Borowski Edward, Bontemps-Gracz Maria M, Piwkowska Agnieszka
Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology, Gdańsk, Poland.
Acta Biochim Pol. 2005;52(3):609-27.
The development of multidrug resistance (MDR) of tumors is a major cause of failure in antitumor chemotherapy. This type of cross-resistance is due to the expression of ABC transporter glycoproteins actively effluxing the drug from the cells against the concentration gradient at the expense of metabolic energy, thus preventing the accumulation in cells of therapeutic concentration of active agents. In this review strategies for overcoming this adverse phenomenon are discussed. They comprise the control of expression of MDR glycoprotein transporters and control of the functioning of the expressed transporter proteins. The latter approach is discussed in more detail, comprising the following general strategies: (i) development of compounds that are not substrates of efflux pump(s), (ii) use of agents that inactivate (inhibit) MDR proteins, (iii) design of cytostatics characterized by fast cellular uptake, surpassing their mediated efflux, (iv) use of compounds competing with the drug for the MDR protein-mediated efflux. Positive and negative aspects of these strategies are analysed, with special attention put on strategy based on the use of MDR modulators in combination therapy, allowing the restoration of cytotoxic activity of clinical cytostatics towards resistant tumor cells.
肿瘤多药耐药（MDR）的产生是抗肿瘤化疗失败的主要原因。这种交叉耐药是由于ABC转运糖蛋白的表达，它以代谢能量为代价，主动将药物逆浓度梯度从细胞中排出，从而阻止活性药物在细胞内蓄积到治疗浓度。在这篇综述中，讨论了克服这一不良现象的策略。这些策略包括控制MDR糖蛋白转运体的表达以及控制已表达转运蛋白的功能。后一种方法将更详细地讨论，包括以下一般策略：（i）开发不是外排泵底物的化合物；（ii）使用使MDR蛋白失活（抑制）的药物；（iii）设计具有快速细胞摄取特性的细胞抑制剂，使其摄取速度超过其介导的外排速度；（iv）使用与药物竞争MDR蛋白介导外排的化合物。分析了这些策略的优缺点，特别关注基于在联合治疗中使用MDR调节剂的策略，该策略可恢复临床细胞抑制剂对耐药肿瘤细胞的细胞毒活性。
