Cardiotoxicity compromises effective use of adriamycin in cancer chemotherapy. Studies have shown that production of reactive oxygen species during its intracellular metabolism is highly responsible for the toxicity of this drug. Metallothionein (MT), a low molecular weight and cysteine-rich protein, has been shown in recent studies to protect the heart from acute adriamycin toxicity. However, it is important to know whether MT functions effectively in protection against chronic adriamycin cardiotoxicity, a significant clinical problem. Also the mechanism by which MT functions in this cardioprotection in vivo is unknown. Therefore, this study will test the hypothesis that MT protects from chronic adriamycin cardiotoxicity by inhibiting the drug-induced oxidative injury. A unique cardiac MT over expressing transgenic mouse model will be used.
The specific aims and experimental approaches are: (1) To test whether elevated MT confers resistance to chronic adriamycin cardiotoxicity, the effects of MT on adriamycin-induced morphological changes in the myocardium, functional alterations in the isolated atrium, and increase in serum creatine phosphokinase activities will be determined in the cardiac MT over expressing transgenic mice and non- transgenic controls. (2) To investigate possible mechanisms by which MT protects the heart from chronic adriamycin toxicity, the subcellular localization, as well as the distribution among cell types, of the elevated cardiac MT, and possible alterations of mineral metabolism associated with the cardiac MT over expression will be measured. Furthermore, effects of MT elevation on adriamycin-induced lipid peroxidation and oxidative DNA lesions, and the reaction of MT with cellular disulfides in the heart will be examined. (3) To determine the specificity of the reaction of MT with GSH disulfide relative to other disulfides, GSH depletion and its effects on the status of cellular disulfides, along with altered adriamycin cardiotoxicity, will be examined. (4) To explore possible strategies for clinical application of MT induction as an approach to decrease adriamycin cardiotoxicity, bismuth with or without hinokitiol will be applied to develop an effectively experimental strategy for cardiac MT induction and protection. This study would provide a substantial base of information for understanding of the role of MT in cardioprotection against chronic adriamycin toxicity, potentially leading to further investigations towards an improved use of adriamycin in cancer chemotherapy.
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