© 1996 Oxford University Press
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Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-ras gene than in control non-transgenic mice
1Department of Pharmacology, School of Medicine, Keio University Shinjuku-ku, Tokyo 160
2Central Institute for Experimental Animals Kawasaki, Kanagawa 216
3Biological Safety Research Center, National Institute of Health Sciences Setagaya-ku, Tokyo 158
4Laboratory Animal Science and Toxicology Laboratories, Sankyo Co. Ltd Fukuroi, Shizuoka 437
5Safety Research Laboratories, Yamanouchi Pharmaceutical Co. Ltd Itabashi-ku, Tokyo 170
6Preliminary Drug Evaluation Laboratory, Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd Gotemba, Shizuoka 412
7Preclinical Research Laboratories Inc. Kawasaki, Kanagawa 216, Japan
8To whom correspondence should be addressed
In this study, we investigated the carcinogenic response of transgenic mice carrying the human prototype c-Ha-ras gene, namely Tg rasH2/CB6F1 mice, to various genotoxic carcinogens and compared it with that of control non-transgenic CB6F1 mice (non-Tg mice). The present studies were conducted as the first step in the evaluation of the Tg rasH2/CB6F1 mouse as a model for the rapid carcinogenicity testing system. Short-term (
6 months) rapid carcinogenicity tests of various genotoxic carcinogens, 4-nitroquinoline-1-oxide, cyclophosphamide, N, N-diethyl-nitrosamine, N-methyl-N-nitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine and methylazoxymethanol, revealed that Tg rasH2/CB6F1 mice are more susceptible to these genotoxic carcinogens than control non-Tg mice. Tg rasH2/CB6F1 mice developed tumors more rapidly compared with non-Tg mice. Malignant tumors were observed only in the carcinogen-treated Tg rasH2/CB6F1 mice, but not in non-Tg mice treated with the same carcinogens. Each carcinogen induced tumors in corresponding target tissues of the Tg rasH2/CB6F1 mice. Only a very few lung adenomas but no other tumors were seen as spontaneous tumors during the 6 months of carcino-genicity tests. These results demonstrate that more rapid onset and higher incidence of more malignant tumors can be expected with high probability after treatment with various genotoxic carcinogens in the Tg rasH2/CB6F1 mice than in control non-Tg mice. The Tg rasH2/CB6F1 mouse seems to be a promising candidate as an animal model for the development of a rapid carcinogenicity testing system.
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