Alhonen-Hongisto L, Levin V A, Marton L J
Cancer Res. 1985 Feb;45(2):509-14.
Uptake characteristics and growth-inhibitory effects of methylglyoxal bis(guanylhydrazone) (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase, were investigated in 9L rat brain tumor cells and in V79 hamster lung cells. Proliferation of 9L cells was only slightly inhibited by treatment with 40 microM MGBG alone, but when used in combination with 0.5 mM alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, proliferation was much more effectively inhibited. The intracellular concentration of MGBG was approximately 2-fold higher 4 days after cells were treated with both DFMO and MGBG, either simultaneously or when MGBG was added after a 48-hr DFMO pretreatment, than that in cells treated with MGBG alone. Polyamine levels in DFMO- and MGBG-treated cells correlated with the antiproliferative effects of the drugs. Used either alone or in combination with 1 mM DFMO, 0.5 microM MGBG inhibited the growth of and eventually killed V79 cells. Simultaneous or sequential treatment with DFMO and MGBG increased intracellular concentrations of MGBG at 4 days by 2- and 3-fold, respectively, compared to treatment with MGBG alone. Intracellular polyamine levels did not correlate with the antiproliferative effect of the two drugs in V79 cells. In both cell lines, polyamines and MGBG share a common transport system. The net transport of polyamines and MGBG was more temperature dependent and up to 10-fold more active in V79 cells than in 9L cells. The Km and Vmax values for spermidine and MGBG measured 10 sec after addition (initial permeation) were not affected by DFMO pretreatment in either cell line. However, 1 hr after administration, the Vmax values for spermidine and MGBG uptake were doubled in V79 cells pretreated for 48 hr with DFMO; no significant change occurred in 9L cells. Mitochondrial function, assessed by pyruvate oxidation, was substantially impaired by MGBG in V79 cells but not in 9L cells when the intracellular concentrations of MGBG were equal in each cell line. Pretreatment with DFMO did not increase MGBG-induced inhibition of pyruvate oxidation in V79 cells. These results show that, compared with V79 cells, the decreased sensitivity of 9L cells to MGBG may be related to decreased intracellular MGBG accumulation but not to cellular permeation such as carrier transport. Results of measurements of both polyamine levels and mitochondrial function indicate that V79 cells may be more susceptible to nonpolyamine-dependent effects of MGBG than are 9L cells.
研究了S-腺苷甲硫氨酸脱羧酶的竞争性抑制剂甲基乙二醛双（脒腙）（MGBG）在9L大鼠脑肿瘤细胞和V79仓鼠肺细胞中的摄取特性和生长抑制作用。单独用40 microM MGBG处理时，9L细胞的增殖仅受到轻微抑制，但与鸟氨酸脱羧酶的不可逆抑制剂0.5 mMα-二氟甲基鸟氨酸（DFMO）联合使用时，增殖受到更有效的抑制。在用DFMO和MGBG同时处理或在DFMO预处理48小时后添加MGBG的细胞中，4天后MGBG的细胞内浓度比单独用MGBG处理的细胞高约2倍。DFMO和MGBG处理的细胞中的多胺水平与药物的抗增殖作用相关。单独使用或与1 mM DFMO联合使用时，0.5 microM MGBG抑制V79细胞的生长并最终杀死它们。与单独用MGBG处理相比，DFMO和MGBG同时或序贯处理在4天时使MGBG的细胞内浓度分别增加2倍和3倍。V79细胞中细胞内多胺水平与这两种药物的抗增殖作用不相关。在这两种细胞系中，多胺和MGBG共享一个共同的转运系统。多胺和MGBG的净转运对温度更依赖，并且在V79细胞中的活性比在9L细胞中高多达10倍。添加（初始渗透）10秒后测量的亚精胺和MGBG的Km和Vmax值在两种细胞系中均不受DFMO预处理的影响。然而，给药1小时后，用DFMO预处理48小时的V79细胞中亚精胺和MGBG摄取的Vmax值增加了一倍；9L细胞中未发生显著变化。当每个细胞系中MGBG的细胞内浓度相等时，通过丙酮酸氧化评估的线粒体功能在V79细胞中受到MGBG的显著损害，但在9L细胞中未受影响。用DFMO预处理并未增加V79细胞中MGBG诱导的丙酮酸氧化抑制。这些结果表明，与V79细胞相比，9L细胞对MGBG敏感性降低可能与细胞内MGBG积累减少有关，而与载体转运等细胞渗透无关。多胺水平和线粒体功能的测量结果表明，V79细胞可能比9L细胞对MGBG的非多胺依赖性作用更敏感。
