ROLE OF IRON IN THE POTENTIATION OF ANTHRACYCLINE CARDIOTOXICITY - IDENTIFICATION OF HEART CELL MITOCHONDRIA AS A MAJOR SITE OF IRON-ANTHRACYCLINE INTERACTION

The role of iron in anthracycline toxicity was studied in rats in vivo in intact animals and in vitro in heart cell cultures. In animals tre ated with 8 mg/kg doxorubicin, iron loading resulted in severe weight loss and a twofold increase in rate of mortality. Studies in cultured heart cells aimed at defining the subcellular target of interaction be tween iron and anthracycline toxicity showed no evidence of anthracycl ine-induced damage to sarcolemmal thiolic enzymes represented by 5'-nu cleotidase and only a limited increase in lysosomal fragility us monit ored by an increase in beta-hexosaminidase activity in cell homogenate s and its release into the culture medium. By contrast, doxorubicin tr eatment resulted in a marked inhibition of mitochondrial function as m onitored by a decrease in carbon 14-labeled palmitate utilization, to 33% +/- 4% of controls, and prior iron loading resulted in a further d ecrease in palmitate utilization, to 18% +/- 3% of controls. Conversel y, iron-chelation treatment by either deferoxamine or deferiprone (L1) eliminated the harmful effects of iron loading and resulted in a part ial inhibition of doxorubicin toxicity in both normal and iron-loaded cells. Our studies represent the first demonstration in intact animals of the potentiation of anthracycline toxicity by iron overload. They also indicate that mitochondria represent an important target of combi ned iron-anthracycline toxicity. These observations provide new insigh ts into the mechanism of anthracycline cardiotoxicity and may be usefu l in developing better strategies for tumor therapy.