抄録
PPAR agonists have been developed as therapeutic agents for the treatment of lipid disorders and diabetes. However, these agents have produced tumors in rodents when tested in 2-year bioassays. PPARα agonists produce liver tumors in rats and mice and Leydig cell and pancreatic acinar tumors in rats by well-defined modes of action (MOAs). PPARγ and dual (PPARα and γ) agonists produce bladder tumors in rats, hemangiosarcomas in mice (and possibly hamsters), and mesenchymal sarcomas in rats (and less commonly in mice). Working groups have been established under the auspices of the ILSI Health and Environmental Sciences Institute (HESI) to define MOAs for these tumors. The working groups, composed of investigators from government, academia, and industry from Japan, the United States, and Europe, will plan, conduct, and interpret studies for this purpose. Among the issues to be investigated are the following. Bladder cancer in rats is thought to arise by a secondary mechanism involving alteration of urine composition leading to formation of urinary solids, with consequent urothelial cytotoxicity and regeneration. Research in rats is planned. A review of the pathology observed in the urothelial tract of monkeys and dogs is also underway to evaluate the pathogenesis (or existence) of urothelial vacuolization and hyperplasia. Investigations of hemangiosarcomas and mesenchymal sarcomas are proposed with a thorough review of pathology and pathogenesis, as both appear to arise predominantly in the subcutaneous adipose tissue.
