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目的本研究通过观察环氧合酶2(Cox-2)抑制剂塞来昔布与哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂依维莫司对大鼠嗜铬细胞瘤细胞PC12的裸鼠移植瘤生长的影响,探讨依维莫司对大鼠嗜铬细胞瘤肿瘤生长和血管生成的抑制作用。方法用大鼠嗜铬细胞瘤细胞PC12接种于裸鼠皮下,建立移植瘤模型,15d后将荷瘤裸鼠随机分为4组,每组12只,分别为依维莫司组(依维莫司灌胃1mg/kg)、塞来昔布组(塞来昔布100mg/kg灌胃)、联合组(依维莫司1mg/kg+塞来昔布100mg/kg灌胃)、对照组(生理盐水灌胃10mL/kg),用药3周,第4周后测量裸鼠移植瘤的体积变化以及裸鼠的生存时间,采用免疫组化方法检测肿瘤组织中血管内皮生长因子(VEGF)的表达,采用Western blotting法检测肿瘤组织中VEGF的表达。结果第4周时移植瘤体积:对照组为(4 159.72±651.84)mm3,依维莫司组为(2 816.49±332.05)mm3,塞来昔布组为(4 018.38±527.46)mm3,联合组为(1 035.28±177.30)mm3,联合组与前3组均存在显著性差异(P<0.01)。平均生存时间:对照组(23.3±2.8)d,依维莫司组(36.8±3.6)d,塞来昔布组(26.4±2.4)d,联合组(45.9±4.5)d,用Kaplan-meier,Log-rank方法分析,联合组与前三组的生存函数的差异有统计学意义(P<0.05)。实验组肿瘤组织的VEGF表达明显低于对照组(P<0.05)。结论塞来昔布联合依维莫司对大鼠嗜铬细胞瘤裸鼠移植瘤有明显抑制作用,并可降低肿瘤组织中VEGF的表达。
OBJECTIVE: To investigate the effects of celecoxib, a cyclooxygenase 2 (Cox-2) inhibitor, and everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on the development of pheochromocytoma PC12 To study the effect of everolimus on tumor growth and angiogenesis of pheochromocytoma in rats. Methods Rat pheochromocytoma cell line PC12 was inoculated subcutaneously in nude mice to establish a transplanted tumor model. After 15 days, nude mice bearing tumors were randomly divided into 4 groups (12 rats in each group), including everolimus (1mg / kg), celecoxib group (celecoxib 100mg / kg), combination group (everolimus 1mg / kg + celecoxib 100mg / kg), control group Saline 10mg / kg) for 3 weeks. After 4 weeks, the volume changes of nude mice xenografts and the survival time of nude mice were measured. The expression of vascular endothelial growth factor (VEGF) in tumor tissue was detected by immunohistochemistry, Western blotting was used to detect the expression of VEGF in tumor tissue. Results The tumor volume at 4 weeks was (4 159.72 ± 651.84) mm3 in the control group, (2 816.49 ± 332.05) mm3 in the everolimus group and (4 018.38 ± 527.46) mm3 in the celecoxib group, (1 035.28 ± 177.30) mm3, there was significant difference between the combined group and the first three groups (P <0.01). The mean survival time was 23.3 ± 2.8 days in the control group, 36.8 ± 3.6 days in the everolimus group, 26.4 ± 2.4 days in the celecoxib group, and 45.9 ± 4.5 days in the combined group. Kaplan-meier , Log-rank analysis showed that there was a significant difference in survival function between the combined group and the first three groups (P <0.05). The expression of VEGF in the experimental group was significantly lower than that in the control group (P <0.05). Conclusion Celecoxib combined with everolimus significantly inhibits the transplanted tumor of pheochromocytoma in nude mice and decreases the expression of VEGF in tumor tissue.