The mechanism of action of quinone antibiotics

The review describes recent studies designed to elucidate the molecular mechanism of action of certain quinone antibiotics which exhibit or have potential for clinical treatment of malignant diseases. Although a large number of quinone antibiotics has been described the review will concentrate on four types, the anthracyclines, the mitomycins, streptonigrin, and the saframycin antibiotics because of their biological significance and because the understanding of their underlying modes of action is perhaps more advanced than in the case of other antibiotics. It will be evident that although the antibiotics bear a common quinone moiety this does not confer a commonality of mechanism. Indeed the variety and precision of the different chemical lesions induced by quinone antibiotics on nucleic acids, their principal cell targets, is remarkable. The particular lesions identified include (i) equilibrium binding, (ii) "permanent' single covalent attachment, (iii) reversible covalent binding, (iv) metal ion sequestration and subsequent DNA binding, (v) DNA groove and base specific binding, (v) interstrand cross-linking, (vi) intercalation with concomitant supercoil relaxation and duplex extension, (viii) redox cycling with production of reactive oxygen species and DNA single strand breaks, and (viii) single strand breaks as a result of phosphotriester formation. In many cases the chemical mechanisms involved in these individual processes may be elucidated in in vitro experiments on purified DNAs by the application of ethidium binding assays in conjunction with certain cellular repair enzymes and utilizing techniques including high field nuclear magnetic resonance and electron paramagnetic resonance spectroscopy. The data obtained in this way complement and extend information from cell culture and in vivo experiments. A coherent description of the multiple cellular effects of these reactive agents is emerging. Such reactions involve bioreductive activation of the quinone the subsequent course of which is precisely controlled by structural and stereochemical factors within the individual antibiotic. The concomitant chemical reactions on cellular macromolecules are beginning to be related to pharmacological properties including in the case of the anthracyclines, a plausible rationale for the molecular origin of the dose limiting cardiotoxicity.