Reddy P G, Graham G M, Datta S, Guarini L, Moulton T A, Jiang H P, Gottesman M M, Ferrone S, Fisher P B
Department of Urology, Columbia University, College of Physicians and Surgeons, New York, NY 10032.
J Natl Cancer Inst. 1991 Sep 18;83(18):1307-15. doi: 10.1093/jnci/83.18.1307.
To study the effect of drug resistance on the response of stage IV astrocytomas to interferon, a human glioblastoma multiforme cell line, GBM-18, was transfected with an expression-vector plasmid containing a human multidrug resistance (MDR) gene (pHaMDR1/A), and clones surviving in colchicine were isolated. GBM-18 multidrug-resistant subclones displayed cross-resistance to other chemotherapeutic agents, including vincristine, doxorubicin, and dactinomycin. The multidrug-resistant phenotype was reversible when GBM-18 multidrug-resistant cells were cultured in colchicine and the calcium-channel blocker verapamil. The level of the MDR1 gene (also known as PGY1) message was increased in GBM-18 multidrug-resistant cells selected for increased resistance to colchicine, and this effect was not correlated with an amplification of the MDR1 gene. In both parental GBM-18 and GBM-18 multidrug-resistant cells, growth was suppressed to a greater degree when cultures were treated with the combination of fibroblast interferon (IFN-beta) and immune interferon (IFN-gamma). Parental cells and multidrug-resistant subclones varied in their de novo and/or interferon-modulated expression of HLA class I and class II antigens, a high-molecular-weight melanoma-associated antigen, and intercellular adhesion molecule 1 (ICAM-1). Of the antigens tested, ICAM-1 and HLA class I antigens were the most sensitive to enhanced expression induced by IFN-beta and IFN-gamma when used alone or in combination. The results of the present study indicate that multidrug-resistant human glioblastoma multiforme cells retain their increased sensitivity to the antiproliferative activity of the combination of IFN-beta plus IFN-gamma, and differences in antigenic phenotype are apparent in independent multidrug-resistant glioblastoma multiforme clones.
为研究耐药性对IV期星形细胞瘤对干扰素反应的影响，用含人多药耐药（MDR）基因（pHaMDR1/A）的表达载体质粒转染人多形性胶质母细胞瘤细胞系GBM - 18，并分离出在秋水仙碱中存活的克隆。GBM - 18多药耐药亚克隆对其他化疗药物，包括长春新碱、阿霉素和放线菌素，表现出交叉耐药性。当GBM - 18多药耐药细胞在秋水仙碱和钙通道阻滞剂维拉帕米中培养时，多药耐药表型是可逆的。在为增强对秋水仙碱的耐药性而选择的GBM - 18多药耐药细胞中，MDR1基因（也称为PGY1）的信使水平升高，且这种效应与MDR1基因的扩增无关。在亲代GBM - 18细胞和GBM - 18多药耐药细胞中，当用成纤维细胞干扰素（IFN - β）和免疫干扰素（IFN - γ）联合处理培养物时，生长受到更大程度的抑制。亲代细胞和多药耐药亚克隆在HLA I类和II类抗原、一种高分子量黑色素瘤相关抗原以及细胞间粘附分子1（ICAM - 1）的从头合成和/或干扰素调节表达方面存在差异。在所测试的抗原中，ICAM - 1和HLA I类抗原对单独或联合使用的IFN - β和IFN - γ诱导的表达增强最为敏感。本研究结果表明，多药耐药的人多形性胶质母细胞瘤细胞对IFN - β加IFN - γ联合的抗增殖活性仍保持其增强的敏感性，并且在独立的多药耐药多形性胶质母细胞瘤克隆中抗原表型存在明显差异。
