Hu X, Yang H, Pan Q R, Zheng S
Cancer Institute, Zhejiang Medical University, Hangzhou, People's Republic of China.
Chemotherapy. 1995 Jul-Aug;41(4):296-305. doi: 10.1159/000239359.
A multidrug-resistant (MDR) variant, K562/Dox, was selected from repeated exposure of human erythroleukemia cell line K562 to doxorubicin (Dox). K562/Dox displayed typical MDR features with respect to its cross-resistance to a variety of functionally and structurally unrelated compounds: vincristine (Vin), Dox, mitomycin C, reduced steady-state intracellular anthracycline accumulation, and elevated P-glycoprotein expression/mdr1 mRNA transcription/mdr1 gene amplification. Nevertheless, by incubation of cells with Dox/epirubicin (Epi)/daunorubicin (Dau) (5-80 micrograms/ml), the initial drug uptake was similar (p > 0.05) in K562/Dox and K562 cells, suggesting P-glycoprotein-mediated drug efflux would not occur unless a relatively high cellular drug concentration was reached. After 8 h incubation of cells with 50 ng/ml Dox (5 times higher than its IC50 to K562 cells), there were only slight differences (p > 0.05) in intracellular drug levels between K562/Dox and K562 cells, clearly indicating that K562/Dox, circumventing drug toxicity in this case, was irrelevant to reduced drug accumulation caused by P-glycoprotein. Similar results were obtained when Epi or Dau was applied. Despite complete restoration of anthracycline accumulation in K562/Dox cells in the presence of 6 mumol/l verapamil, the reversal of their drug resistance was incomplete. These results suggest that P-glycoprotein-mediated drug efflux possibly did not play a primary role in the drug resistance of K562/Dox cells.
通过将人红白血病细胞系K562反复暴露于阿霉素（Dox）中，筛选出了一种多药耐药（MDR）变体K562/Dox。K562/Dox对多种功能和结构不相关的化合物表现出典型的MDR特征：长春新碱（Vin）、Dox、丝裂霉素C、稳态细胞内蒽环类药物积累减少以及P-糖蛋白表达/多药耐药基因1（mdr1）mRNA转录/mdr1基因扩增升高。然而，通过将细胞与Dox/表柔比星（Epi）/柔红霉素（Dau）（5 - 80微克/毫升）孵育，K562/Dox和K562细胞的初始药物摄取相似（p>0.05），这表明除非达到相对较高的细胞药物浓度，否则不会发生P-糖蛋白介导的药物外排。在用50纳克/毫升Dox（比其对K562细胞的半数抑制浓度高5倍）孵育细胞8小时后，K562/Dox和K562细胞之间的细胞内药物水平仅有轻微差异（p>0.05），这清楚地表明在这种情况下，K562/Dox规避药物毒性与P-糖蛋白导致的药物积累减少无关。应用Epi或Dau时也获得了类似结果。尽管在存在6微摩尔/升维拉帕米的情况下，K562/Dox细胞中的蒽环类药物积累完全恢复，但其耐药性的逆转并不完全。这些结果表明，P-糖蛋白介导的药物外排在K562/Dox细胞的耐药性中可能不发挥主要作用。
