Bradshaw D M, Arceci R J
Division of Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
J Clin Oncol. 1998 Nov;16(11):3674-90. doi: 10.1200/JCO.1998.16.11.3674.
For cytotoxic agents to have an effect on tumor cells, drugs must first be transported into the cell, potentially be metabolized to an active form, and interact appropriately with target molecules. A final common pathway of cytotoxic agents is usually the initiation of programmed cell death, or apoptosis. Tumor cells overcome the effects of cytotoxic agents at one or more of these levels. The classic multidrug-resistance (MDR) phenotype, as mediated by the drug efflux pump, P-glycoprotein, is one of the most extensively studied mechanisms of drug resistance. Additional drug transporters, such as the multidrug resistance-associated proteins (MRPs), have also been identified and can convey drug-resistance phenotypes. Important questions remain as to how and whether such transport systems can be specifically measured and effectively targeted to improve therapeutic outcomes. Furthermore, alterations in drug targets, drug metabolism, repair of DNA damage caused by drugs, and the inability to initiate programmed cell death can all contribute to drug resistance and must be ultimately considered in the explanation of tumor-cell resistance to therapy. Continued exploration of the pharmacologic methods to circumvent drug resistance, as well as strategies that involve targeted therapy and immunomodulation, should increase the specificity and efficacy of treatments for patients with cancer.
细胞毒性药物要对肿瘤细胞产生作用，必须首先转运进入细胞，可能代谢为活性形式，并与靶分子进行适当相互作用。细胞毒性药物的最终共同途径通常是启动程序性细胞死亡，即凋亡。肿瘤细胞在这些水平中的一个或多个水平上克服细胞毒性药物的作用。由药物外排泵P-糖蛋白介导的经典多药耐药（MDR）表型是研究最广泛的耐药机制之一。还鉴定出了其他药物转运蛋白，如多药耐药相关蛋白（MRP），它们可传递耐药表型。关于如何以及是否能够特异性测量此类转运系统并有效靶向以改善治疗效果，仍存在重要问题。此外，药物靶点的改变、药物代谢、药物引起的DNA损伤修复以及无法启动程序性细胞死亡都可能导致耐药，在解释肿瘤细胞对治疗的耐药性时必须最终予以考虑。继续探索规避耐药的药理学方法以及涉及靶向治疗和免疫调节的策略，应可提高癌症患者治疗的特异性和疗效。
