Correlation between the kinetics of anthracycline uptake and the resistance factor in cancer cells expressing the multidrug resistance protein or the P-glycoprotein
Correlation between the kinetics of anthracycline uptake and the resistance factor in cancer cells expressing the multidrug resistance protein or the P-glycoprotein
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DOI：
10.1016/s0167-4889(99)00060-9
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发表时间：
1999-07-08
影响因子：
5.1
通讯作者：
Garnier-Suillerot, A
中科院分区：
文献类型：
--
作者：
Marbeuf-Gueye, C;Ettori, D;Garnier-Suillerot, A
已知模型系统中的多药耐药（MDR）由两种不同的整合蛋白质，170-kDa P-糖蛋白（Pgp）和190-kDa多药耐药相关蛋白（MRP 1）赋予。克服耐药性的一种可能的药理学方法是使用特异性抑制剂，其增强已知抗肿瘤剂的细胞毒性。然而，虽然许多化合物已被证明在抑制Pgp活性方面非常有效，但其中只有一些能够抑制MRP 1。另一种可能的方法是基于新的非交叉耐药药物的设计和合成，其物理化学性质有利于耐药细胞对药物的吸收。细胞内药物滞留影响其细胞毒作用。细胞内药物含量的水平是细胞内转运的药物量（流入）和从细胞排出的药物量（流出）的函数。在这项工作中，药物摄取的动力学和动力学的主动外排的几个蒽环类药物衍生物在表达Pgp的K562/Adr细胞和表达MRP 1的GLC 4/Adr细胞进行了测定。我们的数据表明，在这两种细胞系中，耐药因子与这些泵送系统的药物外排动力学之间没有相关性。然而，在这两种细胞系中已经建立了耐药因子和药物摄取动力学之间的非常好的相关性：当药物摄取动力学增加时，耐药因子减小;这项工作清楚地表明，当蒽环类药物的跨膜转运速率足够高时，由蛋白质转运体介导的外排不能与之同步。2蛋白质转运体基本上在无效循环中运行，而阻力因子正趋于一。然而，这并不意味着当阻力因子接近1时，蒽环类药物不被泵输送。(C)1999 Elsevier Science B. V.保留所有权利。
Multidrug resistance (MDR) in model systems is known to be conferred by two different integral proteins, the 170-kDa P-glycoprotein (Pgp) and the 190-kDa multidrug resistance associated protein (MRP1). One possible pharmacological approach to overcome drug resistance is the use of specific inhibitors, which enhance the cytotoxicity of known antineoplastic agents. However, while many compounds have been proven to be very efficient in inhibiting Pgp activity only some of them are able to inhibit MRP1. The other Likely approach is based on the design and synthesis of new non-cross-resistant drugs with physicochemical properties favoring the uptake of the drug by the resistant cells. The intracellular drug retention influences its cytotoxic effect. The level of the intracellular drug content is a function of the amount of drug transported inside the cell (influx) and the amount of drug expelled from the cell (efflux). In this work, the kinetics of drug uptake and the kinetics of active efflux of several anthracycline derivatives in both Pgp expressing K562/Adr cells and MRP1 expressing GLC4/Adr cells was determined. Our data have shown that in both cell lines there is no correlation between the resistance Factor and the kinetics of drug efflux by these pumping systems. However, a very good correlation between the resistance factor and the kinetics of drug uptake has been established in both cell lines: the resistance factor decreases when the kinetics of drug uptake increases; This work has clearly shown that when the rate of transmembrane transport of anthracycline is high enough, the efflux mediated by the protein transporter is not able to pace with it. The protein transporter essentially operates in a futile cycle and the resistance factor is tending to one. It does not mean, however, that when the resistance factor is close to one the anthracycline is not transported by the pump. (C) 1999 Elsevier Science B.V. All rights reserved.