Oxidative destruction of DNA by the adriamycin-iron complex

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Abstract
The 2:1 [antineoplastic drugs] adriamycin-Fe(III) complex is able to bind to DNA and to catalyze its oxidative destruction. The binding of the drug-metal complex to [Escherichia coli and SV40 virus] DNA is indicated by characteristic spectral changes which are different from those seen with adriamycin intercalation and by the propensity of the drug-metal complex to precipitate DNA. Intercalated adriamycin appears not to be available for Fe binding. The resulting ternary complex is quite stable; it is not disrupted by incubation in the presence of EDTA and can be isolated by using Sephadex G-50 column chromatography. Disruption of the ternary complex requires vigorous conditions (extraction with phenol at 60.degree. C). The adriamycin-Fe complex in free solution has the capacity to catalyze the reduction of O2 by thiols. The DNA-bound drug-metal complex preserves this capacity over a wide rnage of complex/DNA ratios. As a consequence of this thiol-dependent O2 reduction, DNA is cleaved. This thiol-dependent DNA cleavage was shown to require H2O2 as an intermediate product. The thiol-dependent DNA cleavage reaction apparently has 2 stages involving reduction of O2 leading to H2O2, and then peroxide-dependent DNA cleavage. An unusual property of this reaction is that the cleavage is not random but gives rise to a defined 2300 base pair fragment.

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