重组溶瘤单纯疱疹病毒抑制小鼠结肠癌肺转移瘤的实验研究

张政; 彭瑞娟; 阿木提喀日·马木提; 刘晓娟; 王雪莹; 马正海

doi:10.13568/j.cnki.651094.651316.2019.08.26.0003

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重组溶瘤单纯疱疹病毒抑制小鼠结肠癌肺转移瘤的实验研究

生命科学与技术 | 更新时间：2026-01-21

- 重组溶瘤单纯疱疹病毒抑制小鼠结肠癌肺转移瘤的实验研究
- 重组溶瘤单纯疱疹病毒抑制小鼠结肠癌肺转移瘤的实验研究
- 新疆大学学报（自然科学版中英文） 2020年37卷第3期页码：294-300
- 作者机构：
  
  新疆大学生命科学与技术学院
- 作者简介：
- 基金信息：
  
  国家自然科学基金（31140018）;新疆维吾尔自治区高技术研究发展项目（2010016）
- DOI：10.13568/j.cnki.651094.651316.2019.08.26.0003
  中图分类号： R735.35
- 纸质出版：2020
- 稿件说明：
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[1]张政,彭瑞娟,阿木提喀日·马木提,等.重组溶瘤单纯疱疹病毒抑制小鼠结肠癌肺转移瘤的实验研究[J].新疆大学学报(自然科学版)(中英文),2020,37(03):294-300.
[1]张政,彭瑞娟,阿木提喀日·马木提,等.重组溶瘤单纯疱疹病毒抑制小鼠结肠癌肺转移瘤的实验研究[J].新疆大学学报(自然科学版)(中英文),2020,37(03):294-300. DOI： 10.13568/j.cnki.651094.651316.2019.08.26.0003.

DOI：10.13568/j.cnki.651094.651316.2019.08.26.0003.

摘要

探讨携载p53和IL-12的重组溶瘤单纯疱疹病毒(Oncolytic Herpes Simplex Virus-1

oHSV) MH1004和MH1006对小鼠结肠癌皮下移植瘤和肺转移瘤的治疗作用.蚀斑法和MTT法分析重组oHSV对结肠癌细胞CT26的感染和溶瘤特性;小鼠背部皮下注射CT26建立皮下移植瘤模型

瘤内注射重组oHSV后分析小鼠血清中IL-12含量

观察肿瘤大小和小鼠生存率;小鼠尾静脉注射CT26建立肺转移模型

尾静脉注射重组oHSV后显微观察肺组织中肿瘤细胞浸润

观察肺脏肿瘤结节和小鼠生存率.重组oHSV能够感染CT26并高效复制和抑制肿瘤细胞.皮下移植瘤小鼠治疗12 d后观察到抑瘤效应

MH1004和MH1006组21 d时肿瘤体积(2 477.31±2 017.02 mm3和1 414.36±1 639.19 mm3)均极显著小于Mock组(7 682.92±2 648.74 mm3)(P <0.01)

42 d时生存率(均为100%)明显高于HSV-wt和Mock组(均为50%);MH1006组小鼠血清中IL-12含量增加

第16 d时极显著高于Mock组(P <0.01);治疗后肿瘤消失小鼠血清中IL-12含量明显增高.肺转移瘤小鼠治疗后

MH1004和MH1006组小鼠肺脏肿瘤结节数在治疗5 d、9 d和13 d时均极显著低于Mock组(P <0.01)

13 d极显著低于HSV-wt组(P <0.01)

且o HSV治疗小鼠肺组织浸润的肿瘤细胞明显减少;60 d时MH1004组、MH1006组、HSV-wt组和Mock组的生存率依次为83.3%、66.7%、66.7%和50%

MH1004组和MH1006组死亡小鼠肺脏肿瘤结节少于Mock组和HSV-wt组.携载IL-12和p53的重组o HSV经尾静脉注射治疗小鼠结肠癌肺转移瘤效果显著

该研究为转移瘤治疗提供了新的思路.

