RAT CARCINOGENICITY STUDY WITH GW501516, A PPAR DELTA AGONIST.
L. E. Geiger1, W. S. Dunsford2, D. J. Lewis2, C. Brennan3, K. C. Liu3 and S. J. Newsholme1. 1Safety Assessment, GlaxoSmithKline, King of Prussia, PA, 2Safety Assessment, GlaxoSmithKline, Ware, United Kingdom and 3Huntingdon Life Sciences, Huntingdon, United Kingdom.
GW501516, a non-genotoxic PPAR? agonist, was assessed for carcinogenic potential by daily administration (oral gavage) to Han Wistar rats for a period of 104 weeks. Males were given 0, 5, 15 or 30 mg/kg/day for the first 6 weeks of the study. For the remainder of the study males were given 0, 5, 20 or 40 mg/kg/day. Females were given 0, 3, 10 or 20 mg/kg/day for the entire study. GW501516 produced test article-related neoplastic findings in multiple tissues at all doses. Increased mortality was seen with females given GW501516 at all doses and uterine endometrial adenocarcinoma contributed to death in a high proportion of these animals. Neoplasms considered test-article related occurred in the liver (hepatocellular adenoma at ? 10 mg/kg/day), urinary bladder (transitional cell carcinoma in males given 20 and 40 mg/kg/day), thyroid (follicular cell adenoma at 3 mg/kg/day and carcinoma in males at 20 mg/kg/day), tongue (squamous cell papilloma in males at 5 mg/kg/day and 40 mg/kg/day), stomach (squamous cell papilloma in males at 5 mg/kg/day and a female at 20 mg/kg/day, and carcinoma in a male at 40 mg/kg/day and a female at 3 mg/kg/day), skin (inverted squamous cell papilloma in males at 5 mg/kg/day and females at 3 or 20 mg/kg/day), Harderian glands (adenoma in males at 5 mg/kg/day and adenocarcinoma in a male at 40 mg/kg/day), testes (interstitial cell adenoma at 40 mg/kg/day), ovary (Sertoli cell adenoma at 10 mg/kg/day) and uterus (polyp and endometrial adenocarcinoma at 3 mg/kg/day). Some of the tumor types observed in this study have not been reported with either PPAR? or PPAR? agonists and may reflect tumor promotion mediated through PPAR? agonism.
