Chong A S, Markham P N, Gebel H M, Bines S D, Coon J S
Department of General Surgery, Rush-Presbyterian, St. Luke's Medical Center, Chicago, IL 60612.
Cancer Immunol Immunother. 1993;36(2):133-9. doi: 10.1007/BF01754414.
Multidrug resistance (MDR) is the phenomenon in which cultured tumor cells selected for resistance to one chemotherapeutic agent simultaneously acquire resistance to several apparently unrelated drugs. MDR in tumor cells is associated with the over-expression of P-glycoprotein, an ATP-dependent cell-membrane transport molecule. P-glycoprotein is also expressed in several normal tissues but its physiological role(s) is unknown. We recently observed that a hierarchy of MDR-like activity exists among human peripheral blood lymphocytes in the order CD8 > CD4 > CD20 (cytotoxic/suppressor T cells, helper T cells and B cells respectively). In this study, we report that natural killer (NK) cells also express MDR-like activity. This activity could be inhibited with verapamil or solutol HS-15, two agents that reverse MDR in tumor cells. These, and four additional reversing agents, were used to investigate the possible role of P-glycoprotein in NK cells. We observed that at 10% of their IC50, five of six reversing agents inhibited NK-cell-mediated cytotoxicity; at higher (but non-toxic) doses, all six agents were inhibitory. These data suggest that NK-cell-mediated cytotoxicity may require the functional expression of an efflux molecule similar or identical to P-glycoprotein.
多药耐药性（MDR）是一种现象，即经过培养筛选出对一种化疗药物具有抗性的肿瘤细胞同时对几种明显无关的药物也产生抗性。肿瘤细胞中的多药耐药性与P-糖蛋白的过度表达有关，P-糖蛋白是一种依赖ATP的细胞膜转运分子。P-糖蛋白也在几种正常组织中表达，但其生理作用尚不清楚。我们最近观察到，人类外周血淋巴细胞中存在类似多药耐药性的活性等级，顺序为CD8＞CD4＞CD20（分别为细胞毒性/抑制性T细胞、辅助性T细胞和B细胞）。在本研究中，我们报告自然杀伤（NK）细胞也表达类似多药耐药性的活性。这种活性可以被维拉帕米或聚山梨醇酯HS-15抑制，这两种药物可逆转肿瘤细胞中的多药耐药性。使用这两种药物以及另外四种逆转剂来研究P-糖蛋白在NK细胞中的可能作用。我们观察到，在六种逆转剂中有五种在其IC50的10%时抑制NK细胞介导的细胞毒性；在更高（但无毒）剂量下，所有六种药物均具有抑制作用。这些数据表明，NK细胞介导的细胞毒性可能需要一种与P-糖蛋白相似或相同的外排分子的功能性表达。
