QUINOBENOXAZINES - A CLASS OF NOVEL ANTITUMOR QUINOLONES AND POTENT MAMMALIAN DNA TOPOISOMERASE-II CATALYTIC INHIBITORS

The antineoplastic quinobenoxazines A-62176 and A-74932 were shown to be potent inhibitors of mammalian DNA topoisomerase II in vivo. This w as demonstrated by their selective inhibition of the SV40 DNA replicat ion stages that require topoisomerase II, Neither drug stabilized a co valent complex of the enzyme with SV40 DNA, which suggests that they a re not poisons of DNA topoisomerase II. A-77601, an analog having litt le antitumor activity, barely inhibited DNA topoisomerase II in vivo, even at high concentrations. These findings were supported by in vitro studies which showed that A-62176 and A-74932, but not A-77601, stron gly inhibited the catalytic activity of mammalian DNA topoisomerase II . A-62176 did not cause topoisomerase II-mediated DNA strand breaks in vitro under conditions in which adriamycin produced extensive DNA bre akage. The antineoplastic and topoisomerase inhibitory activities of t he quinobenoxazines correlate with their ability to unwind DNA. A-6217 6 antagonized the poisoning of topoisomerase II by VM-26 in vivo and i n vitro, but had no effect on PNA breakage induced by camptothecin, a DNA topoisomerase I poison. A-62176 and A-74932 thus inhibit DNA topoi somerase II reactions at a step prior to the formation of the ''cleava ble complex'' intermediate. These findings indicate that stabilization of the DNA topoisomerase II-DNA cleavable complex is not necessary fo r the antitumor activity of this class of quinolones and that the cata lytic inhibition of DNA topoisomerase II may contribute significantly to the anticancer activity of other DNA topoisomerase II inhibitors.