PARADOXICAL INHIBITION OF CARDIAC LIPID-PEROXIDATION IN CANCER-PATIENTS TREATED WITH DOXORUBICIN - PHARMACOLOGICAL AND MOLECULAR REAPPRAISAL OF ANTHRACYCLINE CARDIOTOXICITY

Anticancer therapy with doxorubicin (DOX) and other quinone anthracycl ines is limited by severe cardiotoxicity, reportedly because semiquino ne metabolites delocalize Fe(II) from ferritin and generate hydrogen p eroxide, thereby promoting hydroxyl radical formation and lipid peroxi dation, Cardioprotective interventions with antioxidants or chelators have nevertheless produced conflicting results, To investigate the rol e and mechanism(s) of cardiac lipid peroxidation in a clinical setting , we measured lipid conjugated dienes (CD) and hydroperoxides in blood plasma samples from the coronary sinus and femoral artery of nine can cer patients undergoing intravenous treatments with DOX, Before treatm ent, CD were unexpectedly higher in coronary sinus than in femoral art ery (342+/-131 vs 112+/-44 nmol/ml, mean+/-SD; P < 0.01), showing that cardiac tissues were spontaneously involved in lipid peroxidation, Th is was not observed in ten patients undergoing cardiac catheterization for the diagnosis of arrhythmias or valvular dysfunctions, indicating that myocardial lipid peroxidation was specifically increased by the presence of cancer, The infusion of a standard dose of 60 mg DOX/m(2) rapidly (similar to 5 min) abolished the difference in CD levels betwe en coronary sinus and femoral artery (134+/-95 vs 112+/-37 nmol/ml); m oreover, dose fractionation studies showed that cardiac release of CD and hydroperoxides decreased by similar to 80% in response to the infu sion of as little as 13 mg DOX/m(2), Thus, DOX appeared to inhibit car diac lipid peroxidation in a rather potent manner, Corollary in vitro experiments were performed using myocardial biopsies from patients und ergoing aortocoronary bypass grafting. These experiments suggested tha t the spontaneous exacerbation of lipid peroxidation probably involved preexisting Fe(II) complexes, which could not be sequestered adequate ly by cardiac isoferritins and became redox inactive when hydrogen per oxide was included to simulate DOX metabolism and hydroxyl radical for mation, Collectively, these in vitro and in vivo studies provide novel evidence for a possible inhibition of cardiac lipid peroxidation in D OX-treated patients, Other processes might therefore contribute to the cardiotoxicity of DOX.