Differences in O₂ reduction by the iron complexes of adriamycin and daunomycin: the importance of the sidechain hydroxyl group

Both adriamycin and daunomycin chelate Fe³⁺, forming complexes with similar spectroscopic properties but very different redox chemistry. Anaerobic Fe³⁺-adriamycin and Fe³⁺-daunomycin complexes of identical stoichiometry give rise to identical optical absorbance and EPR spectra with maxima at 600 nm and signals at g = 4.2 and g = 2.01. In anaerobic preparations, however, the 600 nm absorption band and the EPR signals of the Fe³⁺-adriamycin complexes decrease as Fe³⁺ is reduced to Fe²⁺, with the appearance of an adriamycin free-radical signal at g = 2.0035, while the spectra of Fe³⁺-daunomycin complexes remain unchanged, with no free-radical signal appearing. Polarographic measurements demonstrate that the Fe³⁺-adriamycin complexes consume O₂ while the Fe³⁺-daunomycin complexes do not. Measurements in the presence of catalase and superoxide dismutase suggest that 75% of the O₂ consumed by Fe³⁺-adriamycin is reduced to H₂O₂ or .O₂^-. Spin-trapping experiments demonstrate that the Fe³⁺-adriamycin complexes generate .OH, while the daunomycin complexes do not. Qunatitation of .OH generation by Fe³⁺-adriamycin demonstrates that the initital rate of .OH generation approaches the rate of total O₂ consumption. DNA cleavage studies show that only the Fe³⁺-adriamycin complexes cleave DNA in the absence of exogenous added H₂O₂. This DNA cleavage can be blocked by catalasa or .OH radical scavengers. These results indicate that the side-chain hydroxyl group is essential for Fe³⁺ reduction, subsequent O₂ reduction, as well as for the generation of the drug free radical, since adriamycin and daunomycin are structurally identical except for this hydroxyl. The difference in redox chemistry of the iron complexes of adriamycin and daunomycin is the only known mechanism which can explain the difference in anti-tumor potency and cardiotoxicity of these two structurally similar drugs.