Mechetner E B, Roninson I B
Department of Genetics, University of Illinois, Chicago, IL 60612.
Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):5824-8. doi: 10.1073/pnas.89.13.5824.
P-glycoprotein (Pgp), encoded by the MDR1 gene, is an active efflux pump for many structurally diverse lipophilic compounds. Cellular expression of Pgp results in multidrug resistance (MDR) in vitro and is believed to be a clinically relevant mechanism for tumor resistance to chemotherapy. We have developed a mouse monoclonal antibody, UIC2, that recognizes an extracellular epitope of human Pgp. UIC2 inhibited the efflux of Pgp substrates from MDR cells and significantly increased the cytotoxicity of Pgp-transported drugs, under the conditions where no effect was detectable with other anti-Pgp antibodies. Potentiation of cytotoxicity by UIC2 was observed with all the tested drugs associated with MDR (vinblastine, vincristine, colchicine, taxol, doxorubicin, etoposide, actinomycin D, puromycin, and gramicidin D) but not with any of the drugs to which MDR cells are not cross-resistant (methotrexate, 5-fluorouracil, cis-platinum, G418, and gentamicin). The inhibitory effect of UIC2 in vitro was as strong as that of verapamil (a widely used Pgp inhibitor) at its highest clinically achievable concentrations. Our results suggest that UIC2 or its derivatives provide an alternative or supplement to chemical agents for the reversal of MDR in clinical cancer.
由多药耐药基因1（MDR1）编码的P-糖蛋白（Pgp）是一种对多种结构各异的亲脂性化合物具有活性的外排泵。Pgp在细胞中的表达导致体外多药耐药（MDR），并且被认为是肿瘤对化疗产生耐药性的一种临床相关机制。我们研发了一种小鼠单克隆抗体UIC2，它能识别人类Pgp的一个细胞外表位。在其他抗Pgp抗体未检测到作用的条件下，UIC2抑制了Pgp底物从MDR细胞中的外排，并显著增强了Pgp转运药物的细胞毒性。UIC2对所有与MDR相关的测试药物（长春碱、长春新碱、秋水仙碱、紫杉醇、阿霉素、依托泊苷、放线菌素D、嘌呤霉素和短杆菌肽D）都观察到了细胞毒性增强作用，但对MDR细胞无交叉耐药性的任何药物（甲氨蝶呤、5-氟尿嘧啶、顺铂、G418和庆大霉素）均未观察到这种作用。在临床可达到的最高浓度下，UIC2在体外的抑制作用与维拉帕米（一种广泛使用的Pgp抑制剂）一样强。我们的结果表明，UIC2或其衍生物可为临床癌症中逆转MDR的化学药物提供替代或补充。
