热休克蛋白90抑制剂17-DMAG联合5-FU对人胃癌裸鼠移植瘤的抑制作用研究  

Inhibitory effect of HSP90 inhibitor 17-DMAG combined with 5-FU in human gastric cancer transplanted in nude mice

作　　者：吴文辉[1] 朱佳成 罗特东[1] 杨平[1] 曹金鹏[1] 肖隆斌[2] 

机构地区：[1]中山大学附属佛山医院胃肠外科,佛山528000 [2]中山大学附属第一医院东院胃肠外科,广州510080

出　　处：《消化肿瘤杂志（电子版）》2015年第2期99-105,共7页Journal of Digestive Oncology(Electronic Version)

基　　金：广东省科技计划项目(2014A020212693)

摘　　要：目的探讨热休克蛋白90(HSP90)抑制剂17-二甲基胺乙基-17-去甲氧基格尔德霉素(17-DMAG)联合5-FU对人胃癌裸鼠移植瘤生长的抑制作用。方法用人胃癌组织块接种于裸鼠皮下,建立裸鼠人胃癌移植瘤模型;将荷瘤裸鼠随机分为4组,每组10只:17-DMAG组(腹腔注射17-DMAG 25 mg/kg)、5-氟尿嘧啶(5-FU)组(腹腔注射5-FU 20 mg/kg)、联合组(腹腔注射17-DMAG 25 mg/kg,5-FU 20 mg/kg,调整药物浓度到总量10 ml/kg)及对照组(腹腔注射生理盐水10 ml/kg),每周3次,4周后测量裸鼠移植瘤的体积及重量,HE染色观察形态学变化,同时采用免疫组化方法检测肿瘤组织中CD31(以阳性细胞数计算肿瘤微血管密度,MVD)及血管内皮生长因子(VEGF)的表达。结果17-DMAG组移植瘤体积为(286.24±20.83)mm^3,5-FU组移植瘤体积为(358.62±23.54)mm^3,联合组移植瘤体积为(216.82±21.65)mm^3,对照组移植瘤体积为(926.46±108.62)mm^3,前三组与对照组比较,均有统计学差异(均P<0.05)。移植瘤重量比较,联合组(0.55±0.03)g、17-DMAG组(1.13±0.12)g和5-FU组(1.29±0.15)g均明显低于对照组(3.11±0.17)g(均P<0.05);联合组瘤重比其他两组单药实验组明显减轻,有统计学差异(P<0.05);17-DMAG与5-FU两组之间的瘤重比较无统计学差异(P>0.05)。联合组MVD(20.36±1.38)、17-DMAG组MVD(21.43±1.24)比5-FU组(37.28±1.63)、对照组(37.68±1.54)均明显减少(P<0.05);而联合组与17-DMAG组间差异不明显(P>0.05);5-FU组和对照组间差异不明显(P>0.05)。联合组和17-DMAG组肿瘤组织中VEGF的表达分别为(P>0.05)(14.83±3.78)和(15.39±4.37),与5-FU组(25.76±7.12)和对照组(36.45±7.45)分别比较,差异有统计学意义(均P<0.05);联合组和17-DMAG组之间以及5-FU组和对照组之间VEGF的表达差异均无统计学意义。结论热休克蛋白90抑制剂17-DMAG可抑制肿瘤新生血管的生成。当联合使用17-DMAG与5-FU时,对胃癌细胞的生长具有明显的抑制作用,且17-DMAG与5-FU之间具有协同作用Objective To investigate the inhibitory effect of HSP90 inhibitor 17-DMAG combined with 5-FU on tumor growth in human gastric cancer xenograft in nude mice and to explore the probable anticancer mechanism of HSP90 inhibitor. Methods Human gastric cancer tissues were subcutaneous transplanted into nude mice to develop xenograft model. Altogether 40 mice with xenograft tumor were randomly divided into 4 groups ：17-DMAG group, 5-FU group, combination group（17-DMAG combined with 5-FU）and control group（vehicle-treated controls）. Each group respectively received 17-DMAG（25 mg /kg）, 5-FU（20 mg / kg）, 17-DMAG（25 mg / kg） and 5-FU（20 mg / kg）, and NS（10 ml / kg）, three times a week. Four weeks later,tumor volume and weight were record. HE staining was applied to show morphological changes. Immunohistochemical staining was performed for detecting the expression of CD31 to evaluate intratumoral microvessel density（MVD） as well as VEGF expression in the tumors. Results The size of xenografts in 17-DMAG treatment group was（286.24 ±20.83）mm^3, and（358.62 ±23.54）mm^3 in 5-FU treatment group, and（216.82±21.65） mm^3 in combination group, which were both significantly smaller than（926.46±108.62）mm^3 in control group; The tumor weight in combination group was（0.55±0.03）g, 17-DMAG group was（1.13 ±0.12）g, and 5-FU group was（1.29 ±0.15）g, all of which were significantly less than that in control group（3.11 ±0.17）g（all P 〈0.05）. The tumor weight of combination group was significantly less than that in both 17-DMAG group and 5-FU group（all P〈 0.05）. There were significant decrease of MVD in combination group（20.36±1.38）, and in 17-DMAG group（21.43 ±1.24）, as compared with 5-FU group（37.28±1.63） and control group（37.68±1.54）（P〈0.05）. The expression of VEGF in combination group（14.83 ±3.78）, 17-DMAG group（15.39±4.37） were significantly lower than that in 5-FU group（25.76 ±7.12） and control group（36.45 ±7.45）�

关 键 词：胃肿瘤 血管内皮细胞生长因子 HSP90抑制剂 5-氟尿嘧啶 

分 类 号：R735.2[医药卫生—肿瘤]