mTOR抑制剂依维莫司在神经内分泌肿瘤中的作用研究

发布时间：2018-03-29 21:00

本文选题：mTOR抑制剂　切入点：依维莫司　出处：《浙江大学》2014年硕士论文

【摘要】：目的：探讨mTOR抑制剂依维莫司对人神经内分泌肿瘤BON1裸鼠皮下移植瘤模型的治疗作用,并应用18F-FDG microPET对其治疗效果进行活体监测评价,为依维莫司应用于神经内分泌肿瘤的治疗提供实验依据。方法：建立裸鼠人神经内分泌肿瘤BON1皮下移植瘤模型,模型随机分入治疗组和对照组(各6只),治疗组裸鼠腹腔注射依维莫司(1.5mg/kg/d),对照组注射等体积的20%无水乙醇+80%PBS混合液。每天观察裸鼠及肿瘤生长情况,每周3次用游标卡尺测量肿瘤大小,用电子天平称量裸鼠体重；在治疗前第0周及治疗后第1、2及3周分别进行18F-FDG microPET显像,以监测皮下移植瘤的葡萄糖代谢变化；治疗4周后处死裸鼠,剥离肿瘤,用免疫组织化学检测肿瘤Ki-67、caspase-3及vWF的表达,并计算肿瘤的微血管密度(MVD)。结果： (1)依维莫司对BON1裸鼠移植瘤的肿瘤生长有明显抑制作用,自给药后7天起,治疗组肿瘤体积明显小于对照组(P0.05)；4周时,治疗组的肿瘤重量明显小于对照组(P0.05),依维莫司治疗组的抑瘤率为60.08%; (2)在各个时间点,治疗组移植瘤的FDG摄取有低于对照组的趋势,但无统计学意义(P0.05)；对照组治疗后第3周的FDG摄取高于治疗前第0周(P0.05): (3)免疫组织化学结果显示,治疗组的MVD及Ki-67阳性细胞率均低于对照组(P0.05),caspase-3积分光密度值有高于对照组的趋势,但无统计学差异(P0.05)。结论：本研究表明依维莫司对人神经内分泌肿瘤BON1有明显的抑制作用,可能与抗肿瘤细胞增殖及抗肿瘤血管生成有关；18F-FDG PET在评价依维莫司对神经内分泌肿瘤BON1的治疗效果方面作用有限。
[Abstract]:Objective:. To investigate the therapeutic effect of mTOR inhibitor Evimostr on human neuroendocrine tumor BON1 nude mice subcutaneously transplanted tumor model, and to use 18F-FDG microPET to evaluate the therapeutic effect in vivo. To provide experimental basis for the treatment of neuroendocrine tumors with ivermostatin. Methods:. BON1 subcutaneous transplanted tumor model of human neuroendocrine tumor in nude mice was established. The model was randomly divided into treatment group (n = 6) and control group (n = 6 each). The nude mice in the treatment group were intraperitoneally injected with iveratroxide 1.5 mg / kg / d, and the control group were injected with 20% anhydrous ethanol 80%PBS mixture of the same volume. The growth of nude mice and tumor were observed every day. The tumor size was measured with Vernier caliper 3 times a week, and the body weight of nude mice was weighed by electronic balance. 18F-FDG microPET imaging was performed at the 0 th week before treatment and at 2 and 3 weeks after treatment to monitor the glucose metabolism of subcutaneous transplanted tumor. After 4 weeks of treatment, nude mice were killed and the tumor was stripped. The expressions of Ki-67 caspase-3 and vWF were detected by immunohistochemistry, and the microvessel density (MVD) of the tumor was calculated. Results:. 1) the tumor growth of BON1 xenografts in nude mice was significantly inhibited by Evermostr. The tumor volume in the treatment group was significantly smaller than that in the control group at 4 weeks after self-administration of the drug, and the tumor volume in the treatment group was significantly lower than that in the control group at 4 weeks. The tumor weight in the treatment group was significantly lower than that in the control group (P 0.05), and the tumor inhibition rate in the treatment group was 60.08. (2) at each time point, the FDG uptake of transplanted tumor in the treatment group was lower than that in the control group, but there was no significant difference between the two groups (P 0.05). The FDG uptake in the control group was higher than that in the control group at the 3rd week after treatment (P 0.05). 3) the results of immunohistochemistry showed that the positive rates of MVD and Ki-67 in the treatment group were lower than those in the control group (P 0.05), but there was no significant difference between the two groups in the integrated optical density of caspase-3. Conclusion:. This study suggests that Evimostus has a significant inhibitory effect on BON1 in human neuroendocrine tumors. It may be related to anti-tumor cell proliferation and anti-angiogenesis that the 18F-FDG PET may play a limited role in evaluating the efficacy of ivermostatin in the treatment of neuroendocrine tumor BON1.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R739.4

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