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CB6F1-rasH2 Mouse: Overview of Available Data

Central Institute for Experimental Animals, Kawasaki, 216-0001, Japan, usui{at}ciea.or.jp

Mamoru Mutai

Mitsubishi-Tokyo Pharmaceuticals, Inc., Yokohama, 227-0033, Japan

Shigeru Hisada

Teikoku Hormone Mfg. Co. Ltd., Kawasaki, 213-8522, Japan

Masaya Takoaka

Sankyo Co. Ltd., Shizuoka, 437-0065, Japan

Keith A. Soper

Merck & Co., Inc., West Point, Pennsylvania 19486, USA

Bruce Mccullough

Aventis Pharmaceuticals, Bridgewater, New Jersey, 08807-0800, USA

Carl Alden

Millenium Pharmaceuticals, Boston, MA, USA

This article presents data from short-term carcinogenicity studies of compounds tested in the CB6F1-rasH2 transgenic mouse as part of the International Life Sciences Institutes' (ILSI) Health and Environmental Sciences' (HESI) Alternative to Carcinogenicity Testing (ACT) project. Additionally, data from other studies that were not conducted as part of the ILSI program, but used comparable or slightly modifi ed protocols, are included here. A signifi cant number (3 of 4) of the genotoxic carcinogens tested were positive in the rasH2 mouse; the other compound was equivocally positive. The positive control, N-Methyl-N-nitrosurea (MNU), gave reproducible responses across all participating laboratories with tumors noted at multiple sites in the animal. The immunosuppressive human carcinogen, Cyclosporin A, was equivocal. Two hormones that are human tumorigens, Diethylstilbestrol and 17β-Estradiol, gave positive and negative results, respectively. Of the twelve additional compounds tested that are classifi ed as non-genotoxic rodent carcinogens and putative human non-carcinogens, only the two peroxisome proliferators (clofi brate and diethylhexylphthalate(DEHP)) produced a positive response (liver effects). The three non-genotoxic non-carcinogens that were tested also gave negative responses in the rasH2 model. This result provides confi dence that the model is likely to have a low false-positive rate.

Key Words: cHa ras proto-oncogene • transgenic mouse • bioassay • short-term • 26-Weeks • alternatives • carcinogenicity testing.

Toxicologic Pathology, Vol. 29, No. 1 suppl, 90-108 (2001)
DOI: 10.1080/019262301753178500


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