Studies of topoisomerase-targeting anticancer drugs

Lack of drug efficacy and development of drug resistance are two major obstacles for anticancer chemotherapy of human malignancies. Recent advances in the mechanism of drug action of topoisomerase-targeting drugs have provided an opportunity for developing more effective anticancer drugs toward refractory cancers. Towards this end, I have identified two new mechanisms for targeting mammalian DNA topoisomerases and one potential mechanism to overcome MDR1-mediated resistance.;Certain reactive quinones, including menadione, induces covalent association of purified topoisomerase II to 5;The underlying mechanism for overcoming MDR1-mediated drug resistance by topoisomerases I and II drugs were studied. My results suggest that in addition to the interaction between drugs and the MDR1-drug effluxing pump, the diffusion rate of drug molecules across the membrane lipid bilayer is a major determinant for MDR1-sensitivity.;DNA minor groove binding ligands, including Ho33342, were shown to induce highly specific topoisomerase I-mediated single-strand DNA breaks that are 65...