Promotion of colon tumors in C57BL/6J-APC(min)/+ mice by thiazolidinedione PPARgamma agonists and a structurally unrelated PPARgamma agonist.
Thiazolidinedione PPARgamma agonists (troglitazone and rosiglitazone) were previously shown to promote colon tumor formation in C57BL/6J-APC(min)/+ mice, a model for human familial adenomatous polyposis. This study was conducted to determine if another thiazolidinedione PPARgamma agonist, pioglitazone, and a PPARgamma agonist structurally unrelated to the thiazolidinedione family, NID525, (a tetrazole-substituted phenoxymethylquinolone), would also promote colon tumors in this mouse model. Mice were treated in-feed with the thiazolidinediones troglitazone (150 mg/kg/day), rosiglitazone (20 mg/kg/day), or pioglitazone (150 mg/kg/day), or with NID525 (150 mg/kg/day) for 8 weeks. An increased incidence in colon tumors compared to controls was observed for all of the thiazolidinedione-treated groups as well as the NID525-treated group. These results indicate that the tumor-promoting effect of PPARgamma agonists in the colon of C57BL/6J-APC(min)/+ mice is likely related to the pharmacological activity of this group of drugs and not the thiazolidinedione structure.
Pino
Michael V
MV
Aventis Inc, Drug Safety Evaluation, Bridgewater, New Jersey 08807, USA. pino@aventis.com
Kelley
Michael F
MF
Jayyosi
Zaid
Z
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002839:Chromans / Q000737:chemistry / Q000633:toxicity; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D017491:Genes, APC; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D000077205:Pioglitazone; D011804:Quinolines / Q000737:chemistry / Q000633:toxicity; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors; D000077154:Rosiglitazone; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000633:toxicity; D045162:Thiazolidinediones / Q000737:chemistry / Q000633:toxicity*; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors; D000077288:Troglitazone
D002273:Carcinogens; D002839:Chromans; D007004:Hypoglycemic Agents; C490813:NID525; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear; D013777:Tetrazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D000077288:Troglitazone; D000077205:Pioglitazone