FTY720联合雷帕霉素抗胰腺癌细胞增殖作用的实验研究

Antiproliferative and overadditive effects of rapamycin and FTY720 in pancreatic cancer cells in vitro

目的探讨FTY720和雷帕霉素联合用药体外抗胰腺癌细胞增殖的相互作用。方法采用Panc-1和AsPc-1胰腺癌细胞株作为体外研究模型。以不含FTY720或雷帕霉素培养液处理的细胞株为对照组,FTY720单独用药的浓度范围为1～15μmol/L;雷帕霉素单独用药的浓度范围为0.002～200μmol/L,联合用药方案采用两组浓度的雷帕霉素联合7组不同浓度的FTY720;或者采用两组浓度的FTY720联合5组不同浓度的雷帕霉素。采用四甲基偶氮唑盐比色法评估药物对细胞增殖的抑制率,采用双变量相关性分析法统计药物剂量与细胞增殖抑制率之间的相关性。结果单独用药作用下,FTY720或雷帕霉素用药剂量与胰腺癌细胞增殖的抑制率呈现剂量依赖性(FTY720+AsPc-1:r=0.887,P=0.000;雷帕霉素+AsPc-1:r=0.822,P=0.000;FTY720+Panc-1:r=0.796,P=0.000;雷帕霉素+Panc-1:r=0.786,P=0.000)。当10μmol/L FTY720和0.002μmol/L雷帕霉素联用时,对AsPc-1细胞增殖的抑制率达51.8%(P=0.000),对Panc-1细胞增殖的抑制率达37.8%(P=0.000),两药联用具有协同作用。结论FTY720及雷帕霉素在体外均能呈剂量依赖性地抑制胰腺癌细胞增殖,联合用药后能协同抑制胰腺癌细胞的增殖。

Objective Rapamycin inhibits the growth of several tumors including pancreatic carcinoma both in vitro and in vivo. The antitumor effects of FTY720 were also shown recently. The present study was performed to investigate the in vitro antiproliferative capacity of combined treatment with rapamycin and FTY720 on pancreatic carcinoma cell lines. Methods The Pane-1 and AsPc-1 cell lines were employed as the pancreatic carcinoma model in vitro. For monotreatment experiments, rapamycin was added in increasing doses from 0. 002 umoL/L to 200 umol/L; FTY720 was used from 1 umol/L to 15 umol/L. For combined treatment, two concentrations of rapamycin were combined with seven concen- trations of FTY720 ; or two concentrations of FTY720 with five concentrations of rapamycin. The antiproliferative capacity was assessed by the MTTassay. Results Rapamycin and FTY720 inhibited MTT incorporation into Panc-1 and AsPc-1 in a dose-dependent fashion with or without serum stimulation. An effective combination for AsPc-1 was 10 umol/L FTY720 with 0. 002 umol/L rapamycin, resulting in 51.8% inhibition of MTT incorporation, and for Panc-1, 10 p, mol/L FTY720 with 0.002umol/L rapamycin and 10 umol/L FTY720 with 20 umol/L rapamycin; the corresponding inhibition levels reached about 40% and 60%, respectively. Conclusions Rapamycin and FTY720 showed dose-dependent antiproliferative effects on pancreatic carcinoma cell lines in vitro both alone and in combination. The combined use of rapamycin and FTY720 showed additive and supra-additive antiproliferative effects on pancreatic carcinoma cell lines.