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.