Journal Article

Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-<i>ras</i> gene than in control non-transgenic mice

Satoshi Yamamoto, Kunitoshi Mitsumori, Yukio Kodama, Naochika Matsunuma, Sunao Manabe, Hideaki Okamiya, Hiroshi Suzuki, Tatsuya Fukuda, Yoshiyuki Sakamaki, Masao Sunaga, Gakushi Nomura, Kyoji Hioki, Shigeharu Wakana, Tatsuji Nomura and Yuzo Hayashi

in Carcinogenesis

Volume 17, issue 11, pages 2455-2461
Published in print November 1996 | ISSN: 0143-3334
Published online November 1996 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.11.2455
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

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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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Subjects: Clinical Cytogenetics and Molecular Genetics

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