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Several multikinase angiogenesis inhibitors demonstrate mitochondrial and/or cardiovascular toxicity, suggesting an on-target pharmacologic effect. To evaluate whether cardiotoxicity is directly related to vascular endothelial growth factor receptor inhibition, we investigated the effects of sunitinib, sorafenib, and pazopanib on myocardial function and structure. We used a rat model to assess myocardial effects of the inhibitors concurrently exposed to the cardiac stressor dobutamine. Echocardiographic abnormalities including premature ventricular contractions, decreases in heart rate, circumferential strain, and radial and circumferential strain rates were noted with sorafenib, but not with sunitinib or pazopanib. Ultrastructural analysis of ventricular cardiomyocytes by transmission electron microscopy revealed mitochondrial swelling, dense deposits, and matrix cavitation in rats given sunitinib and disrupted mitochondrial cristae in rats given sorafenib, but there were no effects with pazopanib. Effects on neonatal rat cardiomyocyte cultures were assessed, which identified decreases in mitochondrial membrane potential with sunitinib treatment, but not with sorafenib or pazopanib. Intracellular adenosine triphosphate depletion was observed with sunitinib and sorafenib, but not pazopanib. Our results show that cardiotoxicity is not necessarily related to a pharmacologic classwide effect of vascular endothelial growth factor receptor inhibition, and the rat myocardial structural and functional changes identified in this study may be instead a result of inhibition of other kinase pathways, the mechanism of which may be associated with mitochondrial toxicity.

Reports have implicated vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with mitochondrial injury and/or subsequent cardiovascular toxicity, suggesting an on-target pharmacologic effect by this class of promising anticancer agents. Investigative studies were performed to assess myocardiotoxicity and mitochondrial toxicity of 3 VEGFRi's (sunitinib, sorafenib and pazopanib). Mitotoxicity was evaluated in vitro using Laser Scanning Cytometry in neonatal rat ventricular myocyte cultures with endpoints including mitochondrial membrane potential (MMP), cell viability, apoptosis and ATP depletion. Cardiomyocytes were exposed with protein free concentrations of up to 4 micromolar of sunitinib, sorafenib or pazopanib for 48 hours. There were no changes in viability or apoptosis versus vehicle-treated cells. Mitochondrial membrane potential was slightly but significantly decreased with sunitinib treatment but not with sorafenib nor pazopanib. Dose-dependent intracellular ATP depletion was observed with sunitinib and sorafenib, but not with pazopanib. In separate in vivo studies, echocardiographic, histomorphologic and ultrastructural approaches were used to assess cardiotoxicity in rats concurrently exposed to the cardiac stressor dobutamine and one of the VEGFR inhibitors in rats for 21 days. Troponin I and TUNEL were also evaluated and were similar to controls. While hearts were morphologically unremarkable by routine microscopic examination, ultrastructural analysis of myocardiocytes by electron microscopy revealed mitochondrial swelling, dense deposits and matrix cavitation in 6/8 rats given sunitinib, disrupted mitochondrial cristae in 1/7 given sorafenib, but no effects with pazopanib. Echocardiographic abnormalities including premature ventricular contractions, alterations in heart rate, circumferential strain, and radial and circumferential strain rates were also noted with sorafenib, but not with sunitinib or pazopanib after dobutamine stress challenge. Our results indicate there are marked differences in the potential for myocardial toxicity and mitochondrial toxicity between VEGFR inhibitors. Since sunitinib and sorafenib have previously been shown to have differential effects on mitochondria, the mechanism of cardiac/mitochondrial injury with various VEGFRi's may not be a result of similar class-based VEGFR2 pharmacology, but instead reflect separate kinase selectivity profiles. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PR-9.

Introduction Assessing the effects of new chemical entities on cardiovascular function is an essential component of nonclinical safety evaluation. Regulatory guidelines advocate the use of telemetry to evaluate drug effects on the cardiovascular system of animal including electrocardiogram (ECG) waveforms. Currently, standard method is to place ECG electrodes subcutaneously and the ECG signals have a suboptimal signal mainly due to movement artifacts. In order to improve and optimize the ECG signal and minimize movement artifacts, a model for continuous monitoring of the ECG in conscious, unrestrained animals by placing ECG electrodes on the pericardium was evaluated.