Metallothionein and Adriamycin Cardiotoxicity

描述(由申请人提供)：氧化应激导致的心脏毒性影响了阿霉素在癌症治疗中的有效使用。金属硫蛋白(MT)是一种有效的抗氧化剂，可保护心脏免受阿霉素的毒性。为了开发实验和临床方法，在肿瘤被根除的剂量时间表内预防阿霉素的心脏毒性，我们建议进行这项连续性研究，以检验MT保护因有效治疗肿瘤而引起的慢性和迟发性心脏毒性的假设。(1)为了确定MT对阿霉素诱导的慢性和迟发性心脏毒性的保护作用，新发展的乳腺癌转基因和非转基因BALB/c小鼠将接受对肿瘤完全有效的阿霉素剂量方案的治疗。慢性心脏毒性将通过形态计量学分析、功能评估以及心肌重构和心力衰竭的分子标志物来确定。(2)为了探索MT诱导作为预防阿霉素慢性和迟发性心脏毒性的一种可能的临床应用方法，我们将建立一种长期应用铋或Hin okitiol诱导BALB/c小鼠心脏MT的实验策略。这些诱导剂对包括心脏在内的多个器官中MT表达的剂量效应以及长期应用它们的潜在毒性效应将被检测。(3)为了开发MT心肌保护在癌症治疗中的应用，将移植几个已被证明在BALB/c小鼠体内生长的小鼠肿瘤细胞系。荷瘤小鼠将接受已定义的MT诱导方案的治疗。将检测MT在肿瘤中的表达以及阿霉素的心脏毒性，以及肿瘤的治疗效果。这项研究将为了解MT对阿霉素慢性和迟发性心脏毒性的保护作用提供坚实的信息基础，可能导致这种高效抗癌药物的改进使用。

DESCRIPTION (provided by applicant): Cardiotoxicity due to oxidative stress compromises effective use of Adriamycin in cancer treatment. Metallothionein (MT), a potent antioxidant, protects the heart from Adriamycin-induced toxicity. To develop experimental and clinical approaches to preventing cardiotoxicity of Adriamycin in the dose-schedules that tumors are eradicated, we propose this continuation study to test the hypothesis that MT protects from chronic and late-onset cardiotoxicity induced by efficacious treatment of tumors with Adriamycin. A novel MT-overexpressing and tumor-bearing mouse model will be used to carry out the following aims: (1) to determine the efficacy of MT protection from Adriamycin-induced chronic and late-onset cardiotoxicity, newly developed breast tumor-bearing transgenic and non-transgenic BALB/c mice will be treated with dose-schedules of Adriamycin to which the tumors are fully responsive. Chronic cardiotoxicity will be determined by morphometric analysis, functional assessment, and molecular markers for myocardial remodeling and heart failure. (2) To explore possible clinical application of MT induction as an approach to preventing Adriamycin chronic and late-onset cardiotoxicity, we will develop an experimental strategy for a long-term cardiac MT induction by bismuth or hinokitiol in BALB/c mice. The dose-effect of these inducers on MT expression in multiple organs including the heart as well as potential toxic effects for their long-term application will be examined. (3) To develop experimental procedures for application of MT myocardial protection in cancer therapy, several murine tumor cell lines that have proven to grow in the BALB/c mice will be implanted. The tumor-bearing mice will be treated with the defined MT-induction protocol. The expression of MT in tumors as well as Adriamycin cardiac toxicity, and cancer therapeutic efficacy will be examined. This study would provide a substantial base of information for understanding MT protection against Adriamycin chronic and late-onset cardiotoxicity, potentially leading to an improved use of this highly effective anticancer drug.