Abstract

To investigate the inhibitory effects of the recombinant oHSV carrying p53(MH1004) or IL-12(MH1006) on the models of subcutaneous xenograft and lung metastasis of colon cancer in mice

the infection ability and oncolytic property of the recombinant oHSVs in colon cancer cell line CT26 were detected by plaque and MTT analysis. The murine model of subcutaneous xenograft was established by subcutaneous inoculation CT26 cells

subsequently the oHSVs were injected intratumorally

then the IL-12 content in the mice serum was tested

and the tumor volume and survival rate of the mice were measured. The murine model of lung metastasis of colon cancer was established by inoculation CT26 cells through caudal vein

subsequently the o HSVs were injected through caudal vein

then tumor cell infiltration of the lungs was observed with microscope

and the tumor nodules in the lungs and survival rate of the mice were measured. HSV-wt and virus storage(Mock) groups were used as controls of the above experiments. The o HSVs were able to infect CT26 cells

then replicate efficiently and inhibit tumor cell proliferation. The inhibition of subcutaneous tumors was observed after 12 d of treatment; and after 21 d

the tumor volume of MH1004(2 127.31±2 017.02 mm3) and MH1006(1 414.36±1 639.19 mm3) was significant smaller than that of Mock(P <0.01); after 42 d

the survival rates of MH1004 and MH1006(both 100%) were significant higher than that of Mock and HSV-wt(both 50%); the IL-12 content in the mice serum of MH1006 increased after treatment and was significantly higher than that of Mock after 16 d of treatment(P <0.01)

and the IL-12 content in the serum of the mice whose tumor have disappeared was increased significantly. After 5 d

9 d

and 13 d treatment to the lung metastasis of colon cancer in mice

the number of the tumor nodule in the lungs from MH1004 and MH1006 was highly significant lower than that from Mock(P <0.01)

and after 13 d that the number of the tumor nodule in the lungs from MH1004 and MH1006 was also significantly lower than that from HSV-wt(P <0.01)

moreover

the tumor cell infiltration of the lungs from o HSVs treatment was decreased significantly; after 60 d

the survival rates of MH1004

MH1006

HSV-wt and Mock group were 83.3%

66.7%

66.7% and 50% respectively; the number of the tumor nodule in the lungs of the dead mice from MH1004 and MH1006 was significantly lower than that from HSV-wt and Mock. Inoculation oHSVs armed with p53 or IL-12 via caudal vein is a highly effective treatment for the lung metastasis of colon cancer in mice. This study provides a new idea for the treatment of metastatic tumors.

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references

MARTUZA R,MALICK A,MARKERT J,et al.Experimental therapy of human glioma by means of a genetically engineered virus mutant[J].Science,1991,252(5007):854-856.

MARKERT J M,LIECHTY P G,WANG W,et al.Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM[J].Molecular Therapy,2009,17(1):199-207.

KEMENYN,BROWN K,COVEY A,et al.Phase I,open-label,dose-escalating study of a genetically engineered herpes simplex virus,NV1020,in subjects with metastatic colorectal carcinoma to the liver[J].Human Gene Therapy,2006,17(12):1214-1224.

GEEVARGHESE S K,GELLER D A,DE HAAN H A,et al.Phase I/II study of oncolytic herpes simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer metastatic to the liver[J].Human Gene Therapy,2010,21(9):1119-1128.

GASTON D C,WHITLEY R J,PARKER J N.Engineered herpes simplex virus vectors for antitumor therapy and vaccine delivery[J].Future Virology,2011,6(3):321-340.

BRAIDWOOD L,GRAHAM S,GRAHAM A,et al.Oncolytic herpes viruses,chemotherapeutics,and other cancer drugs[J].Oncolytic Virotherapy,2013,2:57-74.

MOESTA A K,COOKE K,PIASECKI J,et al.Local delivery of onco VEX\r,m GM-CSF\r,generates systemic anti-tumor immune responses enhanced by cytotoxic t-lymphocyte-associated protein blockade[J].Clinical Cancer Research,2017:clincanres.0681.2017.

ANDTBACKA R H I,KAUFMAN H L,COLLICHIO F,et al.Talimogene laherparepvec improves durable response rate in patients with advanced melanoma[J].Journal of Clinical Oncology,2015,33(25):2780-2788.

