Iron-mediated formation of an oxidized adriamycin free radical

Electron paramagnetic resonance studies are reported which demonstrate that the reduction of Fe³⁺ to Fe²⁺ by adriamycin results in the formation of an oxidized adriamycin free radical with an EPR signal at g=2.004. A transient iron-adriamycin free radical complex is also observed at g=2.34. The free radical is quantitated and its aerobic stability is determined. Observation of the oxidized adriamycin free radical signal confirms that adriamycin donates an electron to the bound Fe³⁺. In the presence of glutathione the drug-mediated reduction of Fe³⁺ to Fe²⁺ is bypassed, and the oxidized adriamycin radical signal is not observed. The oxidized adriamycin radicals and reduced oxygen radicals which are formed are two different mediators, whose relative concentrations could modulate the therapeutic and toxic effects of adriamycin.