Selenium supplementation decreases the pro-oxidant and cardiotoxicity effects of adriamycin in the rat.

Abstract

Adriamycin (doxorubicin; ADR) is an antineoplastic drug used to treat various cancers; however, its chronic us is unfortunately accompanied by cardiotoxicity. Previous results suggested that a free radical mechanism may contribute to ADR toxicity. Because it is often reported that cancer patients are deficient in selenium (Se), we hypothesised that ADR toxicity might be reduced by antioxidant agents such as vitamin E and Se. ADR-induced cardiotoxicity was examined in rats maintained on a Se-supplemented diet. The animals were kept on either a standard (0.22 mg/kg) or a Se-supplemented (2.5 mg/kg) diet starting 4 weeks prior to the first ADR treatment. ADR, or its excipient, was administered intraperitoneally in six equal injections over a period of 3 weeks giving a cumulative dose of 15 mg/kg body weight. Blood was collected in the thoracic cavity and the heart was subjected to a sequence of perfusion/partial ischemia/reperfusion ex vivo. Se status, GPx activities, vitamins E and C and MDA contents were determined on RBC and cardiac homogenates. ADR-treated rats showed a significant decrease in RBC Se (-29%) and in RBC Se-GPx (-34%) compared to the placebo group, and a significant increase in RBC MDA content (+2000%). This latter increase was attenuated by the Se supplementation (+1600%). In parallel, RBC vitamin E decreased markedly in the ADR-treated group (-50%) and was totally restored by the Se supplementation. Cardiac biochemical analyses confirmed the blood results. The present data confirm that a free radical mechanism does contribute to ADR toxicity, and show the importance of balancing the Se levels in ADR-treated subjects to limit its harmful myocardial action. Adecrease in ADR toxicity with no concomitant decrease in its antineoplastic activity would be of considerable value by improving the therapeutic benefit of the drug.