DNA damage by superoxide-generating systems in relation to the mechanism of action of the anti-tumour antibiotic adriamycin.
A mixture of NADPH and ferredoxin reductase is a convenient way of reducing adriamycin in vitro. Under aerobic conditions the adriamycin semiquinone reacts rapidly with O2 and superoxide radical is produced. Superoxide generated either by adriamycin:ferredoxin reductase or by hypoxanthine:xanthine oxidase can promote the formation of hydroxyl radicals in the presence of soluble iron chelates. Hydroxyl radicals produced by a hypoxanthine:xanthine oxidase system in the presence of an iron chelate cause extensive fragmentation in double-stranded DNA. Protection is offered by catalase, superoxide dismutase or desferrioxamine. Addition of double-stranded DNA to a mixture of adriamycin, ferredoxin reductase, NADPH and iron chelate inhibits formation of both superoxide and hydroxyl radicals. This is not due to direct inhibition of ferredoxin reductase and single-stranded DNA has a much weaker inhibitory effect. It is concluded that adriamycin intercalated into DNA cannot be reduced.
D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA; D004317:Doxorubicin; D005287:Ferredoxin-NADP Reductase; D005609:Free Radicals; D006878:Hydroxides; D017665:Hydroxyl Radical; D009247:NADH, NADPH Oxidoreductases; D010084:Oxidation-Reduction; D011485:Protein Binding; D013481:Superoxides
D005609:Free Radicals; D006878:Hydroxides; D013481:Superoxides; D017665:Hydroxyl Radical; D004317:Doxorubicin; D004247:DNA; D005287:Ferredoxin-NADP Reductase; D009247:NADH, NADPH Oxidoreductases