Tesaglitazar, a PPARα/γ Agonist, Induces Interstitial Mesenchymal Cell DNA Synthesis and Fibrosarcomas in Subcutaneous Tissues in Rats

Abstract

The development of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar as an oral antidiabetic was recently discontinued. Here we present tumor data from a 2-year carcinogenicity study in rats given 0.3, 1, 3, and 10 micromol/kg tesaglitazar is presented with focus on the findings of subcutaneous fibrosarcomas. To investigate the mechanism for induction of fibrosarcomas, replicative DNA synthesis (immunohistochemical detection of BrdU-labeled cells) and expression of PPARgamma (immunohistochemistry and reverse transcription-polymerase chain reaction) in subcutaneous adipose tissues was assessed in rats administered 1 or 10 micromol/kg for 2 weeks or 3 months. Poorly differentiated subcutaneous mesenchymal sarcomas with a predominant spindle cell appearance occurred at the highest dose level of 10 micromol/kg in both sexes, and these tumors were diagnosed as fibrosarcomas. The 10-micromol/kg dose was at or above the maximum tolerated dose and caused considerable cardiovascular mortality. Tesaglitazar stimulated DNA synthesis mainly in subcutaneous interstitial mesenchymal cells. The percentage of BrdU-labeled interstitial cells was increased at 1 and 10 micromol/kg after 2 weeks. The increase in DNA synthesis was still significant at the end of the 12-week treatment at 10 mumol/kg, the dose producing fibrosarcoma. However, at 1 micromol/kg, a dose below the no-observed-effect level for fibrosarcoma, the level of DNA synthesis was similar to control levels at 12 weeks. Immunohistochemical analyses showed no detectable PPARgamma protein in the majority of BrdU-labeled interstitial mesenchymal cells in white and brown fat. This indicates that stimulation of DNA synthesis is not mediated via direct activation of PPARgamma in these cells. The results suggest that the induction of rat fibrosarcoma by tesaglitazar, at exposures 100-fold above the human therapeutic exposure, may involve proliferation of undifferentiated mesenchymal cells in subcutaneous tissues.

Commentary on “Evaluation of Possible Carcinogenic Risk to Humans Based on Liver Tumors in Rodent Assays

“…Morphologic changes in adipose tissue include proliferation of mesenchymal cells and fibrosis in adipose tissue (Long et al 2009;Hellmold et al 2007;Herman et al 2002;Tannehill-Greg et al 2007). These proliferative changes may be associated with later development of sarcomas in rats, but association is not consistent by compound and/or doses.…”

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

“…Mechanistic studies for hemangiosarcoma by a PPAR γ agonist and fibrosarcoma induced by a PPAR γ or dual agonist have recently been reported 21,22 . MOA and the human relevance of PPAR α agonist-induced rodent tumors were previously investigated by the ILSI-HESI, and results of this investigation were published 23 .…”

Proliferative and Molecular Effects of the Dual PPARα/γ Agonist Tesaglitazar in Rat Adipose Tissues: Relevance for Induction of Fibrosarcoma

“…Fibrosarcoma is a malignant tumor that arises in soft tissues (i.e., muscle, connective tissues, blood vessels, joints, and adipose tissue). In an initial investigative study, we observed a proliferative effect on interstitial mesenchymal cells in white and brown adipose tissue at the high dose (10 mmol/ kg) that was sustained for at least 12 weeks (Hellmold et al 2007). …”

“…We have previously reported that tesaglitazar at the dose of 10 mmol/kg induced subcutaneous mesenchymal tumors in rats that were classified as fibrosarcomas (Hellmold et al 2007). Fibrosarcoma is a malignant tumor that arises in soft tissues (i.e., muscle, connective tissues, blood vessels, joints, and adipose tissue).…”