A general mechanism for microsomal activation of quinone anticancer agents to free radicals.

The highly active, quinone-containing anticancer drugs, Adriamycin, daunorubicin, carminomycin, rubidazone, nogalamycin, aclacinomycin A, and steffimycin (benzanthraquinones); mitomycin C and streptonigrin (/V-heterocyclic quiñones);and lapacho! (naphthoquinone) interact with mammalian microsomes and function as free radical carriers. These quinone drugs augment the flow of elec trons from reduced nicotinamide adenine dinucleotide phosphate to molecular oxygen as measured by en hanced reduced nicotinamide adenine dinucleotide phos phate oxidation and oxygen consumption. This reaction is catalyzed by microsomal protein and produces a free radical intermediate form of the drugs as determined by electron paramagnetic resonance spectroscopy. Microsomes from mouse and rat liver, heart, lung, and spleen and mouse L1210 and P388 tumors all catalyze the aug mented oxygen consumption. Apparent Kmvalues deter mined with normal rat liver microsomes range from 0.49 x 10~"Mfor steffimycin to 13.4 x 10~"Mfor lapacho!. Since SKF 525A and carbon monoxide have little effect on this reaction, cytochrome P-450 is probably not involved. Sev eral nonquinone anticancer agents were tested and were found inactive in the system. Since quinone anticancer drugs are associated with chromosomal damage that appears to be dependent on metabolic activation of these drugs, we propose that the intracellular activation of these drugs to a free radical state may be primary to their cytotoxic activity. As free radicals, these drugs, because of their high affinity and selective binding to nucleic acids, have the potential to be "site-specific free radicals" that bind to DMA or RNA and either react directly or generate oxygen-dependent free radicals such as Superoxide radi cal or hydroxyl radical to cause the damage associated with their cytotoxic actions.