Fojo A, Akiyama S, Gottesman M M, Pastan I
Cancer Res. 1985 Jul;45(7):3002-7.
Human KB cells with increasing resistance to colchicine and other chemotherapeutic agents have been isolated in four sequential steps. This report describes the characterization of drug uptake in the parent and four mutant cell lines. Drug uptake in these cell lines occurred via a nonsaturable process. In general, drug accumulation decreased with increasing drug resistance; this relationship was seen best with colchicine, vincristine, vinblastine, and daunomycin and, to a lesser extent, with actinomycin D. The accumulation of dexamethasone, an agent to which all lines were equally sensitive, was similar for the parent and the four mutants. Drug efflux occurred rapidly, and differences among the various cell lines could be detected within the first minute. In the more resistant lines, a greater percentage of the drug was released more rapidly, although the absolute amount of drug released was less. Verapamil partially reversed the multiple drug-resistance phenotype by increasing the initial rate of uptake and accumulation of drugs in the resistant cell lines without an apparent effect on drug efflux. The results suggest that, in this human epithelial cell, the development of resistance to multiple drugs is complex, with changes in drug uptake, accumulation, and efflux.
已通过四个连续步骤分离出对秋水仙碱和其他化疗药物耐药性不断增加的人KB细胞。本报告描述了亲代细胞系和四个突变细胞系中药物摄取的特征。这些细胞系中的药物摄取通过非饱和过程发生。一般来说，药物积累随着耐药性的增加而减少；秋水仙碱、长春新碱、长春花碱和柔红霉素的这种关系最为明显，放线菌素D的这种关系则较弱。所有细胞系对其敏感性相同的地塞米松在亲代细胞和四个突变体中的积累情况相似。药物外排迅速，在第一分钟内就能检测到不同细胞系之间的差异。在耐药性更强的细胞系中，尽管释放的药物绝对量较少，但更大比例的药物释放得更快。维拉帕米通过提高耐药细胞系中药物的初始摄取率和积累，部分逆转了多药耐药表型，而对药物外排没有明显影响。结果表明，在这种人类上皮细胞中，对多种药物耐药性的产生是复杂的，涉及药物摄取、积累和外排的变化。
