塞来昔布对人结肠癌裸鼠移植瘤的抑制作用及其机制

Celecoxib suppresses xenograft tumor of colon cancer in nude mice

目的研究不同剂量环氧化酶-2(COX-2)抑制剂塞来昔布对人结肠癌裸鼠移植瘤生长的影响及机制。方法将人结肠癌HT-29细胞注射于裸鼠背部皮下建立移植瘤模型,16d后,将裸鼠以随机数字表法分为5组:对照组、塞来昔布1组(25mg.kg-1.d-1)、塞来昔布2组(50mg.kg-1.d-1)、塞来昔布3组(75mg.kg-1.d-1)、塞来昔布4组(100mg.kg-1.d-1),并给予相应剂量的塞来昔布。每周测量肿瘤体积,给药35d后,处死裸鼠,切取移植瘤组织检测COX-2,survivin表达,VEGF mRNA表达和微血管密度(MVD)。结果塞来昔布1、2、3、4组的抑瘤率分别为34.94%、39.20%、53.50%、59.20%,与对照组比较移植瘤体积明显缩小(P<0.05)。与对照组比较,塞来昔布各组COX-2、survivin的表达水平均明显降低(P<0.05),并且抑制程度呈药物剂量依赖性。低剂量(25mg·kg-1·d-1)塞来昔布可明显抑制VEGF mRNA表达和结肠癌移植瘤微血管生成(P<0.05,vs对照组),其抑制作用并未随用药剂量的增加而增强。结论不同剂量的塞来昔布均能明显抑制结肠癌移植瘤的生长,其抑制作用呈用药剂量依赖性,这种作用可能是通过抑制sur-vivin的表达实现的。低剂量塞来昔布可抑制人结肠癌裸鼠移植瘤微血管生成,可能对防止肿瘤转移起到重要作用。

Objective To evaluate the effects of celecoxib on tumor growth, COX-2 and survivin expressions and angiogenesis in nude mice. Mothods Xenograft animal model was established by injecting human colon cancer HT-29 cells into the BALB/c nude mice subcutaneously. Fifty mice were randomly divided into 4 groups 16 d after injection：control group, celecoxib group （receiving 25, 50, 75, 100 mg·kg^-1·d^-1 for 35 d）. Tumor volumes were measured every week. The expression level of COX-2, survivin and the microvessel density （MVD） of the xenograft tumor tissues were measured by immunohistochemistry, and mRNA level of VEGF by RT-PCR. Results Celecoxib at dose of 25, 50, 75 and 100 mg·kg^-1·d^-1 inhibited the tumor volume by 34.94%, 39.20%, 53.50%, 59.20% respectively, and showed more effective in suppressing the tumor growth than the control group（ P 〈 0. 05 ）. All celecoxib groups showed a significantly decreased expression of COX-2 and survivin compared with those in the control group （P 〈0. 05 ） and their expression was in a dose-dependent manner. 25 mg·kg^-1·d^-1 celecoxib inhibited VEGF mRNA expression and angiogenesis as compared with the control group （ P 〈 0. 05 ）, but not in a dose-dependent manner. Conclusion Celecoxib can suppress tumor growth partly by inhibiting survivin expression. Low dose of celecoxib can decrease the angiogenesis of xenograft colon cancer, and furthur more prevent the metastasis of coloreetal cancer.