METALLOTHIONEIN AND ADRIAMYCIN CARDIOTOXICITY

金属硫蛋白和阿霉素的心脏毒性

• 批准号: 2854254
• 负责人: Y James KANG
• 金额: $ 20.67万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2854254
• 关键词: DNA damage; bismuth; cardiotoxin; chelating agents; chemoprevention; cytoprotection; disease /disorder model; doxorubicin; drug adverse effect; free radical scavengers; genetically modified animals; glutathione; laboratory mouse; lipid peroxides; metallothionein; oxidative stress; peroxidation

DESCRIPTION: (Adapted from the Investigator's Abstract) Cardiotoxicity compromises effective use of adriamycin in cancer chemotherapy. Studies have shown that production of reactive oxygen species during its intracellular metabolism is highly responsible for the toxicity of this drug. Metallothionein (MT), a low molecular weight and cysteine-rich protein, has been shown in recent studies to protect the heart from acute adriamycin toxicity. However, it is important to know whether MT functions effectively in protection against chronic adriamycin cardiotoxicity, a significant clinical problem. Also the mechanism by which MT functions in this cardioprotection in vivo is unknown. Therefore, this study will test the hypothesis that MT protects from chronic adriamycin cardiotoxicity by inhibiting the drug-induced oxidative injury. A unique cardiac MT over expressing transgenic mouse model will be used. The specific aims and experimental approaches are: (1) To test whether elevated MT confers resistance to chronic adriamycin cardiotoxicity, the effects of MT on adriamycin-induced morphological changes in the myocardium, functional alterations in the isolated atrium, and increase in serum creatine phosphokinase activities will be determined in the cardiac MT over expressing transgenic mice and non- transgenic controls. (2) To investigate possible mechanisms by which MT protects the heart from chronic adriamycin toxicity, the subcellular localization, as well as the distribution among cell types, of the elevated cardiac MT, and possible alterations of mineral metabolism associated with the cardiac MT over expression will be measured. Furthermore, effects of MT elevation on adriamycin-induced lipid peroxidation and oxidative DNA lesions, and the reaction of MT with cellular disulfides in the heart will be examined. (3) To determine the specificity of the reaction of MT with GSH disulfide relative to other disulfides, GSH depletion and its effects on the status of cellular disulfides, along with altered adriamycin cardiotoxicity, will be examined. (4) To explore possible strategies for clinical application of MT induction as an approach to decrease adriamycin cardiotoxicity, bismuth with or without hinokitiol will be applied to develop an effectively experimental strategy for cardiac MT induction and protection. This study would provide a substantial base of information for understanding of the role of MT in cardioprotection against chronic adriamycin toxicity, potentially leading to further investigations towards an improved use of adriamycin in cancer chemotherapy.

描述：（改编自研究者摘要）毒性 损害了阿霉素在癌症化疗中的有效使用。研究 已经表明，活性氧物质的产生， 细胞内代谢是高度负责的毒性， 药金属硫蛋白（MT）是一种富含半胱氨酸的低分子量蛋白， 最近的研究表明，这种蛋白质可以保护心脏免受 阿霉素急性毒性然而，重要的是要知道MT是否 有效地保护对慢性阿霉素 心脏毒性，一个重要的临床问题。此外， MT在体内的这种心脏保护作用中起何种作用尚不清楚。 因此，本研究将检验MT保护 阿霉素通过抑制药物诱导的慢性心脏毒性 氧化损伤一种独特的心肌MT过表达转基因小鼠 模型将被使用。具体目标和实验方法是： (1)为了测试MT升高是否赋予对慢性阿霉素的抗性 心肌毒性，MT对阿霉素诱导的形态学的影响， 心肌的变化，分离的心肌细胞的功能改变， 心房，血清肌酸磷酸激酶活性增加将是 在心脏MT过表达转基因小鼠和非转基因小鼠中测定， 转基因对照。(2)为了研究MT可能的机制， 保护心脏免受慢性阿霉素毒性，亚细胞 定位，以及细胞类型之间的分布， 心脏MT升高，以及可能的矿物质代谢改变 将测量与心脏MT过表达相关的细胞凋亡。 此外，MT升高对阿霉素诱导的脂质过氧化的影响， 过氧化和氧化DNA损伤，以及MT与 将检查心脏中的细胞二硫化物。(3)确定 MT与GSH二硫化物的反应相对于其它二硫化物的特异性 二硫化物，GSH耗竭及其对细胞状态的影响 二硫化物，沿着阿霉素心脏毒性的改变， 考察(4)探讨临床应用的可能策略 MT诱导作为降低阿霉素心脏毒性的方法， 铋与或不与扁柏酚将应用于开发一种 心脏MT诱导的有效实验策略， 保护这项研究将提供大量的资料 了解MT在心脏保护中的作用， 阿霉素毒性，可能导致进一步研究 以改进阿霉素在癌症化疗中的应用。