TOPOISOMERASE TARGETED AGENTS--CHEMISTRY TO CHEMOTHERAPY

DNA拓扑异构酶是通过在遗传物质中制造短暂断裂来调节DNA拓扑状态的基本酶。除了它们的关键生理功能，拓扑异构酶I和拓扑异构酶II是目前用于治疗人类恶性肿瘤的一些最活跃和最广泛处方的抗癌药物的靶标。这些药物引起细胞毒性作用的机制明显不同于其他酶靶向药物。抗癌药物不是抑制酶的催化活性，而是显著提高共价拓扑异构酶（I或II）切割DNA复合物的水平，这些复合物是这些酶催化循环中正常但短暂的中间产物。因此，靶向拓扑异构酶I或II的药物使这些酶中毒，并将其转化为强效的生理毒素，从而对处理细胞的基因组产生损伤。尽管拓扑异构酶I和拓扑异构酶II在癌症化疗中具有重要作用，但这些酶、DNA和抗癌药物之间的相互作用尚未得到很好的表征。此外，将瞬时药物诱导的拓扑异构酶产生的DNA断裂转化为致命染色体断裂的细胞过程尚不清楚。最后，对调节细胞对这些药物的耐药性的因素所知相对较少。为了解决癌症化疗的这些关键问题，本提案的目标是获得资金，以便在密西西比大学牛津校区的国家天然产物开发中心组织和主办第二届国际研讨会，题为“拓扑异构酶靶向药物-化学到化疗”。本次研讨会将汇集不同群体的科学家和临床医生，并将重点关注拓扑异构酶靶向化疗药物的设计、开发和作用机制。

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.