新城疫病毒7793株对结肠癌小鼠肝转移的抑制效果及其可能的机制

Inhibition of liver metastasis of colon cancer cells following treatment with Newcastle disease virus strain 7793:A preliminary observation in a mouse model

目的:以脾脏保留法建立结肠癌小鼠肝转移模型,评价新城疫病毒(Newcastle disease virus,NDV)7793株对小鼠结肠癌肝转移的抑制效果,并初步探讨NDV抑瘤的免疫激活机制。方法:经脾注入1×107/ml小鼠结肠癌细胞CT26的单细胞悬液0.1 ml,建立结肠癌CT26小鼠肝脏转移瘤模型;建模小鼠随机分3组(每组20只):PBS阴性对照组、NDV7793给药组和5-FU给药组,于建模当天起连续5 d经腹腔分别注射PBS(0.1 ml/d)、NDV7793(512 HU/kg)和5-FU(20 mg/kg)。观察各组小鼠的生存状态,分析肝脏成瘤情况,计算抑瘤率和胸腺指数。ELISA法检测模型小鼠肝脏的IFN-γ水平。结果:成功构建小鼠结肠癌肝转移模型。NDV7793给药组小鼠未观察到明显的不良反应,生活状态好于PBS组和5-FU组。NDV7793组和5-FU组小鼠的肝转移瘤数量较PBS组均显著减少[(20.40±5.20)、(205.50±19.21)vs(265.30±35.73)个,均P<0.01],NDV7793组的抑瘤率明显高于5-FU组(75.4%vs 48.0%,P<0.05),NDV7793组小鼠的肝脏癌灶范围小,癌细胞以坏死或凋亡为主。NDV7793组和5-FU组小鼠的中位生存期明显长于PBS阴性对照组(30、22 vs 17 d,P<0.01)。NDV7793组小鼠肝脏IFN-γ的表达和胸腺指数均显著高于5-FU组和PBS组(均P<0.05)。结论:NDV7793株对结肠癌小鼠的肝转移具有较强的抑制效果,并可能通过上调肝脏的IFN-γ以及提升胸腺指数来抑制结肠癌的肝转移。

Objective： To evaluate the liver metastasis-inhibiting and immune-stimulating effects of Newcastle disease virus （NDV） strain 7793 in a mouse model of colon cancer. Methods： CT26 colon cancer cells （1 x 106 cells in 0.1 ml PBS） were injected into the subcapsules of the spleen of BALB/c mice aged 4 -6 weeks through intra-peritoneal injec- tion. Surviving mice beating CT26 colon cancer cells were randomized to receive PBS （0.1 ml/d） , NDV7793 （512 HU/ kg） and fluorouracil （5-FU, 20 mg/kg） , respectively, for 5 before colon cancer cell transplantation, before the designated days. Body weight and general health status were recorded treatments and on post-treatment days 1,5, 10 and 15, re- spectively. On post-treatment day 16, animals were sacrificed. Liver metastasis was assessed gross pathology. Thymus and liver were collected. Histologic assessment was performed on paraffin sections of the liver after H-E staining. Thymus in- dex and metastasis inhibition rate were calculated. IFN-y/levels in static foci in colon cancer cell-bearing mice were significantly less the liver were measured by ELISA. Results ： The meta- （ P 〈 0. 05 ） after treatment with NDV （ 20.40 ± 5.20）and 5-FU （205.50± 19.21 ） respectively than with PBS （265.30 ±35.73 ）. Liver metastasis inhibition rate was signifi- cantly higher for NDV7793 than for 5-FU group （75.4% vs 48.0% , P 〈 0.05 ）. The mean survival time of colon cancer cell-bearing mice was 30 days after NDV7793 treatment, 22 days after 5-FU treatment but only 17 days after PBS treat- ment （P 〈 0.05 ）. Compared with PBS control group and 5-FU group, the increased Thymus index and liver concentra- tions of IFN-y/were significantly higher after treatment with NDV 7793 than with 5-FU and PBS respectively （ P 〈 0. 05 ）. Conclusion： NDV 7793 appears effective to inhibit liver metastasis of colon cancer cells. This effect may be mediated by elevated IFN-y in liver microenvironment.