RAPID INDUCTION OF MORE MALIGNANT-TUMORS BY VARIOUS GENOTOXIC CARCINOGENS IN TRANSGENIC MICE HARBORING A HUMAN PROTOTYPE C-HA-RAS GENE THANIN CONTROL NONTRANSGENIC MICE

In this study, we investigated the carcinogenic response of transgenic mice carrying the human prototype c-aa-ras gene, namely Tg rasH2/CB6F 1 mice, to various genotoxic carcinogens and compared it with that of control nontransgenic CB6F1 mice (non-Tg mice), The present studies we re 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 (less than or equal to 6 months) rapid carcinogenicity tests of v arious genotoxic carcinogens, 4-nitroquinoline-1-oxide, cyclophosphami de, N,N-diethylnitrosamine, N-methyl-N-nitrosourea, N-methyl-N'-nitro- N-nitrosoguanidine and methylazoxymethanol, revealed that Tg rasH2/CB6 F1 mice are more susceptible to these genotoxic carcinogens than contr ol non-Tg mice. Tg rasH2/CB6F1 mice developed tumors more rapidly comp ared with non-Tg mice, Malignant tumors were observed only in the carc inogen-treated Tg rasH2/CB6F1 mice, but not in non-Tg mice treated wit h the same carcinogens, Each carcinogen induced tumors in correspondin g target tissues of the Tg rasH2/CB6F1 mice, Only a very few lung aden omas but no other tumors were seen as spontaneous tumors during the 6 months of carcinogenicity tests, These results demonstrate that more r apid onset and higher incidence of more malignant tumors can be expect ed with high probability after treatment with various genotoxic carcin ogens in the Tg rasH2/CB6F1 mice than in control non-Tg mice. The Tg r asH2/CB6F1 mouse seems to be a promising candidate as an animal model for the development of a rapid carcinogenicity testing system.