Poly(ADP-ribose)Polymerase & Doxorubicin Cardiotoxicity

聚(ADP-核糖)聚合酶

• 批准号: 6473525
• 负责人: JON G MABLEY
• 金额: $ 25万
• 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: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6473525
• 关键词: antineoplastics; cardiac myocytes; cardiotoxin; cell line; cytotoxicity; doxorubicin; drug adverse effect; enzyme activity; free radical oxygen; heart pharmacology; laboratory mouse; neoplastic cell; nitric oxide synthase; pentosyltransferase; peroxynitrites

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.

氧化应激、DNA损伤和核酶聚（ADP-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的作用有可靠且越来越多的实验证据。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，这限制了使用这种强大的方法来抵消这种毒性是非常重要的实际意义。本实验证明：（1）阿霉素引起的心肌抑制的发生与心肌中iNOS的表达和过氧亚硝基阴离子的产生有关，（2）PARP的激活参与了自由基介导的心肌损伤;（3）某些形式的药物诱导的心肌抑制与心肌中的PARP激活有关，以及（4）PARP缺陷小鼠对阿霉素具有抗性。诱发心肌抑制。本研究采用PARP缺陷小鼠和有效的PARP抑制剂联合应用的方法，拟（1）研究PARP在阿霉素诱导的啮齿动物心脏毒性中的作用;（2）探讨多柔比星对离体心肌细胞心脏毒性的分子机制，重点在于PARP的参与和（3）研究PARP抑制是否影响阿霉素在体外各种人癌细胞中的细胞毒性。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，并将促进有效的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，预防抗癌药物诱导的心脏抑制的有效治疗方法的年预期收入就超过1亿美元。