Doxorubicin cardiotoxicity:protection by peroxynitrite

描述（由申请人提供）：阿霉素是一种强效抗癌药物，其心脏毒性作用严重限制了其临床应用。本申请的工作假设（由初步数据支持）是：（1）阿霉素诱导的心肌抑制与心肌细胞内的活性氧和氮物质产生以及过氧亚硝酸盐形成相关，并且是由于其引起的;和（2）过氧亚硝酸盐细胞毒性的药理学抑制可以是对抗抗癌药物诱导的心肌抑制的新策略。本研究表明：（1）阿霉素引起的心肌抑制与心肌中iNOS的表达和过氧亚硝基阴离子的产生有关，（2）过氧亚硝基阴离子的产生参与了自由基介导的心肌损伤;（三）过氧亚硝酸盐分解催化剂如新型专利化合物FP 15在体内和体外条件下具有心脏保护潜力，与过氧亚硝酸根生成有关。最后，（4）我们积累了初步数据，表明过氧亚硝酸根分解催化剂FP 15对阿霉素诱导的小鼠心肌抑制模型具有保护作用。本研究的第一个目的是在抗癌药物诱导的心肌抑制和心肌病的小鼠模型中进行确定性体内研究，以测试过氧亚硝酸盐分解催化剂是否可以减缓或逆转体内抗癌药物诱导的心肌抑制的发生。我们将在阿霉素心脏毒性的急性和慢性模型中建立最小有效剂量以及治疗机会窗。本研究的另一个目的是确认该化合物不会干扰多柔比星的抗肿瘤作用。本申请的结果将促进我们对多柔比星诱导的心脏毒性的基本理解，并且还将促进有效PARP抑制剂作为新治疗剂的临床前开发，以抵消多柔比星的心脏毒性副作用。

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.