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.

本研究的长期目标是在分子水平上表征真核DNA拓扑异构酶I对DNA松弛的性质，并鉴定对表达抗肿瘤活性至关重要的拓扑异构酶I抑制的那些参数。这将允许相同的第二代拓扑异构酶I抑制剂适合于开发为抗肿瘤剂。在所要求的支助期间，具体目标包括更好地确定拓扑异构酶I-DNA共价二元复合物与抑制剂结合的性质，确定高分辨率研究拓扑异构酶I-DNA相互作用的最佳系统，并探索其他细胞因子在拓扑异构酶I抑制剂表达细胞毒性中的可能作用。