DNA topoisomerases essential enzymes that modulate the topological state of DNA by making transient breaks in the genetic material. Beyond their critical physiological functions, topoisomerase I and II are the targets for some of the most active and widely prescribed anticancer agents currently used to treat human malignancies. These drugs elicit their cytotoxic effects by a mechanism that is markedly different than those of other enzyme-targeted agents. Rather than inhibiting the catalytic activity of the enzyme, anticancer drugs dramatically increase levels of covalent topoisomerase (I or II)-cleaved DNA complexes that are normal, but fleeting, intermediates in the catalytic cycle of these enzymes. Thus, agents targeted to topoisomerase I or II, poison these enzymes and convert them to potent physiological toxins that generate damage in the genomes of treated cells. Despite the central importance of topoisomerase I and II to cancer chemotherapy, interactions between these enzymes, DNA, and anticancer drugs have not been well characterized. In addition, the cellular processes that convert transient drug-induced topoisomerase-generated DNA breaks to lethal chromosomal breaks are poorly understood. Finally, relatively little is known about the factors that modulate cellular resistance to these drugs. To address these critical issues of cancer chemotherapy, the goal of this proposal is to obtain funding in order to organize and host the second international symposium entitled: Topoisomerase Targeted Drugs - Chemistry to Chemotherapy"""""""" at the National Center for the Development of Natural Products on the Oxford campus of the University of Mississippi. This symposium will bring together a diverse group of scientists and clinicians and will focus on the design, development, and mechanism of action of topoisomerase-targeted chemotherapeutic agents.
