ENHANCED TOPOISOMERASE II-INDUCED DNA BREAKS AND FREE-RADICAL PRODUCTION BY A NEW ANTHRACYCLINE WITH POTENT ANTILEUKEMIC ACTIVITY

In a previous study we reported that a new anthracycline derivative (m oflomycin) exhibited a higher antileukemic activity compared to other anthracyclines, such as daunorubicin and doxorubicin. To explain the s uperior antileukemic effect of moflomycin and to disclose a possible s tructure-activity relationship, we investigated the three main mechani sms by which anthracyclines are thought to exert their antitumor effec t: DNA binding, free radical production and topoisomerase II inhibitio n. The DNA interaction was assessed both by DNA binding and DNA unwind ing assays, free radical generation was studied by electron spin reson ance, and topoisomerase II interaction by analysis of the stimulation of enzyme-induced DNA breaks. The results showed a higher free radical production and a greater stimulation of topoisomerase II-mediated DNA cleavage by moflomycin than doxorubicin, associated with a lower DNA affinity. The different biochemical characteristics of moflomycin, par ticularly its interaction with topoisomerase II, are related to the st ructural modifications performed on the chromophore. These properties, associated with a higher stability of the molecule induced by the pre sence of an iodine atom on the sugar moiety, are probably responsible for the higher antileukemic activity of this compound.