Toxicological Sciences 68, 226-236 (2002)
Copyright © 2002 by the Society of Toxicology
SAFETY EVALUATION |
Rodent Carcinogenicity with the Thiazolidinedione Antidiabetic Agent Troglitazone
* Pfizer Global Research and Development, Pfizer, Inc., Ann Arbor, Michigan 48105; and
Medicinal Safety Research Laboratories, Sankyo Co., Ltd., Shizuoka 437-0065, Japan
Carcinogenic potential of the thiazolidinedione antidiabetic troglitazone was assessed in 104-week studies in mice and rats. Mice were given 50, 400, or 800 mg/kg, male rats 100, 400, or 800 mg/kg, and female rats 25, 50, or 200 mg/kg. Vehicle and placebo controls were included. Survival was significantly decreased in both sexes of both species at high doses, but was adequate for valid evaluation of carcinogenicity. Hypertrophy and hyperplasia of brown adipose tissue was observed in both species at all doses, and fatty change and hypocellularity of bone marrow was noted in mice at all doses and in female rats at 50 and 200 mg/kg. Hepatocellular vacuolation was observed in mice at 400 and 800 mg/kg, and centrilobular hepatocellular hypertrophy occurred in rats at 
200 mg/kg. Ventricular dilatation, myocardial fibrosis, and atrial myocyte karyomegaly in male rats at 400 and 800 mg/kg and female rats at all doses were morphologically similar to spontaneous lesions, but incidence and severity were increased compared with controls. In mice, the incidence of hemangiosarcoma was increased in females at 400 mg/kg and in both sexes at 800 mg/kg. The incidence of hepatocellular carcinoma was increased in female mice at 800 mg/kg. Troglitazone exposure [AUC(0–24)] at the lowest dose associated with increased tumor incidence in mice was 16 times human therapeutic exposure at 400 mg daily. No tumors of any type were increased in rats at exposures up to 47 times therapeutic exposure.
Key Words: thiazolidinedione; troglitazone; Rezulin®; Noscal®; Romozin®; rodent carcinogenicity; hemangiosarcoma; hepatocellular carcinoma.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Fujimoto, K. Kumagai, K. Ito, S. Arakawa, Y. Ando, S.-i. Oda, T. Yamoto, and S. Manabe Sensitivity of Liver Injury in Heterozygous Sod2 Knockout Mice Treated with Troglitazone or Acetaminophen Toxicol Pathol, February 1, 2009; 37(2): 193 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ohnishi, L. L. Arnold, N. M. Clark, J. L. Wisecarver, and S. M. Cohen Comparison of Endothelial Cell Proliferation in Normal Liver and Adipose Tissue in B6C3F1 Mice, F344 Rats, and Humans Toxicol Pathol, December 1, 2007; 35(7): 904 - 909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Hardisty, M. R. Elwell, H. Ernst, P. Greaves, H. Kolenda-Roberts, D. E. Malarkey, P. C. Mann, and P. A. Tellier Histopathology Of Hemangiosarcomas in Mice and Hamsters and Liposarcomas/Fibrosarcomas in Rats Associated with PPAR Agonists Toxicol Pathol, December 1, 2007; 35(7): 928 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hellmold, H. Zhang, U. Andersson, B. Blomgren, T. Holland, A.-L. Berg, M. Elebring, N. Sjogren, K. Bamberg, B. Dahl, et al. Tesaglitazar, a PPAR{alpha}/{gamma} Agonist, Induces Interstitial Mesenchymal Cell DNA Synthesis and Fibrosarcomas in Subcutaneous Tissues in Rats Toxicol. Sci., July 1, 2007; 98(1): 63 - 74. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M.K. Ong, C. Latchoumycandane, and U. A. Boelsterli Troglitazone-Induced Hepatic Necrosis in an Animal Model of Silent Genetic Mitochondrial Abnormalities Toxicol. Sci., May 1, 2007; 97(1): 205 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yoshizawa, G. E. Kissling, J. A. Johnson, N. P. Clayton, N. D. Flagler, and A. Nyska Chemical-Induced Atrial Thrombosis in NTP Rodent Studies Toxicol Pathol, August 1, 2005; 33(5): 517 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Aleo, C. M. Doshna, and K. A. Navetta Ciglitazone-Induced Lenticular Opacities in Rats: In Vivo and Whole Lens Explant Culture Evaluation J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 1027 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Poulet, M. R. Berardi, W. Halliwell, B. Hartman, C. Auletta, and H. Bolte Development of Hibernomas in Rats Dosed with Phentolamine Mesylate During the 24-Month Carcinogenicity Study Toxicol Pathol, August 1, 2004; 32(5): 558 - 566. [Abstract] [PDF]
|
|
|
|
 |
|
 P. K. Chatterjee, N. S.A Patel, S. Cuzzocrea, P. A.J Brown, K. N Stewart, H. Mota-Filipe, D. Britti, W. Eberhardt, J. Pfeilschifter, and C. Thiemermann The cyclopentenone prostaglandin 15-deoxy-{Delta}12,14-prostaglandin J2 ameliorates ischemic acute renal failure Cardiovasc Res, February 15, 2004; 61(3): 630 - 643. [Abstract] [Full Text] [PDF]
|
|