Results of comparative studies on stimulation of the rates of cofactor consumption, superoxide generation and hydrogen peroxide production by mitoxantrone (Novantrone| dihydroxyanthracenedione; MXN), ametantrone (AM), doxorubicin (DOX) and daunorubicin (DNR) in the presence of NADPH-cytochrome P-450 reductase, NADH dehydrogenase, or rabbit hepatic microsomes have been reported. MXN and AM were substantially less effective in stimulating the rate of cofaetor oxidation, superoxide formation or hydrogen peroxide production relative to the anthracyclines. In the presence of P-450 reductase, the rate of NADPH oxidation or superoxide generation produced by 100/~M MXN or AM was only 15% and 2% respectively of that produced by 100 ~tM anthracycline.
The effects of MXN and AM on lipid peroxidation in hepatic microsomes, cardiac sarcosomes and cardiac mitochondria were determined and compared with those produced by ADM. MXN and AM at 50/~M inhibited the basal rate of NADPH-dependent rabbit liver microsomal lipid peroxidation by 50%; in contrast, DOX enhanced the rate of hepatic microsomal lipid peroxidation by 2-and 2.5-fold at 100 and 200 /~M, respectively. Rabbit cardiac sarcosomal NADPH-dependent lipid peroxidation was inhibited completely at 100 ,uM anthracenedione. NADH-dependent lipid peroxidation in cardiac mitochondria was diminished by 50 #M MXN and AM, whereas 50 l~M DOX produced a 2-fold stimulation in lipid peroxidation. The anthracenediones also effectively inhibited DOX-stimulated lipid peroxidation with 50% inhibition occurring at 4~M (MXN) and 6#M (AM). Moreover, both MXN and AM potently inhibited iron (100/~M)-stimulated lipid peroxidation in rabbit hepatic microsomes with 80% inhibition produced by 15 /~M anthracenedione.
These results are consistent with the diminished cardiotoxicity of mitoxantrone and ametantrone relative to DOX or DNR and may require a reassessment of the role of lipid peroxidation in the mechanism(s) of quinone antineoplastic agent-mediated cardiotoxicity.