中文摘要：

目的研究多西紫杉醇耐药的胃癌细胞中凋亡抑制蛋白（IAP）基因的表达变化，探讨胃癌细胞对多西紫杉醇的耐药机制。方法体外建立多西紫杉醇耐药的胃癌BGC-823细胞株，采用二苯基溴化四氮唑蓝（MTT）法检测胃癌细胞的耐药指数和交叉耐药特性；采用Annexin-V FITC和PI双染法检测多西紫杉醇诱导胃癌细胞的早期凋亡率；采用实时定量PCR法检测胃癌细胞中IAP基因的表达变化。结果在不同终浓度多西紫杉醇的诱导下，建立了BGC-823／R1、BGC-823／112和BGC-823／R3胃癌耐药细胞，其对多西紫杉醇的耐药指数分别为10．2、24．5和56．3。BGC-823／R3细胞对顺铂、氟尿嘧啶和奥沙利铂无交叉耐药，对紫杉醇有部分交叉耐药。随着耐药指数的增加，多西紫杉醇诱导胃癌细胞的凋亡率呈下降趋势。BGC-823／R3细胞中IAP（survivin、livin、XIAP、c—IAP2）基因和bcl-2基因的表达明显升高（P〈0．05）。相关性分析显示，survivin和XIAP基因的表达水平与多西紫杉醇的IC50值呈正相关（r=0．909，P〈0．001；r=0．892，P〈0．001）。结论凋亡途径的抵抗和IAP的表达上调是胃癌细胞对多西紫杉醇耐药的重要机制。IAP可作为逆转紫杉类药物耐药的新靶点。

英文摘要：

Objective Resistance to chemotherapy may indicate an unfavorable outcome for patients with gastric cancer. The purpose of this study was to examine whether docetaxel-resistance could be due in part to the expression of the inhibitor of apoptosis proteins （IAP）. Methods Docetaxel-resistant cells, BGC-823/R1, BGC-823/R2 and BGC-823/R3, were established from parent BGC-823 cells by stepwise increasing concentration of docetaxel. To characterize these cells, we examined the effects of docetaxel on cell growth and apoptosis by MTT assay and double staining with both annexin-V-FITC and PI, and analyzed the cross-resistance to various anticancer drugs. Expression of IAP compared with that in parental cells was evaluated by real-time quantitative PCR. Results The BGC-823 resistant cells, BGC-823/R1, R2 and R3 cells, were 10.2-, 24.5-, 56.3-fold more resistant to docetaxel than parental cells, respectively, and this resistance was paralleled with reduced induction of apoptosis. BGC-823/R3 cells showed cross-resistance to paclitaxel, whereas exhibited weak or no cross-resistance against 5-fluorouracil, cisplatin and oxaliplatin. The expressions of survivin and XIAP were gradually increased with the extent of docetaxel resistance （ r = 0.909, P〈0.001 and r=0.892,P〈0.001, respectively）. Conclusion IAP may make an important contribution to the resistance to the apoptotic effect of docetaxel in gastric cancer, and could be used as a potential therapeutic target.