Adriamycin (ADR) is a potent anthracycline chemotherapeutic agent whose use is limited by the development of a severe cardiomyopathy, the pathophysiologic mechanism of which is undetermined. The proposed program has two main objectives: 1) to evaluate the feasibility of noninvasive clinical detection of ADR-induced cardiotoxicity by NMR spectroscopy, and 2) to employ 31P and 13C NMR spectroscopy to examine the mechanism of chronic ADR-induced cardiotoxicity. ICRF-187, an agent currently used in clinical trials, will be investigated to assess its ability to attenuate or prevent ADR cardiotoxicity. A model of chronic ADR cardiotoxicity will be established in spontaneously hypertensive rats whose hears till be excised at various stages of the treatment protocol, perfused by the Langendorff method, and examined by NMR methods (31P spectra and saturation transfer experiments; 13C NMR studies of metabolic flux employing various 13C-labelled substrates). At the end of each NMR experiment, the hearts will be fixed for subsequent histological analysis. This procedure will enable correlations to be made between metabolic changes and morphologic alterations caused by ADR treatment. Studies on rats will provide a basis for in vivo NMR studies of the development of ADR cardiomyopathy in dogs. Noninvasive 31P and 13C NMR measurements will be made by one-dimensional chemical shift imaging at 4.7 T. These investigations are expected to indicate whether NMR spectroscopy can be employed to monitor the cardiotoxic effects of ADR in patients undergoing chemotherapy.
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