Current Status of Carcinogenicity Assessment of Peroxisome Proliferator-Activated Receptor Agonists by the US FDA and a Mode-of-Action Approach to the Carcinogenic Potential

Abstract

Since it has been revealed that PPAR (Peroxisome Proliferator-Activated Receptor) agonists induce various types of tumors in various organs and tissues in rodents, the US FDA has been requesting performance of 2-year carcinogenicity studies prior to initiation of clinical studies longer than 6 months, and does not accept data from alternative carcinogenicity studies such as those in transgenic mouse models, which are recommended in the ICH S1B guideline. In general, although PPAR agonists do not possess genotoxic potential, the tissue distribution of PPAR does correspond to the target organs and tissues of tumor induction, and carcinogenic potential is closely correlated with potency of PPAR agonistic effect. It is thus not possible to rule out the possibility that the mode of action (MOA) of tumorigenesis by PPAR agonists is receptor- mediated. The ILSI-HESI PPAR Agonist Project was organized and is currently conducting collaborative research to elucidate the MOA of PPAR agonist-induced carcinogenicity (for urinary bladder tumor, hemangioma/hemangiosarcoma, and fibrosarcoma/liposarcoma) and to evaluate the human relevance of the results of rodent bioassays of PPAR agonists. In this paper, carcinogenicity data on PPAR agonists disclosed by the CDER of the US FDA and current activities of the ILSI-HESI PPAR Agonist Project are explained, and the possible usefulness of transgenic mouse models, especially rasH2 mice, for assessing carcinogenic potential and the MOA of PPAR agonists are addressed.