摘要
背景与目的通过药物干预性动物实验,观察重组人血管内皮抑素(rh-endostatin)与多西紫杉醇不同顺序联合用药后MMP-2及相关因子的变化及其对移植瘤生长与血管生成的影响,探索两药联合的作用机制和最佳抗肿瘤方案。方法建立肺腺癌A549荷瘤裸鼠模型,分两个阶段进行实验。第一阶段:将荷瘤小鼠随机分为重组人血管内皮抑素组(重组人血管内皮抑素400μg·d-1,d1-d14)和多西紫杉醇组(多西紫杉醇10mg·kg-1·3d-1,d1-d14);第二阶段:将荷瘤小鼠随机分为同时用药组(重组人血管内皮抑素400μg·d-1、d1-d35,多西紫杉醇10mg·kg-1·3d-1、d1-d19)、先重组人血管内皮抑素组(重组人血管内皮抑素400μg·d-1、d1-d35,多西紫杉醇10mg·kg-1·3d-1、d16-d34)和模型组。实验中动态测量移植瘤体积,结束后以免疫组化方法检测MMP-2、TIMP-2、EMMPRIN表达并计数微血管密度(MVD)。结果两单药组比较,重组人血管内皮抑素组MMP-2和EMMPRIN表达下调较多西紫杉醇组(P=0.024,P=0.081)明显,两组间TIMP-2表达无明显差异(P>0.05)。联合组用药结束时,同时用药组与先重组人血管内皮抑素组的移植瘤体积小于模型组(P<0.001,P=0.003),且MMP-2表达均明显下调、微血管数减少(P<0.05),但同时用药组对肿瘤生长的抑制较先重组人血管内皮抑素组明显;与模型组相比,同时用药组TIMP-2上调(P=0.001)、EMMPRIN下调(P=0.018),先重组人血管内皮抑素组未见相似结果。结论同时用药方案可以从TIMP-2、EMMPRIN两个环节下调MMP-2的表达,从而更好地抑制肿瘤生长。
Background and objective The aim of this study is to observe the changes of MMP-2 and its regulators, and to investigate the mechanism of the two administration sequences of recombinant human endostatin (rh-endostatin) and docetaxel. Methods The experiment was performed as 2 stages. Firstly, nude mice with xenograft tumor were randomized into 2 groups as rh-endostatin-treated group with rh-endostatin 400 μg·d-1, d1-d14 and docetaxel-traeted group with docetaxel 10 mg·kg^-1·3d-1, d1-d14. Secondly, nude mice with xenograft tumor were randomized into 3 groups as concurrent administration group (rh-endostatin 400 μg·d-1, d1-d35, docetaxel 10 mg·kg^-1·3d-1, d1-d19), endo-first group (rh-endostatin 400 μg·d-1, d1-d35, docetaxel 10 mg·kg^-1·3d-1, d16-d34) and model group (positive control, mice burdened tumor without treatment). The volume of tumor was measured during treatment. Detection of the expressions of MMP-2, TIMP-2, EMMPRIN and the count of microvessel density (MVD) by immunohistochemistry stain examination were carried out at the end of experiment. Results Compared with the docetaxel-treated group, more obvious down-regulation of expression of MMP-2, EMMPRIN (P=0.024, P=0.081) were observed in rh-endostatin-treated group. No significant difference was found in TIMP-2 expression between the 2 groups. In combined treatment groups, at the endpoint tumor volumes of concurrent administration group and the endo-first group were remarkably smaller than that in model group (P0.001, P=0.003). According to the administration procedure, concurrent administration inhibited tumor growth stronger than endo-first treatment did. Both of the combined groups down-regulated the expression of MMP-2 and decreased microvessel density (P0.05). Compared with model group, the expression of TIMP-2 was upregulated (P=0.001) as well as EMMPRIN down-regulated (P=0.018) in concurrent adminis-tration group. Oppositely, the same results were not observed in the endo-first group. Conclusion The schedule of the concurrent administration group could inhibit the tumor growth better, and it down-regulated MMP-2 expression through TIMP-2 and EMMPRIN, and thus slow down the tumor growth superiorly to another schedule of treatment.
出处
《中国肺癌杂志》
CAS
2010年第6期580-585,共6页
Chinese Journal of Lung Cancer