摘要
目的溶瘤腺病毒成为近年研究肿瘤靶向治疗的热点之一,目前鲜见溶瘤腺病毒SG600-IL24应用于裸鼠移植瘤的报道。本研究利用携带人黑色素瘤分化相关基因7/白介素24(melanoma differentiation associated gene-7/interleukin-24,MDA-7/IL-24)基因的溶瘤腺病毒SG600-IL24与干扰素联合治疗肝癌裸鼠移植瘤,旨在探讨溶瘤腺病毒基因和新辅助联合治疗肝癌的作用机制。方法构建携带人MDA-7/IL-24基因的溶瘤腺病毒SG600-IL24,单独使用该病毒或干扰素以及两者联合治疗裸鼠肝癌模型,观察其抗肿瘤效应。裸鼠随机分为对照组、新辅助治疗组(IFN组)、基因治疗组(SG600-IL24组)和基因治疗+新辅助治疗组(SG600-IL24+INF组)。采用免疫组化方法检测各组肿瘤组织中基质金属蛋白酶-2(matrix metalloproteinase-2,MMP-2)与血管内皮生长因子(vascular endothelial growth factor,VEGF)表达情况。结果成功构建携带人MDA-7/IL-24基因的溶瘤腺病毒SG600-IL24载体,溶瘤腺病毒SG600-IL24介导的外源基因MDA-7/IL-24在SG600-IL24组和SG600-IL24+INF组裸鼠体内表达明显增高;对照组、IFN组、SG600-IL24组裸鼠平均生存时间分别为(35.2±1.53)、(67.6±2.10)和(59.2±1.16)d,SG600-IL24+IFN联合治疗组有3只裸鼠生存时间超过120d,达到长期生存,与其他3组比较生存期明显延长,F=68.20,P=0.000 1;SG600-IL24+IFN组裸鼠肝癌体积也明显小于SG600-IL24组(P=0.000 9)或IFN组(P=0.000 4);SG600-IL24联合干扰素能明显降低MMP-2[表达率为(2.0±1.9)%]和VEGF表达[MMP-2表达率为(0.8±1.1)%],作用优于SG600-IL24组、IFN组及对照组,差异有统计学意义,均P<0.001。结论溶瘤腺病毒SG600-IL24联合干扰素对裸鼠人肝癌种植模型有很好的协同抗肿瘤作用,其作用机制可能与抗肿瘤侵袭、转移有关。
OBJECTIVE In recent years,oncolytic adenovirus has become a hot spot in the field of tumor-targeted therapy,Oncolytic adenovirus SG600-IL24 is rarely reported on hepatoma xenografts in nude mice.This study aimed to explore the mechanism of hepatoma gene therapy combined with neoadjuvant therapy,according to the study of oncolytic adenovirus SG600-IL24 carrying human MDA-7/IL-24 and Interferon on hepatoma xenografts in nude mice.METHODS The oncolytic adenovirus SG600-IL24 carrying human MDA-7/IL-24(SG600-IL24)was constructed,SG600-IL24 and or interferon were injected into the nude mice and observed the antitumor effects of them.The animals were radomized into four groups:contor group,Neoadjuvant therapy group(IFN group),SG600-IL24 group,SG600-IL24+IFN group.The expressions of matrix metalloproteinase-2(MMP-2)and vascular endothelial growth factor(VEGF)were detected by immunohistochemical method.RESULTS The oncolytic adenovirus SG600-IL24 carrying human MDA-7/IL-24(SG600-IL24)was constructed successfully.The exogenous MDA-7/IL-24 gene was highly expressed in nude mice after infected with SG600-IL24 or SG600-IL24 plus IFN.The survival time of the mice was(35.2±1.53),(67.6±2.10)and(59.2±1.16)d in control group,IFN group and SG600-IL24 group,respectively.The survival time of the mice treated with SG600-IL24 plus interferon had significantly longer(3 mice>120)days and smaller tumor volume than that in other groups(F=68.20,P=0.000 1),and it was smaller tumor volume than SG600-IL24 or IFN group(P=0.000 9;P=0.000 4).The expression of MMP-2 and VEGF can be significantly reduced by SG600-IL24 combined Interferon.The expression rates of MMP-2 and VEGF in tumor tissues were(2.0±1.9)%,(0.8±1.1)%,respectively.The effect was superior to other groups,the difference was statistically significant(MMP-2:P<0.001;VEGF:P<0.001).CONCLUSION Oncolytic adenovirus SG600-IL24 has stronger synergistic antitumor effect on hepatoma xenografts in nude mice combined with Interferon,the mechanism may be associated with anti-tumor invasion and
作者
肖朝文
郑小林
蔡常春
郑建伟
申铭
XIAO Chao-iven;ZHENG Xiao-lin;CAI Chang-chun;ZHENG Jian-uuei;SHEN Ming(Department of Hepatobiliary and Pancreatic Surgery,Central Hospital of Wuhan,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430014,P.R.China;Department of Hepatobiliary and Pancreatic Surgery,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,P.R.China)
出处
《中华肿瘤防治杂志》
CAS
北大核心
2019年第17期1237-1243,共7页
Chinese Journal of Cancer Prevention and Treatment
基金
湖北省自然科学基金（2017CFB248）
武汉市卫生计生委科研项目（WX15B24）
