METALLOTHIONEIN AND ADRIAMYCIN CARDIOTOXICITY

描述：(改编自《调查者摘要》)心脏毒性 影响阿霉素在癌症化疗中的有效使用。研究 已经表明，在其生长过程中产生的活性氧物种 细胞内新陈代谢是其毒性的主要原因。 毒品。富含半胱氨酸的低分子量金属硫蛋白(MT) 蛋白质，最近的研究表明，它可以保护心脏免受 急性阿霉素中毒。然而，重要的是要知道MT是否 对慢性阿霉素的有效保护作用 心脏毒性，这是一个重大的临床问题。此外，该机制通过 目前还不清楚MT在体内的这种心脏保护中起什么作用。 因此，这项研究将检验MT保护免受 阿霉素通过抑制药物诱导的慢性心脏毒性 氧化损伤。一种独特的过表达转基因小鼠的心脏MT 将使用模型。具体目标和实验方法如下： (1)检测MT升高是否使人对慢性阿霉素产生抗药性 心脏毒性，MT对阿霉素诱导的形态结构的影响 孤立性心肌病的心肌改变、功能改变 而血清肌酸磷酸激酶活性的升高将 在心脏MT过度表达转基因小鼠和非转基因小鼠中确定 转基因对照。(2)研究MT的可能机制 保护心脏免受阿霉素的慢性毒性，亚细胞 的定位，以及在细胞类型中的分布 心脏MT升高和可能的矿物质代谢改变 与心脏MT过度表达相关的将被测量。 此外，MT升高对阿霉素诱导的血脂的影响 过氧化和氧化的DNA损伤，以及MT与 将检查心脏中的细胞二硫化物。(三)确定 MT与谷胱甘肽二硫化物反应的特异性 二硫化物、谷胱甘肽耗竭及其对细胞状态的影响 二硫化物，以及改变的阿霉素心脏毒性，将是 检查过了。(4)探讨临床应用的可行策略 MT诱导作为减少阿霉素心脏毒性的一种方法， 含或不含核黄硫醇的铋将用于开发一种 有效的心脏MT诱导和实验策略 保护。这项研究将提供坚实的信息基础。 了解MT在慢性心肌保护中的作用 阿霉素毒性，可能导致进一步调查 改善阿霉素在癌症化疗中的使用。

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.