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首页> 外文期刊>Biochemistry >Quinolones share a common interaction domain on topoisomerase II with other DNA cleavage-enhancing antineoplastic drugs.
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Quinolones share a common interaction domain on topoisomerase II with other DNA cleavage-enhancing antineoplastic drugs.

机译：喹诺酮类药物在拓扑异构酶II上与其他增强DNA裂解的抗肿瘤药具有共同的相互作用域。

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Topoisomerase II is the cytotoxic target for a number of clinically relevant antineoplastic drugs. Despite the fact that these agents differ significantly in structure, a previous study [Corbett, A. H., Hong, D., & Osheroff, N. (1993) J. Biol. Chem. 268, 14394-14398] indicated that the site of action for etoposide on topoisomerase II overlaps those of other DNA cleavage-enhancing drugs. Therefore, to further define interactions between drugs and the enzyme, the functional interaction domain (i.e., interaction domain defined by drug function) for quinolones on Drosophila topoisomerase II was mapped with respect to several classes of antineoplastic agents. This was accomplished by characterizing the effects of ciprofloxacin (a gyrase-targeted antibacterial quinolone) on the ability of etoposide, amsacrine, genistein, and the antineoplastic quinolone, CP-115,953, to enhance topoisomerase II-mediated DNA cleavage. Although ciprofloxacin interacts with the eukaryotic type II enzyme, it shows little ability to stimulate DNA cleavage. Ciprofloxacin attenuated cleavage enhancement by all of the above drugs. Similar results were obtained using a related quinolone, CP-80,080, as a competitor. In addition, kinetic analysis of DNA cleavage indicated that ciprofloxacin is a competitive inhibitor of CP-115,953 and etoposide. Finally, ciprofloxacin inhibited the cytotoxic actions of CP-115,953 and etoposide in mammalian cells to an extent that paralleled its in vitro attenuation of cleavage. These results strongly suggest that several structurally disparate DNA cleavage-enhancing antineoplastic drugs share an overlapping site of action on topoisomerase II. Based on the results of drug competition and mutagenesis studies, a model for the drug interaction domain on topoisomerase II is described.
机译：拓扑异构酶II是许多临床相关抗肿瘤药的细胞毒性靶标。尽管事实上这些药剂在结构上有很大的不同，但是以前的研究[Corbett，A.H.，Hong，D。，＆Osheroff，N。（1993）J.Biol.Chem。，1993，5，1897]。化学268，14394-14398]表明依托泊苷在拓扑异构酶II上的作用位点与其他增强DNA裂解的药物的作用位点重叠。因此，为了进一步定义药物与酶之间的相互作用，针对几类抗肿瘤药绘制了果蝇拓扑异构酶II上喹诺酮的功能相互作用域（即，由药物功能定义的相互作用域）。这是通过表征环丙沙星（一种针对陀螺酶的抗菌喹诺酮）对依托泊苷，amsacrine，染料木黄酮和抗肿瘤喹诺酮CP-115953增强拓扑异构酶II介导的DNA裂解能力的作用来实现的。尽管环丙沙星与II型真核酶相互作用，但它几乎没有刺激DNA裂解的能力。环丙沙星减弱了上述所有药物的切割增强作用。使用相关的喹诺酮CP-80,080作为竞争者可获得相似的结果。此外，对DNA裂解的动力学分析表明，环丙沙星是CP-115,953和依托泊苷的竞争性抑制剂。最后，环丙沙星在哺乳动物细胞中抑制了CP-115,953和依托泊苷的细胞毒作用，其程度与其体外裂解的减弱程度相当。这些结果强烈表明，几种结构上不同的DNA切割增强抗肿瘤药在拓扑异构酶II上具有重叠的作用位点。基于药物竞争和诱变研究的结果，描述了拓扑异构酶II上药物相互作用域的模型。

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