RADICAL FORMATION BY METAL-COMPLEXES OF ANTHRACYCLINES AND THEIR METABOLITES - IS THERE A RELATION WITH CARDIOTOXICITY

Radical mechanisms are involved in anthracycline cardiotoxicity, but e vidence is lacking for the anthracycline metabolites. A series of 13-d ihydro derivatives and aglycons were screened for their ability to ind uce oxygen free radical formation, either alone or as transition metal complex. None of the anthracyclines, parent compounds or metabolites showed direct generation of superoxide anion. When complexated with ir on, doxorubicin and its stereo-isomer 4'-epidoxorubicin as well as the ir aglycons, but not daunorubicin nor all 13-dihydrometabolites, showe d a ferricytochrome c reduction ranging from 0.03 to 0.24 mu M/min. Th us, the presence of a ketone function in combination with a primary al cohol on the C-9 alkyl side chain seems a prerequisite. In the presenc e of ascorbic acid as a reducing agent, all anthracycline-iron complex es induced (partially SOD-inhibitable) oxygen consumption, ranging fro m 2.0 to 5.8 mu M/min. Using HPLC, a range of degradation products of unknown identity were detected. Although 13-dihydro metabolites are mo re cardiotoxic than their parent drugs, they were less active in induc ing oxygen free radical formation. Thus, mechanisms other than radical formation may explain the increased cardiotoxicity of the 13-dihydro metabolites.