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首页> 外文期刊>Molecular cancer therapeutics >Single-Molecule Supercoil Relaxation Assay as a Screening Tool to Determine the Mechanism and Efficacy of Human Topoisomerase IB Inhibitors
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Single-Molecule Supercoil Relaxation Assay as a Screening Tool to Determine the Mechanism and Efficacy of Human Topoisomerase IB Inhibitors

机译：单分子超自联弛豫测定作为筛选工具，以确定人拓扑异构酶IB抑制剂的机制和功效

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摘要

Human nuclear type IB topoisomerase (Top1) inhibitors are widely used and powerful anticancer agents. In this study, we introduce and validate a single-molecule supercoil relaxation assay as a molecular pharmacology tool for characterizing therapeutically relevant Top1 inhibitors. Using this assay, we determined the effects on Top1 supercoil relaxation activity of four Top1 inhibitors; three clinically relevant: camptothecin, LMP-400, LMP-776 (both indenoisoquinoline derivatives), and one natural product in preclinical development, lamellarin-D. Our results demonstrate that Top1 inhibitors have two distinct effects on Top1 activity: a decrease in supercoil relaxation rate and an increase in religation inhibition. The type and magnitude of the inhibition mode depend both on the specific inhibitor and on the topology of the DNA substrate. In general, the efficacy of inhibition is significantly higher with supercoiled than with relaxed DNA substrates. Comparing single-molecule inhibition with cell growth inhibition (IC50) measurements showed a correlation between the binding time of the Top1 inhibitors and their cytotoxic efficacy, independent of the mode of inhibition. This study demonstrates that the single-molecule supercoil relaxation assay is a sensitive method to elucidate the detailed mechanisms of Top1 inhibitors and is relevant for the cellular efficacy of Top1 inhibitors. (C) 2015 AACR.
机译：人核型IB拓扑异构酶（TOP1）抑制剂是广泛使用的和强大的抗癌剂。在该研究中，我们引入并验证单分子超自油弛豫测定作为用于表征治疗相关的TOP1抑制剂的分子药理学工具。使用该试验，我们确定了四个TOP1抑制剂的TOP1超级释放活动的影响;三个临床相关：Camptothecin，LMP-400，LMP-776（Indenoisoquinoline衍生物）和一个天然产物在临床前发育，Lamellarin-D.我们的结果表明，TOP1抑制剂对TOP1活动有两种明显的影响：超级释放率降低和缓解抑制的增加。抑制模式的类型和幅度取决于特异性抑制剂和DNA底物的拓扑。通常，抑制的功效显着高于缓解DNA衬底的超级硅。将单分子抑制与细胞生长抑制（IC50）进行测量，显示TOP1抑制剂的结合时间与其细胞毒性功效之间的相关性，与抑制模式无关。本研究表明，单分子超荷别弛豫测定是阐明Top1抑制剂的详细机制的敏感方法，并与Top1抑制剂的细胞疗效相关。 （c）2015年AACR。

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  • 来源
    《Molecular cancer therapeutics》 |2015年第11期|共8页
  • 作者

    Seol Yeonee; Zhang Hongliang; Agama Keli; Lorence Nicholas; Pommier Yves; Neuman Keir C.;

  • 作者单位

    NHLBI Lab Single Mol Biophys NIH Bethesda MD 20892 USA;

    NCI Lab Mol Pharmacol Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

    NCI Lab Mol Pharmacol Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

    NCI Lab Mol Pharmacol Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

    NCI Lab Mol Pharmacol Dev Therapeut Branch Ctr Canc Res NIH Bethesda MD 20892 USA;

    NHLBI Lab Single Mol Biophys NIH Bethesda MD 20892 USA;

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  • 正文语种 eng
  • 中图分类 肿瘤学;
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