title: Tesaglitazar, a dual PPAR-α/γ agonist, hamster carcinogenicity, investigative animal and clinical studies.
abstract: Tesaglitazar was developed as a dual peroxisome proliferator-activated receptor (PPARα/γ). To support the clinical program, a hamster carcinogenicity study was performed. The only neoplastic findings possibly related to treatment with tesaglitazar were low incidences of hemangioma and hemangiosarcoma in the liver of male animals. A high-power, two-year investigative study with interim necropsies was performed to further elucidate these findings. Treatment with tesaglitazar resulted in changes typical for exaggerated PPARα pharmacology in rodents, such as hepatocellular hypertrophy and hepatocellular carcinoma, but not an increased frequency of hemangiosarcomas. At the highest dose level, there was an increased incidence of sinusoidal dilatation and hemangiomas. No increased endothelial cell (EC) proliferation was detected in vivo, which was confirmed by in vitro administration to ECs. Immunohistochemistry and gene expression analyses indicated increased cellular stress and vascular endothelial growth factor (VEGF) expression in the liver, which may have contributed to the sinusoidal dilatation. A two-fold increase in the level of circulating VEGF was detected in the hamster at all dose levels, whereas no effect on VEGF was observed in patients treated with tesaglitazar. In conclusion, investigations have demonstrated that tesaglitazar does not produce hemangiosarcomas in hamster despite a slight effect on vascular morphology in the liver.
authors: AstraZeneca R&D, Mölndal, Sweden.
authors: Per
authors: P
authors: Lindblom
authors: Anna-Lena
authors: AL
authors: Berg
authors: Hui
authors: H
authors: Zhang
authors: Rolf
authors: R
authors: Westerberg
authors: Jonathan
authors: J
authors: Tugwood
authors: Hanna
authors: H
authors: Lundgren
authors: Maritha
authors: M
authors: Marcusson-Ståhl
authors: Niclas
authors: N
authors: Sjögren
authors: Bo
authors: B
authors: Blomgren
authors: Peter
authors: P
authors: Öhman
authors: Inger
authors: I
authors: Skånberg
authors: John
authors: J
authors: Evans
authors: Heike
authors: H
authors: Hellmold
mesh_terms: D000476:Alkanesulfonates / Q000633:toxicity*; D000818:Animals; D019540:Area Under Curve; D015197:Carcinogenicity Tests; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D005260:Female; D020869:Gene Expression Profiling; D006391:Hemangioma / Q000139:chemically induced; D006394:Hemangiosarcoma / Q000139:chemically induced; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010666:Phenylpropionates / Q000633:toxicity*; D018709:Statistics, Nonparametric; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000476:Alkanesulfonates; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D042461:Vascular Endothelial Growth Factor A; C501413:tesaglitazar