Metallothionein and Adriamycin Cardiotoxicity

金属硫蛋白和阿霉素的心脏毒性

• 批准号: 6990425
• 负责人: Y James KANG
• 金额: $ 4.41万
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6990425
• 关键词: apoptosis; bismuth; breast neoplasms; cardiovascular stress test; cell line; disease /disorder model; doxorubicin; drug adverse effect; gene expression; genetically modified animals; heart failure; laboratory mouse; metallothionein; monoterpenes; morphometry; muscle function; myocardium; myocardium disorder; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; protooncogene; terminal nick end labeling; toxicology

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===========================================

超出所提供的空间。由于氧化应激导致的细胞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）是一种有效的抗氧化剂，可保护心脏免受阿霉素诱导的毒性。为了开发实验和临床方法，以防止心脏毒性的阿霉素的剂量计划，肿瘤被根除，我们提出了这个继续研究，以测试的假设，MT保护从慢性和迟发性心脏毒性引起的有效治疗肿瘤阿霉素。一种新的MT过表达和荷瘤小鼠模型将用于实现以下目标：（1）为了确定MT对阿瑞霉素诱导的慢性和迟发性心脏毒性的保护作用，将用肿瘤完全响应的阿霉素剂量方案治疗新开发的荷乳腺肿瘤转基因和非转基因BALB/c小鼠。将通过形态测定分析、功能评估和心肌重塑和心力衰竭的分子标志物来确定慢性心脏毒性。(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方法的可能临床应用，我们将在BALB/c小鼠中开发铋或扁柏酚长期心脏MT诱导的实验策略。将检查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其长期应用的潜在毒性作用。(3)为了开发MT心肌保护在癌症治疗中的应用的实验程序，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。荷瘤小鼠将采用规定的MT诱导方案进行治疗。将检查肿瘤中MT的表达以及阿霉素心脏毒性和癌症治疗功效。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大量的信息基础，可能导致这种高效抗癌药物的使用得到改善。性能现场=