Doxorubicin (DOX; adriamycin) is an effective cancer chemotherapeutic agent. However, the therapeutic potential of DOX is limited by a potentially lethal, cumulative dose-dependent cardiomyopathy functionally characterized by depressed cardiac contraction and relaxation and morphologically characterized by distended sarcoplasmic reticulum (SR) and T-tubular network. Recent evidence form our laboratories has established that doxorubicinol (DOXol), the major biometabolite of DOX, is more potent than DOX in inhibiting cardiac contraction and relaxation of isolated muscle preparations and calcium pumping by an isolated SR membrane fraction.
The first aim of the proposed project is to relate the onset of DOX-induced cardiomyopathy, as indexed by the onset of histopathologic changes and by abnormalities in cardiac contraction and relaxation in isometrically contracting isolated muscle preparations, with the myocardial levels of DOXol in the heart of rabbits treated with between 4 and 12 doses of DOX (1 mg/kg dose IV twice weekly).
The second aim will be to determine if the onset of DOX-induced myocardial dysfunction is related to alterations in ultrastructure of the SR and calcium uptake and/or release referable to SR in isolated skinned fibers and membrane fractions. If so, an additional aim will be to determine if DOX-induced changes in the SR are related to the myocardial conversion of DOX to and the accumulation of DOXol.
The third aim will be to determine if selenium supplementation reduces myocardial dysfunction by """"""""protecting"""""""" the ultrastructure of the SR and the calcium uptake and/or release referable to the SR. The fourth specific aim will be to evaluate the efficacy of several agents that inhibit aldo-keto reductase to determine if they affect myocardial conversion of DOX to DOXol and delay the onset, or reduce the severity, of the cardiomyopathy. If DOXol mediates, at least in part, the SR membrane damage which is related to the contraction/relaxation abnormalities of DOX- induced cardiomyopathy, this would suggest a novel strategy of inhibiting the conversion of DOX to DOXol to prevent the cardiotoxicity without effecting anti-tumor efficacy, since DOXol and DOX have comparable anti- tumor activity.
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