Evaluation of the E mu-pim-1 transgenic mouse model for short-term carcinogenicity testing

The value of the chronic rodent carcinogenicity assay in adequately predict ing cancer risk in humans has become a matter of debate over the past few y ears. Therefore, more rapid and accurate alternative tests are urgently nee ded. Transgenic mouse models, those harboring genetic changes that are rele vant to the multistage cancer process, may provide such alternative tests. Transgenic E mu-pim-1 mice, developed by Berns and coworkers in 1989, conta in the pim-1 oncogene, which is expressed at elevated levels in their lymph oid compartments. As a result, these mice are predisposed to the developmen t of T-cell lymphomas. Because of the low incidence of spontaneous tumors a nd the increased sensitivity to N-ethyl-N-nitrosourea-induced carcinogenesi s, E mu-pim-1 mice were suggested to be one of the first potential and attr active candidates to be used in short-term carcinogenicity testing. In the present article, the results from 2 recent short-term assays (with mitomyci n C and x-rays) are briefly presented, together with a review of all 11 per formed bioassays and their corresponding histopathologic and molecular data . The overall results allow the first evaluation of the E mu-pim-1 mouse mo del with regard to its usefulness in short-term carcinogenicity testing. It has been shown that the model is primarily suitable as a sensitive short-t erm assay for genotoxic carcinogens that not only induce (at least) gene mu tations and/or large deletions and rearrangements but that also sufficientl y target the lymphoid system. However, the E mu-pim-1 mice lack sufficient sensitivity to justify their routine use in short-term carcinogenicity test ing in general.