Dexrazoxane (ICRF-187) protects cardiac myocytes against hypoxia-reoxygenation damage

Dexrazoxane is a cardioprotective antioxidant that is clinically used to reduce the cardiotoxicity of the chemotherapeutic drug doxorubicin. We examined the hypothesis that dexrazoxane also may be able to protect neonatal rat cardiac myocytes from hypoxia-reoxygenation damage. Hypoxia-reoxygenation damage is thought to involve oxidative stress on the heart muscle, possibly by the production of hydroxyl radicals mediated by iron. The results of this study showed that dexrazoxane was highly effective in protecting myocytes from hypoxia-reoxygenation-induced lactate dehydrogenase release. The metal chelating hydrolysis product of dexrazoxane, ADR-925, also protected myocytes from hypoxia-reoxygenation damage, although it was less effective than dexrazoxane. This study also showed that ADR-925 and dexrazoxane rapidly entered myocytes and displaced iron from a fluorescence-quenched trapped intracellular iron-calcein complex. These results suggest that dexrazoxane may protect myocytes against hypoxia-reoxygenation-induced damage by chelating free or loosely bound iron, thus preventing site-specific iron-based oxygen radical damage. Thus, dexrazoxane or its analogs may have some clinical utility in preventing tissue damage that occurs after a stroke or heart attack.