DNA Degradation by Manganese(II)-Bleomycin plus Peroxide

The DNA-cleaving activity of bleomycin,¹an antitumor glycopeptide antibiotic, had been shown in vitro to depend on the formation of activated bleomycin, a drug complex containing Fe(III) and oxygen.^2,3 This complex can be formed with Fe(III) and peroxide, Fe(III) plus reductants and O₂, or Fe(II) and O₂. Other metals gave no detectable DNA degradation in O₂-dependent reactions, and many inhibit the iron-requiring reaction.⁴ We now report DNA degradation by Mn(II)-bleomycin in the presence of H₂O₂. This activity is not due to endogenous iron salts and differs from that of iron-bleomycin in several respects. DNA does not inhibit the Mn(II)-bleomycin reaction, as it does the iron-bleomycin reaction, but optimal activity is only 1−3% of that of the Fe(III)-drug complex with H₂O₂. DNA products include free bases and base propenals, 5 as with iron bleomycin, but in different proportions. Aerobic solutions of reducing agents such as 2-mercaptoethanol cannot substitute for peroxide in the Reaction with Mn(II) as they do in the reaction with Fe-(III). In this respect, Mn(II)-bleomycin parallels the behavior of Mn(II)-cytochrome P-450, which cannot be activated reductively but can be activated with peroxides.⁶.