ISO-1对结直肠癌生长和微血管形成的影响

目的 观察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对结直肠癌生长及其微血管形成的影响,并探讨其可能机制.方法 MTT法检测不同浓度ISO-1(0.01-100umol/L)在不同时间点(24、48和72 h)对CT26细胞增殖的影响.盲肠造疝原位移植瘤块术建立小鼠结直肠癌模型.将30只成功建模小鼠随机分为3组,分别每周两次腹腔注射相同体积ISO-1(0.2 ml,20 mg/kg)、5%DMSO和无菌生理盐水(NS).治疗后每周两次观察小鼠盲肠肿瘤大小,第4周时处死小鼠.ELSIA法测定小鼠血清中VEGF浓度;CD31染色标记血管内皮细胞测定肿瘤微血管密度(MVD).结果 在体外,ISO-1明显抑制CT26细胞增殖.在体内,ISO-1明显抑制小鼠肿瘤生长,第4周ISO-1组和DMSO组的抑瘤率分别为25.22%和9.65%,差异有统计学意义(P<0.01);并且,ISO-1组移植瘤质量明显小于DMSO组(1.50±0.14)g比(1.80±0.14)g,P=0.017];与DMSO组比较,ISO-1降低小鼠血清中VEGF的水平(14.62±6.49)ng/L比(63.34±10.22)ng/L,P<0.01]及肿瘤组织MVD(16.6±3.7)比(35.8±7.3),P=0.002].结论 ISO-1抑制结直肠癌细胞增殖及原位移植瘤生长,其机制可能为LSO-1抑制MIF生物学活性,从而抑制肿瘤细胞增殖、下调VEGF表达与MVD.

Effect of ISO-1 on the growth and angiogenesis of mouse colorectal cancer xenografts

Objective To investigate the effects of ISO-1, a selective macrophnge migration inhibitory factor(MIF) tautomerase activity inhibitor,on the growth and anginogenesis of colorectal cancer in mouse modal, and to explore its probable mechanism. Methods CT26 cells were treated with various concentrations of ISO-1 (0.01-100 umol/L) for 24,48 and 72 hours. MTr assay was used for detecting the inhibition effect of ISO-1 on CT26 cell proliferation. The method of orthotopic transplantation,with fresh tumor masses planted into the hernial sac of cecum by operation, was used to establish mouse model of colorectal cancer. Thirty mice were divided into three groups randomly and treated with ISO-1 (0.2 ml,20 mg/kg), 5% DMSO and NS (normal sodium) twice a week intraperitoneally. Tumor volumes were measured twice a week.After 4 weeks, the mice were sacrificed and serum VEGF concentratious were tested using ELISA.Immunohistochemical staining of CD31 was used for comparing microvessel density (MVD)of tumor tissues.Results In vitro,ISO-1 significantly inhibited CT26 cell proliferation. Also ISO-1 significantly reduced the tumor volumes in vivo. The inhibition ratio of tumorvolume was 25.22% and 9.65% after 4 weeks in ISO-1 and DMSO group, respectively (P<0.01). Compared with DMSO treatment, ISO-1 reduced the tumor weights (1.50±0.14) g vs (1.80±0.14 ) g, P=0.017]; and decreased VEGF levels and MVD of tumor tissues significantly VEGF: (14.62±6.49) ng/L vs (63.34±10.22) ng/L,P<0.01; MVD: 16.6±3.7vs 35.8±7.3,P=0.002]. Conclusions ISO-1 inhibits CT26 cell proliferation and tumor growth. The probable mechanism may be associated with the inhibition of MIF biological activities, down-regulation of the expression of VEGF and reduction of MVD.