (16.3%), gastric adenocarcinoma 5 (10.4%) and liver carcinoma 3 (6.3%), in contrast to none in the 3 control groups, showing significant differences (P < 0.01, P < 0.01, P < 0.05).. Successful simulation of the layout of esophageal carcinoma high morbidity area and the mimic of chicken gastric fluid strongly support our compost etiological hypothesis that the nitrosified and acidified compost water are carcinogenic, very well causing esophageal, gastric and liver carcinoma.

Topics: Adenocarcinoma; Animals; Carcinoma, Squamous Cell; Chickens; Esophageal Neoplasms; Feces; Female; Liver Neoplasms; Male; Pharyngeal Neoplasms; Random Allocation; Sewage; Sodium Nitrite; Stomach Neoplasms; Water Pollution, Chemical

The effects of sodium nitrite (NaNO2), in combination with one of three antioxidants, tert-butylhydroquinone (TBHQ), alpha-tocopherol (alpha-Toc) and propyl gallate (PG), on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) stomach carcinogenesis were investigated in F344 rats. Groups of 15 male rats were treated with an intragastric dose of 150 mg/kg body weight of MNNG, and starting 1 week later, were treated with 0.5% TBHQ, 1% alpha-Toc, 1% PG or basal diet with or without 0.2% NaNO2 in their drinking water until they were killed at the end of week 36. Macroscopically, in MNNG-treated animals, combined administration of alpha-Toc or PG with NaNO2 significantly increased the areas and numbers of forestomach nodules as compared with the respective antioxidant alone values. Microscopically, in MNNG-treated animals, treatment with TBHQ significantly increased the incidence and multiplicity of forestomach papillomas as compared with basal diet alone value. Combined administration of alpha-Toc with NaNO2 significantly raised the multiplicity of forestomach papillomas, with a tendency to elevation in the incidence as compared with the group given alpha-Toc alone. Incidences of forestomach moderate and/or severe hyperplasias were significantly higher in the TBHQ or PG plus NaNO2 groups than in the single compound groups. In rats without MNNG treatment, combined treatment of antioxidants with NaNO2 significantly increased the incidences of mild or moderate hyperplasia. In the glandular stomach, although the incidence of atypical hyperplasia showed a non-significant tendency for decrease with TBHQ treatment, additional administration of NaNO2 caused significant increase. These results indicate that co-administration of NaNO2 with alpha-Toc, TBHQ or PG and particularly the first, promotes forestomach carcinogenesis. Concurrent alpha-Toc, TBHQ or PG treatment with NaNO2 is likely to induce forestomach tumors in the long term.

Topics: alpha-Tocopherol; Animals; Antioxidants; Body Weight; Carcinoma, Squamous Cell; Drug Combinations; Drug Interactions; Food Preservatives; Hydroquinones; Hyperplasia; Male; Methylnitronitrosoguanidine; Papilloma; Propyl Gallate; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach Neoplasms

The effects of combined treatment with NaNO2 and phenolic compounds on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) stomach carcinogenesis were investigated in F344 rats. In the first experiment, groups of 15-20 male rats were treated with an intragastric dose of 150 mg/kg body weight of MNNG, and starting 1 wk later, were given 2.0% butylated hydroxyanisole, 0.8% catechol, 2.0% 3-methoxycatechol or basal diet either alone or in combination with 0.2% NaNO2 in the drinking water until they were killed at week 52. All three antioxidants significantly enhanced forestomach carcinogenesis without any effect of additional NaNO2 treatment. However, in the absence of MNNG pretreatment, the grade of forestomach hyperplasia in the catechol and 3-methoxycatechol groups was significantly increased by the combined treatment with NaNO2. In a second experiment, the combined effects of various phenolic compounds and NaNO2 on cell proliferation in the upper digestive tract were examined. Groups of 5 rats were given one of 24 phenolic compounds or basal diet either alone or in combination with 0.3% NaNO2 for 4 weeks and then killed. Particularly strong enhancing effects in terms of thickness of the forestomach mucosa were seen with t-butylhydroquinone (TBHQ), catechol, gallic acid, 1,2,4-benzenetriol, dl-3-(3,4-dihydroxyphenyl)-alanine and hydroquinone in combination with NaNO2. In the glandular stomach, similar enhancing effects were evident in 11 cases, and in the esophagus with phenol, TBHQ and gallic acid. These results demonstrate that NaNO2 can augment cell proliferation induced in the stomach epithelium by various phenolic compounds.

Topics: Animals; Butylated Hydroxyanisole; Carcinoma, Squamous Cell; Catechols; Cell Division; Hyperplasia; Male; Methylnitronitrosoguanidine; Phenols; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach; Stomach 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

Effects of simultaneous treatment with NaNO2 and butylated hydroxyanisole, catechol, or 3-methoxycatechol were examined in a rat multiorgan carcinogenesis model. Groups of 15 animals were given a single i.p. injection of 100 mg/kg of body weight diethylnitrosamine, 4 i.p. injections of 20 mg/kg of body weight N-methylnitrosourea, 4 s.c. injections of 40 mg/kg of body weight dimethylhydrazine, p.o. treatment with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for the first 2 weeks and p.o. treatment with 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine in the drinking water for the next 2 weeks of the initial 4-week initiation period. Starting 3 days after the completion of these carcinogen treatments, animals were given diets containing 2% butylated hydroxyanisole, 0.8% catechol, 2% 3-methoxycatechol, or basal diet either alone or in combination with 0.3% sodium nitrite until week 28, when complete autopsy was performed. Histological examination showed that NaNO2 strongly enhanced development of forestomach lesions but inhibited that of glandular stomach lesions in rats simultaneously given catechol or 3-methoxycatechol with or without prior carcinogen exposure. 3-Methoxycatechol promoted esophageal carcinogenesis either with or without NaNO2, but promoting effects of catechol were evident only in the presence of NaNO2. In addition, treatment with NaNO2 after carcinogen exposure enhanced forestomach carcinogenesis. These results indicate that NaNO2 can modify phenolic antioxidant-induced cell proliferation and/or carcinogenesis, particularly in the upper digestive tract.

Topics: Animals; Antioxidants; Body Weight; Butylated Hydroxyanisole; Carcinoma in Situ; Carcinoma, Squamous Cell; Catechols; Cocarcinogenesis; Dimethylhydrazines; Disease Models, Animal; Drug Interactions; Eating; Epithelium; Hyperplasia; Liver; Male; Methylnitrosourea; Neoplasms, Experimental; Organ Size; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach; Stomach Neoplasms

Forestomach papilloma and carcinoma, as well as liver lesion, were induced in mice by gavaging precursors of the new nitrosamine, MAMBNA (N-3-methylbutyl-N-1-methylacetonylnitrosamine) and NaNO2. The results were-similar to those in mice and rats fed on preformed MAMBNA compound. However, the induction of such tumors by in vivo formation of MAMBNA required longer time and much larger doses. Moreover, the lesions of epithelial hyperplasia in the urinary bladder, lymphoid tumor, intestinal carcinoma and interstitial-cell tumor of the testis also developed in some of the experimental animals. This may indicate that the intragastric synthesis of MAMBNA is less effective in the production of forestomach tumors in mice.

Topics: Animals; Carcinoma, Squamous Cell; Male; Mice; Nitrosamines; Papilloma; Sodium Nitrite; Stomach Neoplasms