Mickisch G H, Roehrich K, Koessig J, Forster S, Tschada R K, Alken P M
Department of Urology, Mannheim Hospital, University of Heidelberg, Federal Republic of Germany.
J Urol. 1990 Sep;144(3):755-9. doi: 10.1016/s0022-5347(17)39586-1.
Human renal cell carcinomas show a high degree of intrinsic multidrug resistance. In experimental cell lines, the membrane bound P-170 glycoprotein and the glutathione redox cycle seem to contribute to this phenomenon. P-170 may be inactivated by calcium antagonists; the glutathione redox cycle by buthionine sulfoximine. We studied the resistance patterns of 35 human renal cell carcinomas against vinblastine, doxorubicin and carboplatinum in a tetrazolium-based microculture assay. Concomitantly, P-170 expression was traced immunohistochemically using moab C219 and the glutathione content was determined enzymatically. Reversal of multidrug resistance was examined by applying the R-stereoisomer of verapamil and/or by addition of buthionine sulfoximine. A high degree of chemoresistance was seen in 27 tumors against vinblastine, in 30 tumors against doxorubicin and in 31 tumors against carboplatinum. Chemoresponse was found in eight, five or four cases respectively. P-170 was detected in 70% of highly vinblastine resistant and in 63% of highly doxorubicin resistant tumors, but in none of the less resistant cases. Resistance against carboplatinum and doxorubicin was significantly associated with elevated glutathione levels as compared to less resistant renal cell carcinomas. R-verapamil lead to a strong reversal of vinblastine resistance and to a distinct circumvention of doxorubicin resistance, but revealed no effect in carboplatinum resistance. Buthionine sulfoximine overcame carboplatinum resistance and modified doxorubicin resistance, but had no influence on vinblastine resistance. The combined application of R-verapamil and buthionine sulfoximine reversed doxorubicin resistance but did not act synergistically in vinblastine or carboplatinum resistance. Both mechanisms, P-170 and glutathione, occurred independently of each other and may well explain multidrug resistance of human renal cell carcinomas.
人类肾细胞癌表现出高度的内在多药耐药性。在实验细胞系中，膜结合的P - 170糖蛋白和谷胱甘肽氧化还原循环似乎与这一现象有关。钙拮抗剂可能使P - 170失活；丁硫氨酸亚砜胺可使谷胱甘肽氧化还原循环失活。我们在基于四氮唑的微量培养试验中研究了35例人类肾细胞癌对长春碱、阿霉素和卡铂的耐药模式。同时，使用单克隆抗体C219通过免疫组织化学法追踪P - 170的表达，并通过酶法测定谷胱甘肽含量。通过应用维拉帕米的R - 立体异构体和/或添加丁硫氨酸亚砜胺来检测多药耐药性的逆转情况。在27例肿瘤中观察到对长春碱有高度化学抗性，在30例肿瘤中对阿霉素有高度化学抗性，在31例肿瘤中对卡铂有高度化学抗性。分别在8例、5例或4例中发现有化学应答。在70%对长春碱高度耐药和63%对阿霉素高度耐药的肿瘤中检测到P - 170，但在耐药性较低的病例中均未检测到。与耐药性较低的肾细胞癌相比，对卡铂和阿霉素的耐药性与谷胱甘肽水平升高显著相关。R - 维拉帕米导致长春碱耐药性的强烈逆转和阿霉素耐药性的明显规避，但对卡铂耐药性无影响。丁硫氨酸亚砜胺克服了卡铂耐药性并改变了阿霉素耐药性，但对长春碱耐药性无影响。R - 维拉帕米和丁硫氨酸亚砜胺联合应用逆转了阿霉素耐药性，但在长春碱或卡铂耐药性方面没有协同作用。P - 170和谷胱甘肽这两种机制相互独立存在，很可能解释了人类肾细胞癌的多药耐药性。
