ISO-1对小鼠大肠癌肝转移的影响  

Effects of ISO-1 on liver metastasis of mouse colonic cancer

作　　者：何兴祥[1] 刘成勇[2] 陈萌[2] 郭海波[3] 彭侠彪[4] 全华斌[4] 

机构地区：[1]广东药学院临床医学院内科学教研室,广州510310 [2]广州医学院第二附属医院消化科 [3]广州医学院第二附属医院检验科 [4]中山市人民医院消化科

出　　处：《中华普通外科杂志》2009年第1期62-65,共4页Chinese Journal of General Surgery

基　　金：国家自然科学基金资助项目（30470435）;广东省自然科学基金资助项目（06022450与7101731）;广东省科技计划资助项目（2008A030201001）;广东药学院科研启动基金资助项目（2006LCY07）;广州市科学技术局科技攻关计划资助项目（200623-E0201）;中山市科学技术局科技计划资助项目（20073A185）

摘　　要：目的研究选择性巨噬细胞移动抑制因子（MIF）互变异构酶活性抑制剂ISO-1对BALB／c小鼠大肠癌肝转移的影响及其可能机制。方法微孔迁移法检测ISO-1对CT26细胞体外侵袭的影响。盲肠造疝原位移植瘤块术建立小鼠大肠癌肝转移模型，将30只成功建模小鼠分为3组，每组10只。每周两次腹腔注射相同体积ISO-1（0．2ml，20mg／kg）、5％DMSO和无菌生理盐水（NS）溶液。治疗4周后处死小鼠，肝脏连续病理切片、HE染色，比较各组的肝转移率。L-多巴色素甲酯测定小鼠血清MIF互变异构酶活性；ELISA测定血清中血管内皮生长因子（VEGF）水平；CD31染色标记肿瘤微血管内皮细胞测定肿瘤微血管密度（MVD）。结果100μmol／LISO-1作用24h后CT26细胞穿透聚碳酸酯膜细胞数显著减少[（151±19）比（178±9），P〈0．01]。ISO组比DMSO组小鼠血清MIF互变异构酶活性为51％比81％，P〈0．01。ISO-1组、DMSO组与NS组肝转移率分别为10％、60％与70％（χ^2=8．30，P〈0．05）。ISO-1组、DMSO组与NS组小鼠血清VEGF的水平分别为（15±7）pg／ml、（63±10）pg／ml与（67±8）pg／ml，P〈0．01。ISO-1组、DMSO组与NS组原位肿瘤组织MVD分别为17±4、36±7与38±5，P〈0．01。结论在体外ISO-1减少了CT26细胞的迁移，在体内降低了大肠癌肝转移的发生。其可能机制为ISO-1抑制MIF互变异构酶活性，下调VEGF表达，减少MVD。Objective To investigate the effects of ISO-1, a selective MIF tautomerase activity inhibitor, on liver metastasis in a BALB/c mouse model of colonic cancer. Methods Microporous migration assay was used to determine the effect of ISO-1 on the invasion abilities of CT26 cells. Orthotopic transplantation of fresh colonic tumor fragments into the hernial sac of cecum was used in a BALB/e mouse model of colorectal cancer. Thirty mouse models were divided into three groups and treated respectively with ISO-1 （0. 2 ml, 20 mg/kg） , 5% DMSO and NS （normal sodium） twice a week, intraperitoneally. After 4 weeks, mice were sacrificed and the whole livers were made into serial slices to detect the occurrence of liver metastasis. Serum MIF tautomerase activities were measured using L-dopachrome methyl ester, ELISA was used to test serum VEGF concentrations. Immunohistochemical staining of CD31 was used for comparing microvascular density （MVD） of tumor tissues. Results 100 μmol/L ISO-1 treatment for 24 hours significantly reduced the average number of the cells penetrating polycarbonates, （ 151 ± 19） vs. （ 178 ± 9）, P〈0. 01. Serum MIF tautomerase activities were significantly inhibited after ISO-1 treatment （51% vs. 81%, P 〈 0. 01 ）. Compared with DMSO and NS treatment, ISO-1 decreased the occurrence of liver metastasis （10% ,60% and 70% ,respectively;χ^2 = 8.30, P 〈 0. 05 ）. Also ISO-1 decreased serum VEGF levels （ 15 ±7） pg/ml, （63 ± 11） pg/ml and（67 67± 8） pg/ml,respectively;P 〈 0. 01 and the MVD of tumor tissues （17 ±4） ,（36 ±7） and（ 38 ±5） ,respectively; P 〈0. 01. Conclusion In vitro ISO-1 inhibits the invasion ability of CT26 cells. In vivo ISO-1 reduces the occurrence of liver metastasis, possibly by a mechanism of inhibiting MIF tautomerase activities, down-regulating the expression of VEGF and reducing MVD.

关 键 词：结直肠肿瘤 巨噬细胞游走抑制因子 肿瘤转移 新生血管化 病理性 

分 类 号：R686[医药卫生—骨科学]