The research is there and I have seen it however the dosages they were given were like 40x what we dose at 5/mg per day.
They probably had more GW501516 in the blood than actual blood.
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 PPARδ 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 PPARα or PPARγ agonists and may reflect tumor promotion mediated through PPARδ agonism. 896 MOUSE CARCINOGENICITY STUDY WITH GW501516, A PPAR DELTA AGONIST. S. J. Newsholme1, W. S. Dunsford2, T. Brodie2, C. Brennan3, M. Brown3 and L. E. Geiger1. 1Safety Assessment, GlaxoSmithKline, King of Prussia, PA, 2Safety Assessment, GlaxoSmithKline, Ware, United Kingdom and 3Huntingdon Life Sciences, Huntingdon, United Kingdom.
GW501516, a non-genotoxic PPARδ agonist, was assessed for carcinogenic potential by daily administration (oral gavage) to CD1 mice for 104 weeks at doses of 0, 10, 30, 60 or 80 mg/kg/day. Survival was decreased at doses ≥ 30 mg/kg/day. Neoplasms considered related to test article occurred in liver (hepatocellular carcinoma at ≥ 30 mg/kg/day and adenoma at ≥ 10 mg/kg/day), stomach (squamous cell carcinoma at all doses) and combined squamous cell tumours at all doses (squamous cell papilloma and carcinoma, and keratoacanthoma). There have been conflicting reports in the literature regarding the effects of PPARδ on epithelial cell proliferation. The results of this study demonstrate an increase in proliferation in certain epithelial cell populations, but do not support a role for PPARδ in colon carcinogenesis. The squamous cell tumors observed in this study have not been reported with either PPARα or PPARγ agonists and may reflect tumor promotion mediated through PPARδ agonism. 897 LIGAND-ACTIVATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-BETA/DELTA INHIBITS THE PROLIFERATION OF HUMAN PANCREATIC CANCER CELLS. J. D. Coleman and J. Vanden Heuvel. Pennsylvania State University, State College, PA. Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States, owing to its extremely aggressive nature and resistance to chemotherapeutic regimens. In the present study we report that activation of the nuclear receptor PPAR-β/δ decreases human pancreatic cancer cell growth. The proliferation of three human pancreatic cancer cell lines - BxPc-3 (high COX-2 expression), Panc- 1 and MIA PaCa-2 (COX-2 negative) - was inhibited by the PPAR-α and PPAR-γ- selective agonists, Ciprofibrate and Rosiglitazone, respectively, but most effectively by the PPAR-β/δ-selective agonist GW501516. Treatment of pancreatic cancer cells with a PPAR-β/δ-selective agonist significantly decreased mRNA levels of the cell cycle regulatory gene, cyclin D2, compared with control cells at 24 hours. Furthermore, GW501516 treatment significantly reduced the TNF-α-induced mRNA expression of pro-inflammatory mediators in MIA PaCa-2 and BxPc-3 cells, several of which are known to influence cell proliferation. PPAR-β/δ interacts with NF-κB p50 subunit, although this was not dependent on ligand. PPAR-β/δ is unique among the PPAR isoforms in its association with the transcriptional repressor, Bcl-6. We hypothesize that PPAR-β/δ activation results in Bcl-6 shuttling from the receptor complex to its known consensus sequence in the cyclin D2 promoter where it influences pancreatic cancer cell proliferation.
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