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，由于其心脏毒性作用，其临床应用受到严重限制。目前应用的工作假设（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活性氧和氮的产生以及过氧亚硝酸盐的形成有关，并且是由于活性氧和氮的产生造成的；(2)药物抑制过氧亚硝酸盐细胞毒性可作为对抗抗癌药物诱导心肌抑制的新策略。在本研究中，我们提出了以下证据：(1)阿霉素诱导心肌抑郁的发生与心肌中iNOS的表达和过氧亚硝酸盐的产生有关；(2)过氧亚硝酸盐的生成参与自由基介导的心肌损伤；(3)新型专利化合物FP15等过氧亚硝酸盐分解催化剂在体内和体外与过氧亚硝酸盐生成相关的条件下具有心脏保护潜力。最后，(4)我们积累了初步数据，表明过氧亚硝酸盐分解催化剂FP15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肿瘤药物诱导的心肌抑制和心肌病小鼠模型中进行明确的体内研究，以测试过氧亚硝酸盐分解催化剂是否可以减缓或逆转抗肿瘤药物诱导的心肌抑制在体内的发展。我们将建立最小有效剂量，以及治疗的机会窗口，在急性和慢性模型阿霉素心脏毒性。该研究的另一个目的是确认该化合物不会干扰阿霉素的抗肿瘤作用。本应用的结果将促进我们对阿霉素诱导的心脏毒性的基本认识，并将推动有效的PARP抑制剂作为对抗阿霉素心脏毒性副作用的新型治疗药物的临床前开发。

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.