Oxygen Radical Formation During Redox Cycling of Bleomycin-Fe(III) Catalyzed by NADPH-Cytochrome P-450 Reductase of Liver Microsomes and Nuclei

Abstract

Bleomycin, a glycopeptide antibiotic is successfully used in the chemotherapy of various tumors. It has been suggested that its anticancer activity is due to oxygen radicals formed by a reduced complex of bleomycin and iron ions (for review see Burger et al., 1981). A bleomycin-Fe(II)-complex damages DNA resulting in the formation of strand breaks and the release of free bases and malondialdehyde, the latter originating from the deoxyribose moiety of DNA (Giloni et al., 1981; Gutteridge et al., 1981). The bleomycin-Fe-complex can be reduced chemically or by xanthine oxidase (Sausville et al., 1978). Furthermore, increases in DNA damage have been observed when microsomes of different organs and NADPH were incubated with bleomycin and iron ions (Bickers et al., 1984; Trush et al., 1982; Yamanaka et al., 1978). We found that isolated liver microsomal NADPH-cytochrome P-450 reductase is able to catalyze bleomycinrelated DNA strand breaks and base and malondialdehyde release in the presence of ferric ions (Scheulen et al., 1981; Scheulen and Kappus, 1984). This has been confirmed and extended recently (Kilkuskie et al., 1984). Therefore, it is obvious that this enzyme is responsible for the effects observed in microsomes.