Yoshida T, Shimizu K, Ushio Y, Hayakawa T, Mogami H, Sakamoto Y
Department of Neurosurgery, Osaka University Medical School, Japan.
J Neurooncol. 1987;5(3):195-203. doi: 10.1007/BF00151222.
In order to study the mechanism of the resistance to chemotherapeutic agents, especially ACNU [1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride), two variant cell lines (C6/ACNU and 9L/ACNU) resistant to ACNU were selected in vivo from rat C6 and 9L glioma, respectively. Uptake and efflux of ACNU in these resistant cells were studied with Ethylene[14C]ACNU. The result indicated that the resistance exhibited by both sublines were due to both the reduced uptake of the drug and the increased efflux. The study of the effects of oxidative phosphorylation inhibitor, DNP (2,4-dinitrophenol), on the uptake and retention of ACNU suggested that there is an active outward transport mechanism for ACNU in both glioma sublines and that enhanced activity of this efflux mechanism renders cells highly resistant to the cytotoxic action of ACNU. In an attempt to clarify the more detailed biochemical mechanisms of this active efflux system, we surveyed various membrane-modifying agents which potentiate the sensitivity of these resistant cells to ACNU. Among a number of membrane-modifying agents, reserpine was found to retain ACNU in the resistant cells and to enhance the action of ACNU on these resistant cell lines. It may be concluded that drugs such as reserpine may overcome a mechanism of ACNU resistance.
为了研究对化疗药物尤其是ACNU[1-(4-氨基-2-甲基-5-嘧啶基)甲基-3-(2-氯乙基)-3-亚硝基脲盐酸盐]产生耐药性的机制，分别从大鼠C6和9L胶质瘤体内筛选出了对ACNU耐药的两种变异细胞系（C6/ACNU和9L/ACNU）。用乙烯[14C]ACNU研究了这些耐药细胞中ACNU的摄取和流出情况。结果表明，两个亚系所表现出的耐药性是由于药物摄取减少和流出增加所致。对氧化磷酸化抑制剂DNP（2,4-二硝基苯酚）对ACNU摄取和滞留影响的研究表明，两种胶质瘤亚系中均存在ACNU的主动外向转运机制，且这种流出机制活性增强使细胞对ACNU的细胞毒性作用具有高度耐药性。为了阐明这种主动流出系统更详细的生化机制，我们研究了各种能增强这些耐药细胞对ACNU敏感性的膜修饰剂。在众多膜修饰剂中，发现利血平能使ACNU滞留在耐药细胞中，并增强ACNU对这些耐药细胞系的作用。可以得出结论，利血平之类的药物可能会克服ACNU的耐药机制。
