TOPOISOMERASE TARGETED AGENTS--CHEMISTRY TO CHEMOTHERAPY

拓扑异构酶靶向药物——化学到化疗

• 批准号: 6090227
• 负责人: David E Graves
• 金额: $ 0.2万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-17 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6090227
• 关键词: DNA topoisomerases; antineoplastics; drug resistance; enzyme activity; enzyme inhibitors; intermolecular interaction; meeting /conference /symposium; travel

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.

DNA拓扑异构酶必需的酶通过使遗传物质的短暂断裂来调节DNA的拓扑状态。除了其关键的生理功能外，拓扑异构酶I和II是目前用于治疗人类恶性肿瘤的一些最活跃和处方抗癌药的目标。 这些药物通过一种与其他靶向酶的剂明显不同的机制引起的细胞毒性作用。抗癌药物没有抑制酶的催化活性，而是显着增加了共价拓扑异构酶（I OR II）分解的DNA复合物，但在这些酶的催化循环中是正常但短暂的中间体。因此，针对拓扑异构酶I或II的药物中毒，将其转化为有效的生理毒素，可在处理过的细胞的基因组中损伤。尽管拓扑异构酶I和II对癌症化学疗法具有至关重要的重要性，但这些酶，DNA和抗癌药物之间的相互作用尚未得到很好的特征。此外，对瞬时药物诱导的拓扑异构酶生成的DNA断裂的细胞过程已被鲜为人知。 最后，对调节细胞耐药性这些药物的因素的了解相对较少。为了解决癌症化学疗法的这些关键问题，该提案的目的是获得资金，以组织和接待第二个国际国际题为：拓扑异构酶的针对药物的专题讨论会 - 化学疗法的化学疗法”在国家自然产品中心的化学疗法中心，在密西西比州牛津大学牛津大学校园的自然产物中心开发。拓扑酶靶向化学治疗剂。