Effects of Camptothecin Analogues on DNA Transformations Mediated by Calf Thymus and Human DNA Topoisomerases I

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• 作者：Xiangyang Wang ; Glenn F. Short ; III ; William D. Kingsbury ; Randall K. Johnson ; and Sidney M. Hecht
• 刊名：Chemical Research in Toxicology
• 出版年：1998
• 出版时间：November 1998
• 年：1998
• 卷：11
• 期：11
• 页码：1352 - 1360
• 全文大小：134K
• 年卷期：v.11,no.11(November 1998)
• ISSN：1520-5010

文摘

Camptothecin (CPT) and 10 structural analogues were studied to characterize their effectson specific rearrangements of DNA structure mediated by human and calf thymus DNAtopoisomerases I. A 30 base pair DNA duplex containing a single high-efficiency topoisomerasecleavage site was incubated with each of the enzymes in the presence of the inhibitors.Individual inhibitors stabilized the covalent enzyme-DNA binary complex to different extents,as anticipated. However, for several of the inhibitors, the extent of ternary complex formationdiffered substantially for the human and calf thymus enzymes. In common with calf thymustopoisomerase I, the human enzyme was shown to mediate the rearrangement of branched,nicked, and gapped DNA substrates that constitute models for illegitimate recombination.However, some of these rearrangements proceeded with different rates and efficiencies in thepresence of human topoisomerase I. When inhibition of three of the rearrangements by CPTanalogues was studied, most of the analogues exhibited differential effects on a giventransformation, depending on the source of the enzyme employed.