Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Mol Pharmacol. 2012 Dec;82(6):1008-21. doi: 10.1124/mol.112.079129. Epub 2012 Jul 23.
Multidrug resistance (MDR), which is mediated by multiple drug efflux ATP-binding cassette (ABC) transporters, is a critical issue in the treatment of acute leukemia, with permeability glycoprotein (P-gp), multidrug resistance-associated protein 1, and breast cancer resistance protein (i.e., ABCG2) consistently being shown to be key effectors of MDR in cell line studies. Studies have demonstrated that intrinsic MDR can arise as a result of specific gene expression profiles and that drug-induced overexpression of P-gp and other MDR proteins can result in acquired resistance, with multiple ABC transporters having been shown to be overexpressed in cell lines selected for resistance to multiple drugs used to treat acute leukemia. Furthermore, numerous anticancer drugs, including agents commonly used for the treatment of acute leukemia (e.g., doxorubicin, vincristine, mitoxantrone, and methotrexate), have been shown to be P-gp substrates or to be susceptible to efflux mediated by other MDR proteins, and multiple clinical studies have demonstrated associations between P-gp or other MDR protein expression and responses to therapy or survival rates in acute leukemia. Here we review the importance of MDR in cancer, with a focus on acute leukemia, and we highlight the need for rapid accurate assessment of MDR status for optimal treatment selection. We also address the latest research on overcoming MDR, from inhibition of P-gp and other MDR proteins through various approaches (including direct antagonism and gene silencing) to the design of novel agents or novel delivery systems for existing therapeutic agents, to evade cellular efflux.
多药耐药性（MDR）是由多种药物外排 ATP 结合盒（ABC）转运蛋白介导的，是急性白血病治疗中的一个关键问题，在细胞系研究中，一直表明多药耐药相关蛋白 1（MDR1）和乳腺癌耐药蛋白（即 ABCG2）是 MDR 的关键效应物。研究表明，固有 MDR 可能是由于特定基因表达谱引起的，并且 P-糖蛋白和其他 MDR 蛋白的药物诱导过表达可导致获得性耐药，已经表明多种 ABC 转运蛋白在对用于治疗急性白血病的多种药物耐药的细胞系中过表达。此外，许多抗癌药物，包括用于治疗急性白血病的常用药物（如阿霉素、长春新碱、米托蒽醌和甲氨蝶呤），已被证明是 P-糖蛋白的底物，或易受其他 MDR 蛋白介导的外排影响，多项临床研究表明 P-糖蛋白或其他 MDR 蛋白表达与急性白血病治疗反应或生存率之间存在关联。在这里，我们回顾了 MDR 在癌症中的重要性，重点是急性白血病，并强调了快速准确评估 MDR 状态以优化治疗选择的必要性。我们还讨论了克服 MDR 的最新研究进展，包括通过各种方法（包括直接拮抗和基因沉默）抑制 P-糖蛋白和其他 MDR 蛋白，以及设计用于现有治疗剂的新型药物或新型输送系统，以逃避细胞外排。
