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目的通过观察热休克蛋白90(HSP90)抑制剂17-丙烯胺-17-去甲氧格尔德霉素(17-AAG)对大鼠嗜铬细胞瘤裸鼠移植瘤生长的影响,探讨17-AAG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2组,每组12只,分别为实验组(腹腔注射17-AAG 40mg/kg)和对照组(腹腔注射生理盐水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HSP90、血管内皮生长因子(VEGF)的表达,采用Western blotting法检测肿瘤组织中HSP90、VEGF的表达。结果第4周时,移植瘤体积的对照组和实验组分别为(5 070.13±630.42)mm3和(2 218.80±336.29)mm3,两组移植瘤体积存在显著性差异(P<0.05);平均生存时间对照组和实验组分别为(26.0±5.1)、(42.7±7.5)d,用Kaplan-Meier、Log-Rank方法分析两组的生存函数的差异有统计学意义(P<0.05)。免疫组化显示HSP90在对照组中呈高表达(10/12,83.3%),在实验组中呈低表达(4/12,33.3%);VEGF在对照组中呈高表达(11/12,91.7%),在实验组中呈低表达(4/12,33.3%);实验组肿瘤组织的HSP90、VEGF表达明显低于对照组(P<0.05)。Western blotting法也显示两种蛋白在实验组上的表达明显低于对照组(P<0.01)。结论 17-AAG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HSP90和VEGF的表达。
Objective To investigate the effects of heat shock protein 90 (HSP90) inhibitor 17-acrylamido-17-demethoxygeldanamycin (17-AAG) on the growth of rat pheochromocytoma xenografts in nude mice, Inhibition of AAG on tumor growth and angiogenesis in pheochromocytoma in rats. Methods The rat pheochromocytoma cell line PC12 was inoculated subcutaneously in nude mice to establish a transplanted tumor model. After 15 days, the nude mice bearing tumor were randomly divided into 2 groups (n = 12 each), which were experimental group (intraperitoneal injection of 17-AAG 40mg / kg) and control group (intraperitoneal injection of normal saline 10mL / kg) for 3 weeks. After 4 weeks, the volume changes of xenografts in nude mice and the survival time of nude mice were measured. Immunohistochemistry was used to detect the expression of HSP90 and vascular endothelial growth factor (VEGF) in tumor tissue. Western blotting was used to detect the expression of HSP90 and VEGF in tumor tissue. Results At 4 weeks, the volume of tumor in control group and experimental group were (5 070.13 ± 630.42) mm3 and (2 218.80 ± 336.29) mm3, respectively. There was significant difference between the two groups in tumor volume (P <0.05) The time-control group and experimental group were (26.0 ± 5.1) and (42.7 ± 7.5) days, respectively. There was significant difference in survival function between the two groups by Kaplan-Meier and Log-Rank methods (P <0.05). Immunohistochemistry showed that HSP90 was highly expressed (10/12, 83.3%) in the control group and low in the experimental group (4/12, 33.3%). VEGF was highly expressed in the control group (11/12, 91.7%). The expression of HSP90 and VEGF in the experimental group was significantly lower than that in the control group (P <0.05). Western blotting also showed that the expression of both proteins in the experimental group was significantly lower than that in the control group (P <0.01). Conclusion 17-AAG can significantly inhibit the xenografts of pheochromocytoma in nude mice and decrease the expression of HSP90 and VEGF in tumor tissues.