Analysis of topoisomerase I/DNA complexes in patients administered topotecan.
Analysis of topoisomerase I/DNA complexes in patients administered topotecan.
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发表时间：
1995-05
期刊：
影响因子：
11.2
通讯作者：
D. Subramanian;E. Kraut;A. Staubus;D. Young;M. Muller
中科院分区：
文献类型：
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作者：
D. Subramanian;E. Kraut;A. Staubus;D. Young;M. Muller
作为拓扑替康II期临床试验的一部分，通过检测外周血中的共价拓扑异构酶/DNA中间体来测量体内DNA断裂。ICE（体内酶复合物）生物测定用于评估患者输注治疗前、期间和之后外周血中的拓扑替康活性。结果可以概括为：（a）ICE生物测定法是用于拓扑异构酶I介导的DNA损伤的特异性、基于抗体的测定法。拓扑异构酶I/DNA复合物的形成可以在不存在托泊替康的情况下明确地监测，以建立内源性酶对DNA作用的基础水平;（B）托泊替康的输注显著刺激共价酶/DNA复合物的形成。在输注后5分钟内检测到复合物，并在30分钟的治疗过程中增加;（c）输注终止后，复合物形成在30分钟内减少3-4倍，表明切割复合物在停药后迅速重新密封;（d）复合物的形成在患者之间差异很大。ICE生物测定法可以评价拓扑异构酶I抑制剂对靶组织的影响，因此，它可能有价值的预测对这些药物的反应。
As part of a Phase II clinical trial of topotecan, DNA breakage in vivo was measured by detecting covalent topoisomerase/DNA intermediates in peripheral blood. The ICE (in vivo complex of enzyme) bioassay was used to assess topotecan activity in the peripheral blood of patients before, during, and after infusion therapy. The results can be summarized as: (a) ICE bioassay is a specific, antibody-based assay for topoisomerase I-mediated DNA damage. Topoisomerase I/DNA complex formation can be monitored unambiguously in the absence of topotecan to establish a basal level of endogenous enzyme action on DNA; (b) infusion of topotecan significantly stimulated formation of covalent enzyme/DNA complexes. Complexes were detected within 5 min postinfusion and increased over the course of a 30-min treatment; (c) after termination of infusion, complex formation decreased by 3-4-fold within 30 min, showing that cleavage complexes quickly reseal after drug withdrawal; and (d) formation of complexes varied widely between patients. The ICE bioassay can evaluate the effects of topoisomerase I inhibitors on target tissues; thus, it may valuable in predicting response to these drugs.