The dose-dependent cardiomyopathy that develops on chronic administration of adriamycin (ADR), an anthracycline effective in the treatment of a wide variety of human malignancies, severely limits its long-term usage. A number of studies aimed at understanding the cardiopathogenic nature of this drug have been reported. However, the mechanism of cardiotoxicity remains unknown.
The aim of this project is to investigate various aspects of our in vitro pulsating cardiac cell system as they relate to ADR cardiotoxicity in man. The uniqueness and importance of an in vitro cardiac cell system is that it provides a sensitive measure of the metabolic effects of drugs on cellular function. The consistency and precision of autorhythmicity of heart cells in culture offers a unique way to investigate these effects. A microscope stage has been designed here to accurately control temperature and pH, two variables to which cardiac cell function is particularly sensitive. An electronic system has been developed which quantitatively records beating patterns. Other techniques that will be used to study the mechanism of toxicity of ADR, ADR analogues (AD 32) and other anti-cancer agents include: Light and electron microscopy, to assess structural damage; RNA and DNA assays, to evaluate synthesis and repair; metabolic inhibitors, as probes for distinguishing between glycolytic and electron transport effects and ATP assays to determine the biochemical effects of these agents. These studies are anticipated to lead to methods of preventing cardiotoxicity.
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