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目的 探讨环孢霉素A(CsA )对肝癌 (BEL 740 2 /ADM )多药耐药性的逆转作用。方法 以四唑蓝法测定CsA对抗癌药细胞毒性的影响 ,用流式细胞仪检测细胞膜转运蛋白 (Pgp)的表达和罗丹明 (R12 3 )浓度 ,以人肝癌裸小鼠原位移植耐药模型进行在体实验。结果 CsA在 4.0μmol/L以下对BEL 740 2 /ADM细胞无明显毒性 ,超过此浓度 ,其毒性呈剂量效应 ,半数抑制率(IC50 )为 10 .0 μmol/L。CsA(4 .0 μmol/L)能增加BEL 740 2 /ADM对R12 3的蓄积并减缓其外排 ,对阿霉素 (ADM )、表阿霉素、氟尿嘧啶的逆转倍数分别为 2 .72、6.0 6和 1.3 1倍 ,并可部分下调BEL 740 2 /ADM细胞Pgp的表达 ;体内实验显示 ,CsA +ADM组 (每周腹腔注射CsA 2 .0mg/kg体重与ADM 1.5mg/kg体重 ,共 8次 )肿瘤体积和肿瘤重量分别为 (0 .2 0± 0 .0 4)cm3 和 (0 .82± 0 .18) g ,明显小于ADM组的 (0 .67± 0 .3 9)cm3 和 (1.5 5± 0 .5 8) g ,两组间差异有显著性 (P <0 .0 5 ) ,抑瘤率达 70 .15 %。结论 CsA可有效逆转肝癌耐药性 ,其主要机制是通过抑制细胞Pgp泵功能同时部分下调Pgp表达水平。
Objective To investigate the reversal effects of cyclosporin A (CsA) on multidrug resistance in hepatocellular carcinoma (BEL 740 2 / ADM). Methods The effect of CsA on the cytotoxicity of anti-cancer drugs was determined by tetrazolium method. The expression of Pgp and the concentration of rhodamine (R12 3) were detected by flow cytometry. Drug model for in vivo experiments. Results CsA had no toxicity to BEL 740 2 / ADM cells below 4.0 μmol / L. When the concentration of CsA was above the concentration, the toxicity was dose-effect and the IC50 was 10. 0 μmol / L. CsA (4 .0 μmol / L) increased the accumulation of R12 3 and slowed its efflux of BEL 740 2 / ADM. The reversal multiple of ADM, epirubicin and fluorouracil were 2.72, 6.06 and 1.3 times as many as those in control group, and partially downregulated the expression of Pgp in BEL 7402 / ADM cells. In vivo, the CsA + ADM group (intraperitoneal injection CsA 2.0 mg / kg body weight and ADM 1.5 mg / kg body weight per week, 8) tumor volume and tumor weight were (0.20 ± 0.04) cm3 and (0.82 ± 0.18) g respectively, which were significantly lower than those in ADM group (0.67 ± 0.39 cm3 And (1.55 ± 0.58) g respectively. The difference between the two groups was significant (P <0.05), and the tumor inhibition rate was 70.15%. Conclusion CsA can effectively reverse the drug resistance of hepatocellular carcinoma. The main mechanism is that CsA can down-regulate the expression of Pgp by inhibiting the Pgp pump function.