Disruption of P-glycoprotein anticancer drug efflux activity by a small recombinant single-chain Fv antibody fragment targeted to an extracellular epitope

被引:19
作者
Haus-Cohen, M
Assaraf, YG
Binyamin, L
Benhar, I
Reiter, Y [1 ]
机构
[1] Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel
[2] Tel Aviv Univ, Fac Life Sci, Dept Mol Microbiol & Biotechnol, IL-69978 Tel Aviv, Israel
关键词
P-glycoprotein; multidrug resistance; single-chain Fv;
D O I
10.1002/ijc.20037
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Inherent and acquired MDR is characterized by simultaneous resistance to diverse anticancer drugs and continues to be a major impediment in the curative chemotherapy of cancer. The MDR I gene product, Pgp, is an ATP-driven efflux pump, which extrudes a variety of dissimilar hydrophobic cytotoxic compounds from MDR cells. Pgp overexpression results in MDR of tumor cell lines in vitro as well as of a variety of human malignancies. Thus, one major goal is to develop strategies aimed at specifically disrupting Pgp drug-efflux activity. To this end, we have developed a small recombinant antibody capable of potent reversal of MDR, by disrupting Pgp drug-efflux activity. Using a phage display approach, we isolated a small scFv recombinant antibody fragment that specifically reacts with the first extracellular loop of human Pgp. This scFv fragment binds specifically to various Pgp-overexpressing human MDR carcinoma cell lines, consequently disrupts Pgp drug-efflux function and thereby reverses the MDR phenotype. We have successfully disrupted anticancer drug-extrusion pump activity in MDR cells using a small recombinant scFv fragment. We propose that these novel small Fv-based recombinant antibody molecules may lead to the development of a new class of antibody fragment-based agents that specifically inhibit Pgp drug extrusion. Hence, these small recombinant antibody fragments may be applied in combination chemotherapy to overcome MDR in various human cancers. (C) 2004 Wiley-Liss, Inc.
引用
收藏
页码:750 / 758
页数:9
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