Possible mechanism on enhanced carcinogenesis of genotoxic carcinogens and unsolved mechanisms on lesser carcinogenic susceptibility to some carcinogens in rasH2 mice

Abstract

The rasH2 mice are hemizygous transgenic mice carrying the human prototype c-Ha-ras gene with its own promoter region, and have been used in 6-month short-term carcinogenicity tests for pharmaceutical drugs in accordance with the recommendation of the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH). Based on the validation studies, it has been recognized that they are very susceptible to genotoxic carcinogens. To elucidate the mechanism of the enhanced carcinogenesis, spontaneous and chemically induced tumors in rasH2 mice have been subjected to molecular analyses, but the results have thus far been equivocal. This article focuses on the possible molecular mechanism of enhanced carcinogenesis in rasH2 mice, based on the results of a search in the literature. In addition, there are several reports suggesting lesser carcinogenic susceptibility of rasH2 mice to some carcinogens: Malignant lymphomas were induced by treatment with phenolphthalein in heterozygous p53 knockout mice, but not in rasH2 mice, and ethinylestradiol, uterine tumor promoter, resulted in depression of uterine proliferative lesions in rasH2 mice. In this review, the possible mechanisms of why rasH2 mice were less sensitive for these carcinogens are also discussed.