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PPAR Research
Volume 2008, Article ID 103167, 14 pages
http://dx.doi.org/10.1155/2008/103167
Review Article

Rat Urinary Bladder Carcinogenesis by Dual-Acting PPAR Agonists

1Molecular Toxicology, Novo Nordisk A/S, 2760 Maalov, Denmark
2Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York, York YO10 5YW, UK
3Biopharm Toxicology and Safety Pharmacology, Novo Nordisk A/S, 2760 Maalov, Denmark

Received 14 August 2008; Accepted 7 October 2008

Academic Editor: Dipak Panigrahy

Copyright © 2008 Martin B. Oleksiewicz et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Despite clinical promise, dual-acting activators of PPAR and (here termed PPAR + agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPAR is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPAR can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPAR as well as PPAR , making it plausible that the urothelial carcinogenicity of PPAR + agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPAR + agonist ragaglitazar, and the available literature about the role of PPAR and in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPAR + agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.