Metallothionein and Adriamycin Cardiotoxicity

超出所提供的空间。氧化应激引起的心脏毒性损害了阿霉素在癌症治疗中的有效使用。金属硫蛋白（MT），一种有效的抗氧化剂，保护心脏免受阿霉素引起的毒性。为了开发实验和临床方法来预防阿霉素在肿瘤根除剂量计划中的心脏毒性，我们提出了这项继续研究，以验证MT可以保护阿霉素有效治疗肿瘤引起的慢性和晚发性心脏毒性的假设。一种新的MT过表达和荷瘤小鼠模型将用于实现以下目的：(1)为了确定MT对阿霉素诱导的慢性和晚发性心脏毒性的保护效果，将新开发的乳腺荷瘤转基因和非转基因BALB/c小鼠用肿瘤完全应答的阿霉素剂量计划进行治疗。慢性心脏毒性将通过形态计量学分析、功能评估和心肌重构和心力衰竭的分子标记来确定。(2)为了探索MT诱导作为预防阿霉素慢性和晚发性心脏毒性的可能临床应用，我们将在BALB/c小鼠中建立一种长期使用铋或扁桃酚诱导心脏MT的实验策略。这些诱导剂对包括心脏在内的多器官MT表达的剂量效应以及长期应用的潜在毒性效应将被研究。(3)为了建立MT心肌保护在癌症治疗中的应用实验程序，将植入几种已被证明在BALB/c小鼠中生长的小鼠肿瘤细胞系。荷瘤小鼠将按照规定的mt诱导方案进行治疗。我们将研究MT在肿瘤中的表达以及阿霉素的心脏毒性和癌症治疗效果。这项研究将为了解MT对阿霉素慢性和晚发型心脏毒性的保护提供实质性的信息基础，可能导致这种高效抗癌药物的改进使用。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. Cardiotoxicity due to oxidative stress compromises effective use of Adriamycin in cancer reatment. 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 Ariamycin-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 antJcancer drug. PERFORMANCE SITE ========================================Section End===========================================