Kanamaru H, Kakehi Y, Yoshida O, Nakanishi S, Pastan I, Gottesman M M
Department of Urology, Faculty of Medicine, Kyoto University, Japan.
J Natl Cancer Inst. 1989 Jun 7;81(11):844-9. doi: 10.1093/jnci/81.11.844.
We examined the distribution of RNA levels expressed by the multidrug-resistance gene (MDR1, also known as PGY1) in 42 renal cell carcinoma (RCC) samples (38 primary and four metastatic lesions). The median MDR1 RNA level for the 38 primary lesions, expressed relative to the level for KB-3-1 cells, was approximately one-half of the level in multidrug-resistant KB-8-5 cells. Elevated MDR1 RNA levels were also observed in three of the four metastatic lesions. The mean MDR1 RNA level was higher in well-differentiated RCCs than in those that were poorly differentiated, suggesting that the increased expression of the MDR1 gene in RCCs originates from the increased expression in renal proximal tubule cells. To clarify the association of the MDR1 protein product P-glycoprotein with natural resistance to doxorubicin (ADR) in RCCs, we evaluated the effects of quinidine on in vitro sensitivity to ADR in 16 RCC samples, using a [3H]thymidine incorporation assay. The enhancing effect of quinidine (7.5 micrograms/mL) on sensitivity to ADR was statistically significant only in the group with high MDR1 RNA levels. Similar enhancement by quinidine of sensitivity to ADR was also observed in the established RCC cell lines in which MDR1 RNA levels were high. These results suggest that P-glycoprotein is active in the natural resistance of RCCs to ADR.
我们检测了多药耐药基因（MDR1，也称为PGY1）在42例肾细胞癌（RCC）样本（38例原发性肿瘤和4例转移灶）中所表达的RNA水平分布。相对于KB-3-1细胞的水平，38例原发性肿瘤的MDR1 RNA水平中位数约为多药耐药性KB-8-5细胞水平的一半。在4例转移灶中的3例也观察到MDR1 RNA水平升高。高分化RCC的平均MDR1 RNA水平高于低分化RCC，提示RCC中MDR1基因表达增加源于肾近端小管细胞表达的增加。为了阐明MDR1蛋白产物P-糖蛋白与RCC对阿霉素（ADR）天然耐药性的关系，我们使用[3H]胸腺嘧啶核苷掺入试验，评估了奎尼丁对16例RCC样本体外ADR敏感性的影响。仅在MDR1 RNA水平高的组中，奎尼丁（7.5微克/毫升）对ADR敏感性的增强作用具有统计学意义。在MDR1 RNA水平高的已建立的RCC细胞系中也观察到奎尼丁对ADR敏感性的类似增强作用。这些结果提示P-糖蛋白在RCC对ADR的天然耐药中发挥作用。
