对可裂解复合物形成拓扑异构酶II抑制剂耐药的细胞系对ICRF-159的反应。

Response to ICRF-159 in cell lines resistant to cleavable complex-forming topoisomerase II inhibitors.

作者信息

Davies S L, Bergh J, Harris A L, Hickson I D

机构信息

Imperial Cancer Research Fund Laboratories, University of Oxford, UK.

出版信息

Br J Cancer. 1997;75(6):816-21. doi: 10.1038/bjc.1997.146.

DOI:10.1038/bjc.1997.146

PMID:9062401

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2063389/

Abstract

We have studied the relationship between expression of genes implicated in mediating resistance to cleavable complex-forming topoisomerase II (topo II) inhibitors and cellular sensitivity to ICRF-159, a 'catalytic' inhibitor of topo II. Overexpression of the membrane transporters, P-glycoprotein and multidrug resistance-related protein (MRP), or down-regulation of topo IIalpha and/or -beta, did not confer ICRF-159 resistance. Indeed, marked topo IIalpha down-regulation appeared to be associated with collateral sensitivity to ICRF-159. Our results indicate that the resistance mechanisms that pertain to cleavable complex-forming topo II inhibitors and ICRF-159 are distinct. The evidence presented here suggests that topo IIalpha, not topo IIbeta, is more likely to be the major in vivo target for ICRF-159.

摘要

我们研究了与介导对可裂解复合物形成的拓扑异构酶II（拓扑II）抑制剂耐药相关的基因表达与细胞对拓扑II的“催化”抑制剂ICRF-159的敏感性之间的关系。膜转运蛋白P-糖蛋白和多药耐药相关蛋白（MRP）的过表达，或拓扑IIα和/或-β的下调，均未赋予对ICRF-159的耐药性。事实上，明显的拓扑IIα下调似乎与对ICRF-159的协同敏感性相关。我们的结果表明，与可裂解复合物形成的拓扑II抑制剂和ICRF-159相关的耐药机制是不同的。此处提供的证据表明，拓扑IIα而非拓扑IIβ更有可能是ICRF-159在体内的主要靶点。