DNA topoisomerase II as the primary target of anti-tumor anthracyclines

Abstract

Recent structure-activity relationship studies emphasize the critical role of topoisomerase II-mediated DNA cleavage on the cytotoxic activity of anthracycline anti-tumor antibiotics. Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives. The strength of DNA binding apparently does not correlate with the stimulatory effect of anthracyclines on topoisomerase II-mediated DNA cleavage and with their cytotoxic potency. However, drug intercalation is still required for optimal drug activity. Such an observation suggests that the specific mode of DNA interaction, rather than the strength of binding, is important in determining the cytotoxic potency. The extent of anthracycline-induced cleavage results from a balance between a stimulation and a suppressive effect of the drug on topoisomerase II DNA cleavage. Anthracyclines are sequence selective in the induction of DNA cleavage by purified topoisomerase II. Despite the extensive effort in developing DNA intercalating agents as anti-tumor drugs, the limited success of such an approach could be rationalized in terms of the still inadequate 'rational design', since the molecular basis of specific drug-DNA topoisomerase II interaction (e.g. sites of cleavage, cell response to DNA damage, etc.) is not completely understood. Such studies indicating structural requirements in anthracycline molecules, which are critical for specific drug interference with topoisomerase II functions, provide the opportunity to re-examine the mechanism of action of these agents and to design new, more selective derivatives.