| 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... |
