Oxidative destruction of DNA by the adriamycin-iron complex.
The 2:1 adriamycin-Fe(III) complex is able to bind to DNA and to catalyze its oxidative destruction. The binding of the drug-metal complex to 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. Furthermore, intercalated adriamycin appears not to be available for iron 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 degrees C). The adriamycin-iron complex in free solution has the capacity to catalyze the reduction of oxygen by thiols. The DNA-bound drug-metal complex preserves this capacity over a wide range of complex/DNA ratios. As a consequence of this thiol-dependent oxygen reduction, DNA is cleaved. This thiol-dependent DNA cleavage has been shown to require hydrogen peroxide as an intermediate product. These results have led us to propose that the thiol-dependent DNA cleavage reaction has two stages involving (1) reduction of oxygen leading to hydrogen peroxide and then (2) 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.
D055598:Chemical Phenomena; D002621:Chemistry; D004269:DNA, Bacterial / Q000302:isolation & purification; D004279:DNA, Viral / Q000302:isolation & purification; D004317:Doxorubicin; D004926:Escherichia coli; D005290:Ferric Compounds; D005978:Glutathione; D006861:Hydrogen Peroxide; D007501:Iron; D007700:Kinetics; D010084:Oxidation-Reduction; D013539:Simian virus 40; D013053:Spectrophotometry
D004269:DNA, Bacterial; D004279:DNA, Viral; D005290:Ferric Compounds; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D007501:Iron; D005978:Glutathione