二氢吡啶盐酸右尼群地平抑制真核生物DNA拓扑异构酶I的切割和重新连接反应。

The dihydropyridine dexniguldipine hydrochloride inhibits cleavage and religation reactions of eukaryotic DNA topoisomerase I.

作者信息

Straub T, Boesenberg C, Gekeler V, Boege F

机构信息

Medizinische Poliklinik, University of Würzburg Medical School, Würzburg, Germany.

出版信息

Biochemistry. 1997 Sep 2;36(35):10777-83. doi: 10.1021/bi970417q.

DOI:10.1021/bi970417q

PMID:9271509

Abstract

Dexniguldipine hydrochloride (B859-35, a dihydropyridine with antitumor and multidrug resistance-reverting activity) inhibits both the DNA cleavage and religation reactions of purified human DNA topoisomerase I at concentrations >1 microM, whereas at concentrations <1 microM it inhibits selectively the religation step and stabilizes the covalent topoisomerase I-DNA intermediate in a similar fashion as camptothecin. Inhibition of religation by camptothecin can be overcome by increasing the concentration of the DNA substrate in the religation reaction, indicating a competitive type of inhibition. In contrast, dexniguldipine hydrochloride decreases rate constants of topoisomerase I-mediated DNA religation independently of the concentration of the DNA substrate, suggesting a noncompetitive mechanism of inhibition, which is different from that of camptothecin.

摘要

盐酸地尼莫地平（B859 - 35，一种具有抗肿瘤和逆转多药耐药活性的二氢吡啶）在浓度大于1微摩尔时可抑制纯化的人DNA拓扑异构酶I的DNA切割和重新连接反应，而在浓度小于1微摩尔时，它选择性地抑制重新连接步骤，并以与喜树碱类似的方式稳定共价拓扑异构酶I - DNA中间体。喜树碱对重新连接的抑制作用可通过增加重新连接反应中DNA底物的浓度来克服，这表明是一种竞争性抑制类型。相比之下，盐酸地尼莫地平降低拓扑异构酶I介导的DNA重新连接的速率常数，且与DNA底物浓度无关，提示其抑制机制为非竞争性，这与喜树碱不同。