DOXORUBICIN CARDIOTOXICITY:PROTECTION BY PEROXYNITRITE

DESCRIPTION (provided by applicant): Doxorubicin is a powerful anticancer drug, the clinical utility of which is severely restricted by its cardiotoxic action. The working hypothesis of the present application (supported by preliminary data) is that (1) the doxorubicin induced myocardial depression is associated with, and is due to reactive oxygen and nitrogen species production and peroxynitrite formation within the cardiac myocytes; and (2) that pharmacological inhibition of peroxynitrite cytotoxicity can be a novel strategy to counteract anticancer drug induced myocardial depression. In this proposal, we present evidence that (1) the development of doxorubicin-induced myocardial depression is associated with the expression of iNOS and the production of peroxynitrite in the myocardium; (2) that peroxynitrite generation participates in free-radical mediated myocardial injury; (3) that peroxynitrite decomposition catalysts such as the novel proprietary compound FP15 are of cardioprotective potential in vivo and in vitro in conditions associated with peroxynitrite generation. Finally, (4) we have accumulated preliminary data showing that the peroxynitrite decomposition catalyst FP15 is of protective effect in murine models of doxorubicin-induced myocardial depression. The first aim of the study is to perform definitive in vivo studies in murine models of anticancer drug induced myocardial suppression and cardiomyopathy in order to test whether peroxynitrite decomposition catalysts can slow down or reverse the onset of the development of anticancer drug induced myocardial depression in vivo. We will establish the minimal effective dose, as well as the therapeutic window of opportunity, in an acute and a chronic model of doxorubicin cardiotoxicity. An additional aim of the study is to confirm that the compound does not interfere with the antitumor effects of doxorubicin. The results of the present application will advance our basic understanding on doxorubicin-induced cardiotoxicity and will also advance preclinical development of potent PARP inhibitors as novel therapeutic agents to counteract the cardiotoxic side effects of doxorubicin.