Bando T, Kasahara K, Shibata K, Numata Y, Nakatsumi Y, Fujimura M, Matsuda T
Third Department of Internal Medicine, Kanazawa University School of Medicine, Japan.
Anticancer Res. 1995 May-Jun;15(3):769-72.
There are some active transport systems in the cell membrane, such as potassium pump, calcium pump, and proton pump. Although it has been reported that sodium/potassium and sodium/calcium pumps of cell membrane play roles in the intracellular accumulation of anticancer agents, the significance of the active transport channels in accumulation of mitomycin C (MMC), one of the most active agents for non-small cell lung cancer (NSCLC) has been unclear. In this study, we evaluated the role of the potassium pump, calcium pump, and proton pump as determinants of the sensitivity to MMC in vitro by using the selective inhibitors, ouabain, verapamil or AG-2000 (an active metabolite of Lansoplazole), respectively. PC-9 and PC-9/MC4 cell lines which are sensitive and resistant to MMC were used for these experiments. PC-9/MC4 was 9.4-fold more resistant to MMC than PC-9 cells. Relative resistance was not significantly changed by co-incubation with a non-cytotoxic dosage of these inhibitors. From these results, it was revealed that the active transport systems in cell membrane do not play a role in determining the sensitivity to MMC and the acquisition of resistance to MMC in PC-9 cell lines. Intracellular bioactivation may be an important factor to determine sensitivity to MMC in NSCLC cells under aerobic conditions.
细胞膜中存在一些主动转运系统，如钾泵、钙泵和质子泵。尽管已有报道称细胞膜的钠/钾泵和钠/钙泵在抗癌药物的细胞内蓄积中发挥作用，但作为非小细胞肺癌（NSCLC）最有效的药物之一，丝裂霉素C（MMC）蓄积过程中主动转运通道的意义尚不清楚。在本研究中，我们分别使用选择性抑制剂哇巴因、维拉帕米或AG - 2000（兰索拉唑的活性代谢产物）评估了钾泵、钙泵和质子泵作为体外对MMC敏感性决定因素的作用。对MMC敏感和耐药的PC - 9和PC - 9/MC4细胞系用于这些实验。PC - 9/MC4对MMC的耐药性是PC - 9细胞的9.4倍。与这些抑制剂的非细胞毒性剂量共同孵育后，相对耐药性没有显著变化。从这些结果可以看出，细胞膜中的主动转运系统在决定对MMC的敏感性以及PC - 9细胞系对MMC耐药性的获得方面不起作用。细胞内生物活化可能是在有氧条件下决定NSCLC细胞对MMC敏感性的一个重要因素。
