Poly(ADP-ribose)Polymerase & Doxorubicin Cardiotoxicity

越来越多的实验证据表明，氧化应激、DNA损伤和核酶多聚核糖（adp - ri核糖）聚合酶（PARP）的激活在各种细胞毒性药物诱导的心肌细胞损伤的发病机制中所起的作用。我们假设PARP通路参与了细胞毒性抗癌药物阿霉素的心脏毒性作用。由于心脏毒性是主要的限制因素，因此限制使用这种强有力的方法来抵消这种毒性具有重要的实际意义。在本研究中，我们提出了以下证据：(1)多柔比康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)自由基介导的心肌损伤中，PARP活化参与自由基的作用；(3)某些形式的药物诱导的心肌抑制与心肌中PARP的激活有关；(4)PARP缺陷小鼠对阿霉素诱导的心肌抑制具有抗性。采用PARP缺陷小鼠和有效的药理PARP抑制剂的联合方法，我们提出(1)研究PARP在阿霉素诱导的啮齿动物心脏毒性中的作用；(2)探索多柔比康体外诱导心肌细胞心脏毒性的分子机制，重点研究PARP的参与；(3)研究PARP抑制是否会影响多柔比康体外对多种人类癌细胞的细胞毒性。目前的项目将扩展我们对阿霉素诱导的心脏毒性机制的理解，并将促进有效PARP抑制剂的临床前开发，以改善阿霉素的严重副作用。拟议的商业应用：仅在美国，一种预防抗癌药物引起的心脏抑郁的有效治疗方法的年预期收入就超过1亿美元。

There is solid and increasing experimental evidence for the role of oxidative stress, DNA injury and the activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) in the pathogenesis of cardiac myocyte injury induced by various cytotoxic drugs. We hypothesize that the PARP pathway is involved in the cardiotoxic action of the cytotoxic anti-cancer drug doxorubican. Since cardiotoxicity is the main limiting factor, which restricts the use of this powerful approaches to counteract this toxicity are of great practical importance. In this proposal, we present evidence that (1) the developmental of doxorubican-induced myocardial depression is associated with the expression of iNOS and the production of peroxynitrite in the myocardium; (2) that PARP activation participate in free-radical in free-radical mediated myocardial injury; (3) that certain forms of drug-induced myocardial depression are associated with PARP activation in the myocardium and (4) that PARP deficient mice are resistant against doxorubican-induced myocardial depression. Using a combination approach of PARP deficient mice and potent pharmacological PARP inhibitors, here we proposed to (1) investigated the role of PARP in doxorubican-induced cardiotoxicity in rodent hearts in vivo; (2) to explore the molecular mechanisms of doxorubican- induced cardiotoxicity in cardiac myocytes in vitro, with focus on the involvement of PARP and (3) to investigated whether PARP inhibition influences the cytotoxicity of doxorubican in various human cancer cells in vitro. The current project will extend our understanding on the mechanism of doxorubican-induced cardiotoxicity, and will facilitate the preclinical development of potent PARP inhibitors to ameliorate this severe side effects of doxorubican. PROPOSED COMMERCIAL APPLICATIONS: The annual anticipated revenues for an effective therapeutic to prevent anti-cancer-drug induced cardiodepression is over $100 million in the US alone.