The production of hydroxyl radical by bleomycin and iron (II)

Bleomycin 1s a glycopeptidlc antlblotlc used for the treatment of cancer [l] . In vitro, a major effect of bleomycm 1s the mtroduction of strand breaks into DNA [2,3]. Efficient breakage of DNA by bleomycm requues the presence of reducing agents, such as 2-mercaptoethanol, dltiothreitol, ascorbate, or hydrogen peroxlde [3,4]. Although reducing agents alone are injurious to DNA [5,6], the combination ofbleomycin and a reducing agent is far more effective m degrading DNA than 1s either bleomycin or reducmg agent alone [7,8] Limted damage to DNA may be observed with tigh concentrations of bleomycm alone [8,9]. Since bleomycin binds to DNA 111 the absence of added reducmg agents [lo] , the role of the latter compounds has recently been studied in detail. It has been established that Fe(I1) can substitute for the reducmg agents to effectively degrade DNA [ 111. Bleomycm and Fe(H) together were far more efficient m cleaving DNA than either species alone. This result has been venfied [ 121. It was suggested [ 121, but no convmcing evidence was provided, that hydroxyl radical may be responsible for bleomycininduced damage to DNA. Fe(II1) cannot replace Fe(H) m the degradation of DNA by bleomycm m the absence of reducmg agent, but III the presence of reducing agent, either Fe(I1) or FE(II1) greatly stimulates DNA degradation by bleomycin [ 1 l] . Metal chelators and other metal ions mhiblt DNA degradation [ 131. Superoxide radical (0,~) stimulates DNA degradation by bleomycm [13,14]. These observations have led to the proposal of the followmg model for the action of bleomycin