Department of Obstetrics and Gynecology, Medical and Health Science Center, University of Debrecen, Nagyerdei krt. 98. H-4032, Debrecen, Hungary.
Eur J Pharm Sci. 2010 Dec 23;41(5):665-9. doi: 10.1016/j.ejps.2010.09.009. Epub 2010 Oct 1.
P-glycoprotein (Pgp, ABCB1) is one of the active efflux pumps that are able to extrude a large variety of chemotherapeutic drugs from the cells, causing the phenomenon of multidrug resistance. It has been shown earlier that the combined application of a class of Pgp modulators (e.g. cyclosporine A and SDZ PSC 833) used at low concentrations and UIC2 antibody is a novel, specific, and effective way of blocking Pgp function (Goda et al., 2007). In the present work we study the UIC2 antibody mediated Pgp inhibition in more detail measuring the accumulation of tumor diagnostic radiotracers, 2-[(18)F]fluoro-2-deoxy-d-glucose ((18)FDG) and [(99m)Tc]hexakis-2-methoxybutyl isonitrile ((99m)Tc-MIBI), into Pgp(+) (A2780AD) and Pgp(-) (A2780) human ovarian carcinoma cells. Co-incubation of cells with UIC2 and cyclosporine A (CSA, 2μM) increased the binding of UIC2 more than 3-fold and reverted the rhodamine 123 (R123), daunorubicin (DNR) and (99m)Tc-MIBI accumulation of the Pgp(+) 2780AD cells to approx. the same level as observed in Pgp(-) cells. Similarly, 50μM paclitaxel (Pacl) increased UIC2 binding, and consequently reinstated the uptake of R123, DNR and (99m)Tc-MIBI into the Pgp(+) cells. Blocking Pgp by combined treatments with CSA+UIC2 or Pacl+UIC2 also decreased the glucose metabolic rate of the A2780AD Pgp(+) cells measured in (18)FDG accumulation experiments suggesting that the maintenance of Pgp activity requires a considerable amount of energy. Similar treatments of the A2780 Pgp(-) cells did not result in significant change in the R123, DNR, (99m)Tc-MIBI and (18)FDG accumulation demonstrating that the above effects are Pgp-specific. Thus, combined treatment with the UIC2 antibody and Pgp modulators can completely block the function of Pgp in human ovarian carcinoma cells and this effect can be followed in vitro by using tumor-diagnostic radiotracers, (99m)Tc-MIBI and (18)FDG.
P-糖蛋白（Pgp，ABCB1）是一种主动外排泵，可以将多种化疗药物从细胞中排出，导致多药耐药现象。先前已经表明，联合应用一类 Pgp 调节剂（如环孢素 A 和 SDZPSC833），以低浓度和 UIC2 抗体使用，是一种新型、特异和有效的阻断 Pgp 功能的方法（Goda 等人，2007 年）。在本工作中，我们更详细地研究了 UIC2 抗体介导的 Pgp 抑制作用，通过测量肿瘤诊断放射性示踪剂 2-[[18]F]氟-2-脱氧-D-葡萄糖（[18]FDG）和[[99m]Tc]六（2-甲氧基丁基）异腈（[99m]Tc-MIBI）在 Pgp(+)（A2780AD）和 Pgp(-)（A2780）人卵巢癌细胞中的积累。细胞与 UIC2 和环孢素 A（CSA，2μM）共孵育，使 UIC2 的结合增加了 3 倍以上，并使 Pgp(+)2780AD 细胞的罗丹明 123（R123）、柔红霉素（DNR）和[99m]Tc-MIBI 积累恢复到与 Pgp(-)细胞相同的水平。同样，50μM 紫杉醇（Pacl）增加了 UIC2 的结合，从而恢复了 R123、DNR 和[99m]Tc-MIBI 进入 Pgp(+)细胞的摄取。CSA+UIC2 或 Pacl+UIC2 的联合治疗阻断 Pgp 也降低了[18]FDG 积累实验中 A2780AD Pgp(+)细胞的葡萄糖代谢率，表明维持 Pgp 活性需要相当多的能量。对 A2780 Pgp(-)细胞的类似处理没有导致 R123、DNR、[99m]Tc-MIBI 和[18]FDG 积累的显著变化，表明上述效应是 Pgp 特异性的。因此，UIC2 抗体和 Pgp 调节剂的联合治疗可以完全阻断人卵巢癌细胞中 Pgp 的功能，并且可以通过使用肿瘤诊断放射性示踪剂[99m]Tc-MIBI 和[18]FDG 在体外跟踪这种效应。
