Our long term objectives are to understand the mechanisms of action of topoisomerase-targeting antitumor drugs and to develop more effective antitumor drugs for cancer chemotherapy. In the past funding periods, we and others have established that both human DNA topoisomerase I and topoisomerase II are important antitumor drug targets. Their mechanisms of action have also been partially elucidated. More recently, some topoisomerase drugs have been shown to overcome MDR1-mediated resistance and to exhibit strong antitumor activity against many refractory human solid tumor xenografts in nude mice. To further understand the mechanisms of action of topoisomerase-targeting drugs and to develop more effective antitumor drugs for cancer chemotherapy, we plan to: (1) investigate the mechanism of action of DNA minor groove binding drugs which we have recently shown to be a new class of topoisomerase I-targeting drugs; (2) investigate the mechanism(s) of action naphthoquinones and quinolones which may represent a new class(es) of topoisomerase II-targeting drugs. The roles of both 170 kDa and 180 kDa isoforms of human DNA topoisomerase II in drug action will also be studied. (3) investigate the roles of topoisomerases in genome rearrangements using specific topoisomerase-targeting antitumor drugs. (4) investigate the mechanism of drug specificity of human MDR1 and to overcome MDR1-mediated resistance using topoisomerase-targeting antitumor drugs.
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