RIBAS A,DUMMER,REINHARD,et al.Oncolytic virotherapy promotes intratumoral t cell infiltration and improves anti-PD-1immunotherapy[J].Cell,2017,170(6):1109-1119.

王雪莹,赵晓飞,李永鑫,等.一种新型1型单纯庖疹病毒载体系统的建立[J].中国生物化学与分子生物学报,2015,31(3):322-329.WANG X Y,ZHAO X F,LI Y X,et al.The development of a herpes simplex virus type 1 vector system[J].Chinese Journal of Biochemistry and Molecular Biology,2015,31(3):322-329.

王雪莹,朱慧,汪习,等.携带p53基因的重组1型单纯疱疹病毒溶瘤特性的实验观察[J].中华医学杂志,2016,96(5):370-374.WANG X Y,ZHU H,WANG X,et al.Oncolytic property of HSV-1 recombinant viruses carrying the p53 gene[J].National Medical Journal of China,2016,96(5):370-374.

刘晓娟,王雪莹,郭景霞,等.携载人IL-12的重组1型单纯疱疹病毒溶瘤特性的观察[J].中华医学杂志,2017,97(27):2135-2140.LIU X J,WANG X Y,GUO J X,et al.Oncolytic property of HSV-1 recombinant viruses carrying the human IL-12[J].National Medical Journal of China,2017,97(27):2135-2140.

SIEGEL RL,MILLER KD,FEDEWA SA,et al.Colorectal cancer statistics,2017[J].CA:A Cancer Journal for Clinicians,2017,67:177-193.

SAHA D,MARTUZA R L,RABKIN S D.Macrophage polarization contributes to glioblastoma eradication by combination immunovirotherapy and immune checkpoint blockade[J].Cancer Cell,2017,32(2):253-267.

LEONI V,VANNINI A,GATTA V,et al.A fully-virulent retargeted oncolytic HSV armed with IL-12 elicits local immunity and vaccine therapy towards distant tumors[J].PLo SPathog,2018,14(8):e1007209.

XIUHONG L,SHUANG W,XIANGHUA G,et al.Exogenous p53 and ASPP2 expression enhances r Ad V-TK/GCV-induced death in hepatocellular carcinoma cells lacking functional p53:[J].Oncotarget,2016,7(14):18896-18905.

FAN X,LU H,CUI Y,et al.Overexpression of p53 delivered using recombinant NDV induces apoptosis in glioma cells by regulating the apoptotic signaling pathway[J].Exp,Ther Med,2018,15(5):4522-4530.

REALE A,VITIELLO A,CONCIATORI V,et al.Perspectives on immunotherapy via oncolytic viruses[J].Infectious Agents and Cancer,2019,14:1-8.

WONG RJ,PATEL SG,KIM S,et al.Cytokine gene transfer enhances herpes oncolytic therapy in murine squamous cell carcinoma[J].Hum Gene Ther,2001,12(3):253-265.

BAUER DF,LARISA P,YANCEY GG,et al.Effect of HSV-IL12 loaded tumor cell-based vaccination in a mouse model of high-grade neuroblastoma[J].Journal of Immunology Research,2016,2016:1-10.

VOEST EE,KENYON BM,O”REILLY MS,et al.Inhibition of angiogenesis in vivo by interleukin 12[J].Journal of the National Cancer Institute (Bethesda),1995,87(8):581-586.

BENNETT JJ,MALHOTRA S,WONG RJ,et al.Interleukin 12 secretion enhances antitumor efficacy of oncolytic herpes simplex viral therapy for colorectal cancer[J].Annals of Surgery,2001,233(6):819-826.

THOMAS ED,MEZA-PEREZ S,BEVIS KS,et al.IL-12 expressing oncolytic herpes simplex virus promotes anti-tumor activity and immunologic control of metastatic ovarian cancer in mice[J].Journal of Ovarian Research,2016,9(1):70.

NAKAYAMA M,OSHIMA M.Mutant p53 in colon cancer[J].J Mol Cell Biol,2019,11(4):267-276.

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