Doxorubicin cardiotoxicity:protection by peroxynitrite

阿霉素心脏毒性：过氧亚硝酸盐的保护

• 批准号: 6548807
• 负责人: CSABA SZABO
• 金额: $ 5.89万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6548807
• 关键词: cardiotoxin; catalyst; cell cycle; cell proliferation; cytoprotection; doxorubicin; drug adverse effect; drug screening /evaluation; free radical oxygen; free radical scavengers; heart pharmacology; laboratory mouse; metalloporphyrins; myocardium disorder; nitric oxide synthase; oxidative stress; peroxynitrites; tissue /cell culture

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.

说明(申请人提供)：阿霉素是一种强大的抗癌药物，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)阿霉素引起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；(2)药物抑制过氧亚硝酸盐的细胞毒性可以成为对抗抗癌药物引起的心肌抑制的一种新策略。在这项提议中，我们提出证据表明：(1)阿霉素诱导的心肌抑制的发生与心肌中iNOS的表达和过氧亚硝酸盐的产生有关；(2)过氧亚硝酸盐的产生参与了自由基介导的心肌损伤；(3)过氧亚硝酸盐分解催化剂，如新的专利化合物FP15，在与过氧亚硝酸盐产生相关的条件下，在体内和体外具有心脏保护潜力。最后，(4)我们积累的初步数据表明，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有保护作用。本研究的第一个目的是在抗癌药物引起的心肌抑制和心肌病的小鼠模型上进行确定性的体内研究，以测试过氧亚硝酸盐分解催化剂是否能够减缓或逆转抗癌药物引起的在体心肌抑制的发生。在阿霉素心脏毒性的急性和慢性模型中，我们将建立最小有效剂量以及治疗机会窗。这项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心脏毒性的基本了解，也将促进有效的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。