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Effects of Phenolic Antioxidants in Low Dose Combination on Forestomach Carcinogenesis in Rats Pretreated with N-Methyl-N'-nitro-N-nitrosoguanidine¹

First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan

The combined effects of low doses of promoters or carcinogens on two-stage forestomach carcinogenesis were examined in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine. Groups of 15 rats were given a single 150 mg/kg body weight intragastric dose of N-methyl-N'-nitro-N-nitrosoguanidine. Starting 1 week later they were fed a diet containing low doses of known forestomach promoters/carcinogens (0.5% caffeic acid, 0.2% catechol, 0.5% butylated hydroxyanisole, or 0.25% 2-tert-butyl-4-methylphenol), alone or in combination, or basal diet without antioxidant supplement for 35 weeks.

Histopathological examination revealed the incidences of forestomach squamous cell carcinomas in animals treated with N-methyl-N'-nitro-N-nitrosoguanidine followed by caffeic acid, catechol, butylated hydroxyanisole, 2-tert-butyl-4-methylphenol, and basal diet to be 27, 20, 13, 13, and 7%, respectively, whereas the incidence increased to 80% by the combined treatment with these four chemicals. The present results thus show that although the low doses of individual promoters/carcinogens did not have significant promoting activity, their combination exerted a strong enhancing influence on rat forestomach carcinogenesis. The findings indicate the importance of summation and synergism at a low dose for agents present in the human environment.

¹ Supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture; a grant from the Ministry of Health and Welfare of Japan; and a grant from the Society for Promotion of Pathology of Nagoya, Japan.

² To whom requests for reprints should be addressed, at the First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuhocho, Mizuho-ku, Nagoya 467, Japan.

Received 6/ 5/90. Accepted 11/20/90.

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