Department of Physiology and Pharmacology, Campus Miguel de Unamuno E.I.D., Salamanca, Spain.
Curr Cancer Drug Targets. 2012 May;12(4):402-38. doi: 10.2174/156800912800190875.
Refractoriness to the pharmacological treatment of cancer is dependent on the expression levels of genes involved in mechanisms of chemoresistance and on the existence of genetic variants that may affect their function. Thus, changes in genes encoding solute carriers may account for considerable inter-individual variability in drug uptake and the lack of sensitivity to the substrates of these transporters. Moreover, changes in proteins involved in drug export can affect their subcellular localization and transport ability and hence may also modify the bioavailability of antitumor agents. Regarding pro-drug activation or drug inactivation, genetic variants are responsible for changes in the activity of drug-metabolizing enzymes, which affect drug clearance and may determine the lack of response to anticancer chemotherapy. The presence of genetic variants may also decrease the sensitivity to pharmacological agents acting through molecular targets or signaling pathways. Recent investigations suggest that changes in genes involved in DNA repair may affect the response to platinum-based drugs. Since most anticancer agents activate cell death pathways, the evasion of apoptosis plays an important role in chemoresistance. Several genetic variants affecting death-receptor pathways, the mitochondrial pathway, downstream caspases and their natural modulators, and the p53 pathway, whose elements are mutated in more than half of tumors, and survival pathways, have been reported. The present review summarizes the available data regarding the role of genetic variants in the different mechanisms of chemoresistance and discusses their potential impact in clinical practice and in the development of tools to predict and overcome chemoresistance.
癌症药物治疗的耐药性取决于参与耐药机制的基因的表达水平，以及可能影响其功能的遗传变异的存在。因此，编码溶质载体的基因变化可能导致药物摄取的个体间差异很大，并且这些转运体的底物缺乏敏感性。此外，参与药物外排的蛋白质的变化会影响它们的亚细胞定位和运输能力，因此也可能改变抗肿瘤药物的生物利用度。关于前药激活或药物失活，遗传变异可导致药物代谢酶活性的变化，这会影响药物清除率，并可能决定对癌症化疗的无反应。遗传变异的存在也可能降低通过分子靶点或信号通路发挥作用的药理制剂的敏感性。最近的研究表明，参与 DNA 修复的基因变化可能会影响对铂类药物的反应。由于大多数抗癌药物激活细胞死亡途径，因此逃避细胞凋亡在耐药性中起着重要作用。已经报道了几种影响死亡受体途径、线粒体途径、下游半胱天冬酶及其天然调节剂以及 p53 途径的遗传变异，这些途径的元素在超过一半的肿瘤中发生突变，以及生存途径。本综述总结了关于遗传变异在不同耐药机制中的作用的现有数据，并讨论了它们在临床实践和开发预测和克服耐药性的工具中的潜在影响。
