Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γ Agonists
Joint Authors
Iversen, Lars
Egerod, Frederikke L.
Oleksiewicz, Martin B.
Southgate, Jennifer
Source
Issue
Vol. 2008, Issue 2008 (31 Dec. 2008), pp.1-14, 14 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2009-01-28
Country of Publication
Egypt
No. of Pages
14
Main Subjects
Natural & Life Sciences (Multidisciplinary)
Biology
Abstract EN
Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ 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 PPARα is invariably associated with cancer in rats and mice.
Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice.
Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology).
Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ 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.
American Psychological Association (APA)
Oleksiewicz, Martin B.& Southgate, Jennifer& Iversen, Lars& Egerod, Frederikke L.. 2009. Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γ Agonists. PPAR Research،Vol. 2008, no. 2008, pp.1-14.
https://search.emarefa.net/detail/BIM-446546
Modern Language Association (MLA)
Oleksiewicz, Martin B.…[et al.]. Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γ Agonists. PPAR Research No. 2008 (2008), pp.1-14.
https://search.emarefa.net/detail/BIM-446546
American Medical Association (AMA)
Oleksiewicz, Martin B.& Southgate, Jennifer& Iversen, Lars& Egerod, Frederikke L.. Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γ Agonists. PPAR Research. 2009. Vol. 2008, no. 2008, pp.1-14.
https://search.emarefa.net/detail/BIM-446546
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-446546