Choudhuri S K, Chatterjee A
Department of Biochemistry, Chittaranjan National Cancer Institute (Research Wing), Calcutta, India.
Anticancer Drugs. 1998 Oct;9(9):825-32. doi: 10.1097/00001813-199810000-00013.
A drug-resistant cell line (EAC/Dox) was developed by repeated exposure of Ehrlich ascites carcinoma cells to Doxorubicin (Dox) in vivo in male albino Swiss mice (6-8 weeks old). The weekly i.p. injections of Dox to mice (2 or 4 mg/kg/week for 4 months) gave rise to Dox-resistant cell line EAC/Dox, which displayed typical multidrug resistant (MDR) features of cross-resistance to a number of structurally and functionally unrelated drugs like doxorubicin, vinblastine and cisplatin. Moreover, the EAC/Dox cell line had lower drug accumulation than drug-sensitive (EAC/S) cells. Study of Western blots and immunofluorescence revealed that P-glycoprotein 170 kDa (P-gp) was absent in EAC/Dox cells. The drug resistance appeared to be due to the presence of a higher level of reduced glutathione (GSH) and glutathione S-transferase (GST) in EAC/Dox cells than in drug-sensitive (EAC/S) cells. The two structurally similar hydroxamic acid derivatives, i.e. oxalyl bis(N-phenyl)hydroxamic acid (X1) and succinyl bis(N-phenyl)hydroxamic acid (X2), having very low in vitro toxicity (IC50 value 250 microg/ ml), were investigated for their efficacy to reverse MDR. The compound X1 was able to reverse the effect of MDR and reduce GST in EAC/Dox cells. The compound X2 had no ability to reverse the effect of MDR. Further study on the mechanism of glutathione depletion and the resistance modifying property of X1 on other cell lines is warranted.
通过在雄性瑞士白化小鼠（6 - 8周龄）体内将艾氏腹水癌细胞反复暴露于阿霉素（Dox），建立了耐药细胞系（EAC/Dox）。每周给小鼠腹腔注射Dox（2或4 mg/kg/周，持续4个月），产生了对Dox耐药的细胞系EAC/Dox，该细胞系表现出典型的多药耐药（MDR）特征，即对许多结构和功能不相关的药物如阿霉素、长春碱和顺铂具有交叉耐药性。此外，EAC/Dox细胞系的药物蓄积低于药物敏感（EAC/S）细胞。蛋白质免疫印迹和免疫荧光研究显示，EAC/Dox细胞中不存在170 kDa的P - 糖蛋白（P - gp）。耐药性似乎是由于EAC/Dox细胞中还原型谷胱甘肽（GSH）和谷胱甘肽S - 转移酶（GST）的水平高于药物敏感（EAC/S）细胞。研究了两种结构相似的异羟肟酸衍生物，即草酰双（N - 苯基）异羟肟酸（X1）和琥珀酰双（N - 苯基）异羟肟酸（X2），它们的体外毒性非常低（IC50值为250 μg/ml），研究了它们逆转MDR的效果。化合物X1能够逆转EAC/Dox细胞中的MDR效应并降低GST。化合物X2没有逆转MDR效应的能力。有必要进一步研究谷胱甘肽耗竭的机制以及X1对其他细胞系的耐药性修饰特性。
