Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Drug Resist Updat. 2012 Feb-Apr;15(1-2):98-105. doi: 10.1016/j.drup.2012.03.002. Epub 2012 Apr 6.
While chemotherapy remains the most effective treatment for disseminated tumors, acquired or intrinsic drug resistance accounts for approximately 90% of treatment failure. Multidrug resistance (MDR), the simultaneous resistance to drugs that differ both structurally and mechanistically, often results from drug efflux pumps in the cell membrane that reduce intracellular drug levels to less than therapeutic concentrations. Expression of the MDR transporter P-glycoprotein (P-gp, MDR1, ABCB1) has been shown to correlate with overall poor chemotherapy response and prognosis. This review will focus on collateral sensitivity (CS), the ability of compounds to kill MDR cells selectively over the parental cells from which they were derived. Insights into CS may offer an alternative strategy for the clinical resolution of MDR, as highly selective and potent CS agents may lead to drugs that are effective at MDR cell killing and tumor resensitization. Four main mechanistic hypotheses for CS will be reviewed, followed by a discussion on quantitative and experimental evaluation of CS.
虽然化疗仍然是治疗弥散性肿瘤最有效的方法，但获得性或内在药物耐药性约占治疗失败的 90%。多药耐药（MDR），即同时对结构和机制上不同的药物产生耐药性，通常是由于细胞膜中的药物外排泵导致细胞内药物水平降低到低于治疗浓度。已经表明，多药耐药转运蛋白 P-糖蛋白（P-gp，MDR1，ABCB1）的表达与整体化疗反应不良和预后差相关。本综述将重点介绍协同敏感性（CS），即化合物选择性杀死 MDR 细胞而不杀死其来源的亲本细胞的能力。对 CS 的深入了解可能为临床解决 MDR 提供一种替代策略，因为高选择性和高效的 CS 剂可能导致对 MDR 细胞杀伤和肿瘤再敏化有效的药物。本文将综述 CS 的四个主要机制假说，然后讨论 CS 的定量和实验评估。
