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目的:探讨环氧化酶-2(COX-2)抑制剂塞来昔布和survivin反义寡核苷酸(ASODN)联合作用对胰腺癌荷瘤裸鼠的治疗作用。方法:构建胰腺癌荷瘤裸鼠模型,将成瘤裸鼠随机分为4组:对照组、塞来昔布组(给予1000ppm的塞来昔布饮水)、survivin ASODN组(瘤内注射40μg/200μL的survivin ASODN)、联合组(给予1000ppm的塞来昔布饮水的同时瘤内注射40μg/200μL的survivin ASODN);观测裸鼠肿瘤生长情况并测量不同时间的体积变化,于接种肿瘤的35天处死裸鼠,测瘤体质量,应用cas- pase-3试剂盒检测caspase-3活性,免疫组织化学法检测肿瘤增殖指数(PI)和微血管密度(MVD)。结果:治疗组平均体积均明显低于对照组(491.97±4.62mm~3,427.34±14.62mm~3,300.39±6.59mm~3 vs 703.56±12.51 mm~3,P<0.01),其中联合治疗组体积明显低于塞来昔布组或survivin ASODN组(P<0.01);平均抑瘤率分别为32.26%、50.86%、62.07%。治疗组caspase-3相对活性明显高于对照组(0.026±0.003、0.040±0.018、0.059±0.005 vs 0.006±0.001,P<0.01),其中联合治疗组caspase-3相对活性明显高于塞来昔布组(P<0.01)或survivin ASODN组(P<0.05);治疗组平均PI和MVD均明显低于对照组(P<0.01,或P<0.05),其中联合治疗组平均PI和MVD明显低于塞来昔布组或survivin ASODN组(P<0.01,或P<0.05)。结论:COX-2抑制剂塞来昔布和survivin ASODN联合应用可显著抑制荷胰腺癌裸鼠的肿瘤生长,其作用机制可能是通过共同提高caspase-3活性来诱导细胞凋亡,通过抑制肿瘤细胞的增殖和新生血管的形成来发挥抗肿瘤效应,为胰腺癌的治疗提供了新的思路。
Objective: To investigate the therapeutic effect of cyclooxygenase-2 (COX-2) inhibitor celecoxib combined with survivin antisense oligonucleotide (ASODN) on pancreatic cancer-bearing nude mice. Methods: The nude mice bearing pancreatic cancer were established. The nude mice were randomly divided into 4 groups: control group, celecoxib group (1000ppm of celecoxib water), survivin ASODN group (intratumoral injection of 40μg / 200μL Of survivin ASODN), combined group (given 1000ppm of celecoxib drinking water while intratumoral injection of 40μg / 200μL of survivin ASODN); observation of tumor growth in nude mice and measurement of volume changes over time, inoculated with tumor after 35 days of sacrifice The nude mice were sacrificed and the tumor mass was measured. The caspase-3 activity was detected by caspase-3 kit and the proliferation index (PI) and microvessel density (MVD) were measured by immunohistochemistry. Results: The average volume of the treatment group was significantly lower than that of the control group (491.97 ± 4.62mm ~ 3,427.34 ± 14.62mm ~ 3,300.39 ± 6.59mm ~ 3 vs 703.56 ± 12.51mm ~ 3, P <0.01), and the volume of the combined treatment group was significantly lower than that of the control group Celecoxib group or survivin ASODN group (P <0.01). The average tumor inhibition rates were 32.26%, 50.86% and 62.07% respectively. The relative activity of caspase-3 in treatment group was significantly higher than that in control group (0.026 ± 0.003,0.040 ± 0.018,0.059 ± 0.005 vs 0.006 ± 0.001, P <0.01), and the relative activity of caspase-3 in combination therapy group was significantly higher than that in celecoxib (P <0.01) or survivin ASODN group (P <0.05). The mean PI and MVD in the treatment group were significantly lower than those in the control group (P <0.01 or P <0.05), and the mean PI and MVD in the combination group were significantly lower than those in the control group Celecoxib group or survivin ASODN group (P <0.01, P <0.05). Conclusion: COX-2 inhibitor celecoxib combined with survivin ASODN can significantly inhibit tumor growth in nude mice bearing pancreatic cancer. The mechanism may be through the joint activation of caspase-3 to induce apoptosis. By inhibiting tumor cells Proliferation and neovascularization to exert anti-tumor effect, which provides a new idea for the treatment of pancreatic cancer.