木犀草素对人胃癌裸鼠移植瘤的抑制效应及其机制

Inhibitory effects of luteolin on human gastric carcinoma xenografts in nude mice and its mechanism

目的评价木犀草素对人胃癌BGC-823细胞裸鼠移植瘤的作用及其作用机制。方法建立BGC-823胃癌裸鼠移植瘤模型，裸鼠皮下接种BGC-823细胞，成瘤后，根据裸鼠体重，进行区组随机化分组，共分成5组（各8只）：对照组（生理盐水，0．2ml／只），5氟尿嘧啶组（30mg／kg），木犀草素低（10mg／kg）、中（20mg／kg）、高（40mg／kg）剂量组；各组给药期间测定瘤体积，绘制肿瘤生长曲线；各组用药结束后处死，称瘤重，计算抑瘤率，比较各组荷瘤鼠瘤重的差异；利用HE染色观察肿瘤形态学变化，免疫组化检测肿瘤血管内皮生长因子A（VEGF—A）及基质金属蛋白酶9（MMP-9）表达变化。结果肿瘤生长曲线结果表明，5氟尿嘧啶组，木犀草素低、中、高剂量组的肿瘤均有不同程度被抑制；木犀草素高剂量组肿瘤重量显著低于对照组[（0．29±O．01）比（0．38±0．03）g，P〈0．01]，抑瘤率达到24．87％；HE染色结果表明，随着木犀草素剂量的增大，瘤体坏死灶边缘有较多淋巴细胞浸润，且坏死区面积有增大趋势；免疫组化结果显示：中、高剂量组VEGF—A阳性细胞积分分别为1．25±0．17和1．00±0．07，均明显低于对照组（1．50±0．15，均P〈0．05）；高剂量组MMP-9阳性细胞积分亦显著低于对照组（3．75±1．43比9．00±1．08，P〈0．01）。结论木犀草素在体内可抑制肿瘤生长，其主要机制是可刺激体内免疫反应，同时抑制肿瘤细胞的EGF—A、MMP-9蛋白表达。

Objective To explore the tn vwo antlcancer ettects ot luteonn vnm gasmc carcinoma xenografts in nude mice and elucidate its mechanism. Methods After modeling of gastric carcinoma xenografts in nude mice, 40 BALB/c （nu/nu） nude mice were randomly divided into 5 groups （n = 8 each）. And an intraperitoneal injection of luteofin was administered at 10 mg/kg （low-dose）, 20 mg/kg （middle-dose） and 40 mg/kg （high-dose） groups. And 5-fluorouracil （30 mg/kg） and control groups were also established. The growth curves of xenografts in nude mice were drawn and weight inhibition rates measured. The morphological features were detected expression levels of vascular endothelial growth factor 9） were measured by immunohistochemistry. Results by hematoxylin and eosin staining. And the protein A （VEGF-A） and matrix metalloproteinase 9 （MMP- In vivo tumor formation test showed that tumor volume in nude mice treated with luteolin was smaller than that of control group. Tumor weights of high-dose luteoin group were lighter than those of the control （ （0. 29±0. 01） vs （0. 38 ±0. 03）g）. And the difference was statistically significant （ P 〈 0. 01 ）. The rate of tumor inhibition in high-dose luteoin group was up to 24. 87%. Lymphocytic invasion of tumor tissue was observed under light microscope in the treatment groups. Results of immunohistochemistry showed the positive cell integral of VEGF in middle and high-dose luteoin groups were 1.25 ± 0. 17 and 1.00±0. 07 respectively. Both were significantly lower than that of control group （I. 50 ± 0. 15, both P 〈 0. 05 ）. The positive cell integral of MMP-9 in high-dose luteoin group wasmarkedly lower than that of control group （ 3. 75 ± l. 43 vs 9. 00 ±1. 08 , P〈0.01）. Conclusions Luteolin can effectively inhibit the in vivo growth of gastric tumor. The mechanism may be correlated with the stimulation of immune response and the down-regulated expressions of VEGF-A and MMP-9.