Rodent Carcinogenicity with the Thiazolidinedione Antidiabetic Agent Troglitazone

Abstract

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 > or = 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.

Troglitazone and liver injury

“…Increased incidence of liver hemangiosarcomas and hepatocellular carcinomas occurred with TGZ in mice at 20 and 40 times the human therapeutic dose. 41 No tumors of any type were induced by TGZ in rats at 40 times or in monkeys at 160 times the human therapeutic dose. [41][42][43] Furthermore, TGZ was neither mutagenic in bacteria nor clastogenic in bone marrow of mice or rats, indicating no genotoxic risk.…”

“…41 No tumors of any type were induced by TGZ in rats at 40 times or in monkeys at 160 times the human therapeutic dose. [41][42][43] Furthermore, TGZ was neither mutagenic in bacteria nor clastogenic in bone marrow of mice or rats, indicating no genotoxic risk. 152 In addition, none of the analyzed 165 tumors in mice had inactivating p53 mutations, and fewer than 5% had mutations of Ki-and Ha-ras oncogenes.…”

“…[36][37][38] The liver injury associated with TGZ is idiosyncratic 39 ; it is unpredictable, neither timenor dose-dependent, 40 and cannot be reproduced in animals. [41][42][43] Although the mechanism of liver injury induced by TGZ is believed to be a metabolic idiosyncrasy (nonimmunological), 39 some of the case reports had histological evidences suggestive of an immunological reaction 16,25,27,36 or responded favorably to corticosteroids. 28,38 One of these patients promptly developed a similar destructive, granulomatous cholangitis when treated subsequently with rosiglitazone, a related PPAR-␥ agonist, 38 supporting the diagnosis of an immunological reaction and suggesting a class effect.…”

“…16 None of the apoptotic features have been reported in the liver or other tissues, after TGZ treatment, in the other 19 case reports, 21-34,36-38 or in animal studies. 41,43,70,76,77,110 The presence of acidophilic bodies, in the absence of any typical pathological evidence of apoptosis, is mentioned in a few case reports in association with severe necrosis and inflammation. 25,27,35 The speculation that TGZ-induced liver injury without increased serum aminotransferases, bilirubin, or alkaline phosphatase 3 is not supported by the following findings: i) TGZ did not induce liver apoptosis in animals, 43,70,76,77,110 and ii) stimulation of hepatocyte apoptosis by bile acids, TNF-␣/actinomycin or concanavalin A in mice is not silent because it resulted in substantial increases in serum ALT.…”

Current Status of Carcinogenicity Assessment of Peroxisome Proliferator-Activated Receptor Agonists by the US FDA and a Mode-of-Action Approach to the Carcinogenic Potential

“…Common tumor findings in rodent carcinogenicity studies of PPAR agonists are hemangioma/hemangiosarcoma, urinary bladder/renal pelvic tumors, and lipoma/liposarcoma. 1) Hemangioma/hemangiosarcoma: These tumors were observed in multiple organs such as the spleen, liver, skin and adipose tissues of male and female CD-1 and B6C3F1 mice and hamsters treated with 8/12 PPAR agonists (4 γ agonists including troglitazone 11,12 and 4 dual agonists). It has also been reported that hemangiomatous hyperplasia and angiectasia were observed in rodent and non-rodent species treated with the other compounds of the same class.…”