MECHANISM AND INHIBITION OF HUMAN DNA TOPOISOMERASE I

人类DNA拓扑异构酶I的作用机制及抑制作用

• 批准号: 6475817
• 负责人: Sidney Michael Hecht
• 金额: $ 18.99万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-23 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6475817
• 关键词: DNA; DNA topoisomerases; antineoplastics; chemical reaction; covalent bond; enzyme inhibitors; enzyme mechanism; human genetic material tag; intermolecular interaction; mutant

The long term goals of this research are characterization of the nature of DNA relaxation by eukaryotic DNA topoisomerase I at a molecular level and identification of those parameters of topoisomerase I inhibition that are critical for the expression of anti-tumor activity. This should permit the identical of second generation topoisomerase I inhibitors suitable for development as anti-tumor agents. For the period of requested support, the specific aims include better definition of the nature of inhibitor binding by the topoisomerase I-DNA covalent binary complex, the identification of an optimal system for studying topoisomerase I-DNA interaction at high resolution and exploration of the possible role of other cellular factors in the expression of cytotoxicity by topoisomerase I inhibitors.

这项研究的长期目标是在分子水平上通过真核DNA DNA拓扑酶I对DNA松弛的性质的表征，以及鉴定拓扑异构酶I抑制的参数，这对于抗肿瘤活性的表达至关重要。这应允许第二代拓扑异构酶I抑制剂适合于抗肿瘤剂的发育。在要求的支持期间，具体目的包括对拓扑异构酶I-DNA共价二元复合物的抑制剂结合的性质的更好定义，这是研究在高分辨率上研究拓扑异构酶I-DNA相互作用的最佳系统，并探索了其他细胞因子在细胞毒性中的作用在细胞毒性中通过拓扑酶酶的表达的作用。