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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059225-07
Application #
6970896
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Massicot-Fisher, Judith
Project Start
1999-04-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2007-11-30
Support Year
7
Fiscal Year
2006
Total Cost
$295,305
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Kang, Y James (2011) Copper and homocysteine in cardiovascular diseases. Pharmacol Ther 129:321-31
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Purohit, Vishnudutt; Bode, J Christian; Bode, Christiane et al. (2008) Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium. Alcohol 42:349-61
Zhou, Yang; Jiang, Youchun; Kang, Y James (2008) Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size. J Mol Cell Cardiol 45:106-17
Kang, Y James; Jiang, Youchun; Saari, Jack T (2007) Changes in copper and zinc status and response to dietary copper deficiency in metallothionein-overexpressing transgenic mouse heart. J Nutr Biochem 18:714-8
Lynes, Michael A; Kang, Y James; Sensi, Stefano L et al. (2007) Heavy metal ions in normal physiology, toxic stress, and cytoprotection. Ann N Y Acad Sci 1113:159-72
Feng, Wenke; Wang, Yuehui; Cai, Lu et al. (2007) Metallothionein rescues hypoxia-inducible factor-1 transcriptional activity in cardiomyocytes under diabetic conditions. Biochem Biophys Res Commun 360:286-9
Kang, Y James (2007) Antioxidant defense against anthracycline cardiotoxicity by metallothionein. Cardiovasc Toxicol 7:95-100
Merten, Kevyn E; Jiang, Youchun; Kang, Y James (2007) Zinc inhibits doxorubicin-activated calcineurin signal transduction pathway in H9c2 embryonic rat cardiac cells. Exp Biol Med (Maywood) 232:682-9

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