Simon S, Roy D, Schindler M
Laboratory of Cellular Biophysics, Rockefeller University, New York, NY 10021.
Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1128-32. doi: 10.1073/pnas.91.3.1128.
Many anticancer drugs are classified as either weak bases or molecules whose binding to cellular structures is pH dependent. Accumulation of these drugs within tumor cells should be affected by transmembrane pH gradients. Indeed, development of multidrug resistance (MDR) in tumor cells has been correlated with an alkaline shift of cytosolic pH. To examine the role of pH in drug partitioning, the distribution of two drugs, doxorubicin and daunomycin, was monitored in fibroblasts and myeloma cells. In both cell types the drugs rapidly accumulated within the cells. The highest concentrations were measured in the most acidic compartments--e.g., lysosomes. Modifying the cellular pH in drug-sensitive cells to mimic reported shifts in MDR caused an immediate change in the cellular drug concentration. Drug accumulation was enhanced by acidic shifts and reversed by alkaline shifts. All of these effects were rapid and reversible. These results demonstrate that the alkaline shift observed in MDR is sufficient to prevent the accumulation of chemotherapeutic drugs independent of active drug efflux.
许多抗癌药物被归类为弱碱或其与细胞结构的结合依赖于pH的分子。这些药物在肿瘤细胞内的积累应受跨膜pH梯度的影响。事实上，肿瘤细胞中多药耐药性（MDR）的产生与胞质pH的碱性变化有关。为了研究pH在药物分配中的作用，监测了两种药物阿霉素和柔红霉素在成纤维细胞和骨髓瘤细胞中的分布。在这两种细胞类型中，药物都迅速在细胞内积累。在酸性最强的区室（如溶酶体）中测得的浓度最高。将药物敏感细胞中的细胞pH值改变以模拟MDR中报道的变化，会导致细胞内药物浓度立即改变。酸性变化会增强药物积累，碱性变化则使其逆转。所有这些效应都是快速且可逆的。这些结果表明，在MDR中观察到的碱性变化足以阻止化疗药物的积累，而与活性药物外排无关。
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