Bleomycin: New perspectives on the mechanism of action

The bleomycin group antitumor antibiotics have long been of interest as a c onsequence of their efficacy in the treatment of certain tumors, not to men tion their unique structures and properties in mediating dioxygen activatio n and sequence selective degradation of DNA. At a chemical level, the struc ture originally assigned to bleomycin was subsequently reassigned and the n ew structure has been confirmed by total synthesis. Through the elaboration of structurally modified bleomycin congeners and fragments, synthetic effo rts have also facilitated an understanding of the contribution of individua l structural domains in bleomycin to sequence selective DNA binding and cle avage, and have also provided insights into the nature of the chemical proc esses by which DNA degradation takes place. Within the last several years, it has also become apparent that bleomycin can mediate the oxidative degrad ation of all major classes of cellular RNAs; it seems entirely plausible th at RNA may also represent an important locus of action for this class of an titumor agent. In parallel with ongoing synthetic and mechanistic efforts u sing classical methods, the study of bleomycins attached to solid supports has been shown to provide important mechanistic insights, and the actual el aboration of modified bleomycins by solid phase synthesis constitutes a log ical extension of such efforts.