Fojo A T, Shen D W, Mickley L A, Pastan I, Gottesman M M
Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892.
J Clin Oncol. 1987 Dec;5(12):1922-7. doi: 10.1200/JCO.1987.5.12.1922.
The cloning of the cDNA for the mdr1 gene, whose expression is associated with the development of multidrug-resistance in cultured cells, has made it possible to explore the mechanism of multidrug resistance in human tumors. We have found that normal human kidney, six of eight adenocarcinomas of the kidney, and four cell lines derived from kidney adenocarcinomas express high levels of mdr1 mRNA. Two criteria suggest that primary multidrug resistance in human adenocarcinomas of the kidney results, at least in part, from expression of the mdr1 gene: (1) mdr1 mRNA levels are elevated in four unselected kidney adenocarcinoma cell lines that show a multidrug-resistant phenotype; and (2) multidrug resistance in these kidney cancer cell lines is reversed by verapamil and quinidine, agents known to reverse mdr1-associated drug resistance in cell lines selected for multidrug resistance in vitro. These results suggest that appropriate pharmacological intervention to reverse multidrug resistance might make adenocarcinomas of the kidney more sensitive to chemotherapy with agents such as Adriamycin (Adria Laboratories, Columbus, OH) and the vinca alkaloids.
mdr1基因的cDNA克隆使得人们能够探索人类肿瘤中多药耐药的机制，该基因的表达与培养细胞中多药耐药的产生有关。我们发现，正常人类肾脏、八例肾腺癌中的六例以及四株源自肾腺癌的细胞系均高水平表达mdr1 mRNA。有两条标准表明，人类肾腺癌中的原发性多药耐药至少部分是由mdr1基因的表达所致：（1）在四株未经过筛选的表现出多药耐药表型的肾腺癌细胞系中，mdr1 mRNA水平升高；（2）这些肾癌细胞系中的多药耐药可被维拉帕米和奎尼丁逆转，这两种药物已知可逆转体外选择的多药耐药细胞系中与mdr1相关的耐药。这些结果表明，采取适当的药理学干预措施来逆转多药耐药，可能会使肾腺癌对阿霉素（阿德里亚实验室，俄亥俄州哥伦布市）和长春花生物碱等药物的化疗更敏感。
