K6/ODC transgenic mice as a sensitive model for carcinogen identification

Ornithine decarboxylase (ODC), an important enzyme in the polyamine biosynt hetic pathway, is aberrantly regulated in many epithelial tumors of rodents and humans. In murine skin, it has been shown that ODC overexpression prov ides a sufficient condition for tumor promotion. Therefore, we hypothesized that K6/ODC transgenic mice in which ODC overexpression was targeted to ha ir follicle keratinocytes might provide a sensitive model for identifying g enotoxic carcinogens. Ten known carcinogens or noncarcinogens have been tes ted in the model so far and results are highly concordant with 2 year roden t bioassays (100% concordant). More importantly, each of two chemicals test ed that is recognized as a human carcinogen was identified as a carcinogen in K6/ODC transgenic mice. In addition, 7,12-dimethylbenz(a)anthracene (DMB A) dose response studies indicated that even at a very low dose, 2 nmol, a high percentage of mice (50%) had already developed tumors 8 weeks after tr eatment. We conclude that the K6/ODC transgenic mouse model is very sensiti ve to topical application of genotoxic carcinogens and could therefore be a useful mouse model for carcinogen identification and chemical risk assessm ent. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.