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Evaluation of the Eµ-pim-1 Transgenic Mouse Model for Short-Term Carcinogenicity Testing

Laboratory of Health Effects Research, Department of Carcinogenesis, Mutagenesis, and Genetics, National Institute of Public Health and the Environment, Bilthoven, The Netherlands

C. Willemien Van Der Houven Van Oordt

MGC-Department of Molecular Cell Biology, Laboratory of Molecular Carcinogenesis, Leiden University, Leiden, The Netherlands

E. Dinant Kroese

Laboratory of Health Effects Research, Department of Carcinogenesis, Mutagenesis, and Genetics, National Institute of Public Health and the Environment, Bilthoven, The Netherlands

Ilona Kryspin Sørensen

Danish Veterinary and Food Administration, Institute of Toxicology, Søborg, Denmark

Marco L. Breuer

MGC-Department of Molecular Cell Biology, Laboratory of Molecular Carcinogenesis, Leiden University, Leiden, The Netherlands

Richard D. Storer

Merck Research Laboratories, Department of Genetic Toxicology, West Point, Pennsylvania 19486, USA

The value of the chronic rodent carcinogenicity assay in adequately predicting cancer risk in humans has become a matter of debate over the past few years. Therefore, more rapid and accurate alternative tests are urgently needed. Transgenic mouse models, those harboring genetic changes that are relevant to the multistage cancer process, may provide such alternative tests. Transgenic Eµ-pim-1 mice, developed by Berns and coworkers in 1989, contain the pim-1 oncogene, which is expressed at elevated levels in their lymphoid compartments. As a result, these mice are predisposed to the development of T-cell lymphomas. Because of the low incidence of spontaneous tumors and the increased sensitivity to N-ethyl-N-nitrosourea-induced carcinogenesis, Eµ- pim-1 mice were suggested to be one of the first potential and attractive candidates to be used in short-term carcinogenicity testing. In the present article, the results from 2 recent short-term assays (with mitomycin C and x-rays) are briefly presented, together with a review of all 11 performed bioassays and their corresponding histopathologic and molecular data. The overall results allow the first evaluation of the Eµ-pim-1 mouse model with regard to its usefulness in short-term carcinogenicity testing. It has been shown that the model is primarily suitable as a sensitive short-term assay for genotoxic carcinogens that not only induce (at least) gene mutations and/or large deletions and rearrangements but that also sufficiently target the lymphoid system. However, the Eµ-pim-1 mice lack sufficient sensitivity to justify their routine use in short-term carcinogenicity testing in general.

Key Words: Cancer bioassay • lymphoma • carcinogen • genotoxic • X-irradiation • oncogenes • tumor suppressor genes

Toxicologic Pathology, Vol. 26, No. 6, 750-756 (1998)
DOI: 10.1177/019262339802600606


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