MECHANISM AND INHIBITION OF HUMAN DNA TOPOISOMERASE I

本研究的长期目标是在分子水平上表征真核生物DNA拓扑异构酶I对DNA松弛的性质，并确定拓扑异构酶I抑制的参数，这些参数对抗肿瘤活性的表达至关重要。这应该允许相同的第二代拓扑异构酶I抑制剂适合发展为抗肿瘤药物。在请求支持期间，具体目标包括更好地定义拓扑异构酶I- dna共价二元复合物结合抑制剂的性质，确定高分辨率研究拓扑异构酶I- dna相互作用的最佳系统，以及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。

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.