Bähr Oliver, Rieger Johannes, Duffner Frank, Meyermann Richard, Weller Michael, Wick Wolfgang
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, Germany.
Brain Pathol. 2003 Oct;13(4):482-94. doi: 10.1111/j.1750-3639.2003.tb00479.x.
Understanding and overcoming multidrug resistance (MDR) may be a promising strategy to develop more effective pharmacotherapies for malignant gliomas. In the present study, human malignant glioma cell lines (n=12) exhibited heterogeneous mRNA and protein expression and functional activity of the mdr gene-encoded P-glycoprotein (PGP) and MDR-associated protein (MRP). Correlation between mRNA expression, protein levels and functional activity was strong. Inhibition of PGP activity by verapamil or PSC 833 enhanced the cytotoxic effects of vincristine, doxorubicin, teniposide and taxol. Inhibition of MRP activity by indomethacin or probenecid enhanced the cytotoxic effects of vincristine, doxorubicin and teniposide. The human cerebral endothelial cell line, SV-HCEC, exhibited the strongest PGP activity of all cell lines. Five primary human glioblastomas and one anaplastic astrocytoma displayed heterogenous protein levels of PGP and MRP-1 in tumor cells and of PGP in biopsy specimens in vivo, but no functional activity of these proteins upon ex vivo culturing. These data suggest that the glioma cell line-associated MDR-type drug resistance is a result of long-term culturing and that cerebral endothelial, but not glioma cells, may contribute to MDR-type drug resistance of gliomas in vivo.
了解并克服多药耐药性（MDR）可能是开发更有效的恶性胶质瘤药物疗法的一种有前景的策略。在本研究中，人类恶性胶质瘤细胞系（n = 12）表现出mdr基因编码的P-糖蛋白（PGP）和多药耐药相关蛋白（MRP）的mRNA和蛋白质表达以及功能活性的异质性。mRNA表达、蛋白质水平和功能活性之间的相关性很强。维拉帕米或PSC 833对PGP活性的抑制增强了长春新碱、阿霉素、替尼泊苷和紫杉醇的细胞毒性作用。吲哚美辛或丙磺舒对MRP活性的抑制增强了长春新碱、阿霉素和替尼泊苷的细胞毒性作用。人脑血管内皮细胞系SV-HCEC在所有细胞系中表现出最强的PGP活性。5例原发性人类胶质母细胞瘤和1例间变性星形细胞瘤在肿瘤细胞中显示出PGP和MRP-1的蛋白质水平异质性，在体内活检标本中显示出PGP的蛋白质水平异质性，但在体外培养时这些蛋白质无功能活性。这些数据表明，胶质瘤细胞系相关的MDR型耐药性是长期培养的结果，并且脑血管内皮细胞而非胶质瘤细胞可能在体内导致胶质瘤的MDR型耐药性。
