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ToxSci Advance Access published online on April 27, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm094
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Tesaglitazar, a PPAR{alpha}/{gamma} Agonist, Induces Interstitial Mesenchymal Cell DNA Synthesis and Fibrosarcomas in Subcutaneous Tissues in Rats

Heike Hellmold*,1, Hui Zhang*, Ulf Andersson*, Bo Blomgren*, Tom Holland{dagger}, Anna-Lena Berg*, Marie Elebring{ddagger}, Niclas Sjögren{ddagger}, Krister Bamberg§, Björn Dahl, Rolf Westerberg*, Birgitta Dillner*, Jonathan Tugwood{dagger}, Ruth Roberts{dagger}, Erik Lundholm||, German Camejo|||, Inger Skånberg* and John Evans{dagger}

* AstraZeneca R&D Södertälje, Safety Assessment, Södertälje, Sweden {dagger} AstraZeneca R&D Alderley Park, Safety Assessment, Macclesfield, United Kingdom {ddagger} AstraZeneca R&D Mölndal, DMPK & Bioanalytical Chemistry, Mölndal, Sweden § AstraZeneca R&D Mölndal, Molecular Pharmacology, Mölndal, Sweden AstraZeneca R&D Mölndal, Toxicology Science, Mölndal, Sweden || AstraZeneca R&D Mölndal, Integrative Pharmacology, Mölndal, Sweden ||| AstraZeneca R&D Mölndal, Scientific Advisory Group, Mölndal, Sweden

1 To whom correspondence should be addressed at: Molecular Toxicology B681, AstraZeneca R&D Södertälje, 151 85 Södertälje, Sweden. Tel: +46-8-55254232, Fax: +46-8-55258823. E-mail: heike.hellmold{at}astrazeneca.com

Received December 30, 2006; revision received April 17, 2007; accepted April 17, 2007


  Abstract

The development of the dual PPAR{alpha}/{gamma} agonist tesaglitazar as an oral antidiabetic was recently discontinued. Here we present tumour data from a 2-year carcinogenicity study in rats given 0.3, 1, 3 and 10 µmol/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 PPAR{gamma} (immunohistochemistry and RT-PCR) in subcutaneous adipose tissues was assessed in rats administered 1 or 10 µmol/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 µmol/kg in both sexes and these tumours were diagnosed as fibrosarcomas. The 10 µmol/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 µmol/kg after 2 weeks. The increase in DNA synthesis was still significant at the end of the 12-weeks treatment at 10 µmol/kg, the dose producing fibrosarcoma. However, at 1 µmol/kg, a dose below the no observed effect level (NOEL) for fibrosarcoma, the level of DNA synthesis was similar to control levels at 12 weeks. Immunohistochemical analyses showed no detectable PPAR{gamma} 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 PPAR{gamma} 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.

Key Words: PPAR; tesaglitazar; fibrosarcoma; cell proliferation; DNA synthesis.


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