表达mIL-21的溶瘤痘苗病毒对小鼠乳腺癌的治疗作用  

Therapeutic effect of the oncolytic vaccinia viruses with expression of mI L-21 on breast cancer of mouse

作　　者：刘超[1,2,3] 王继伟[2,3] 王鹏举[2,3] 张忠献[2,3] 褚永超 吕鹏威[1] 谷元廷[1] 王尧河[2,3] 

机构地区：[1]郑州大学第一附属医院乳腺外科,河南郑州450052 [2]郑州大学中英分子肿瘤学研究中心暨国家细胞与基因治疗国际联合研究中心,河南郑州450052 [3]郑州大学医学科学院细胞与基因治疗中心,河南郑州450052

出　　处：《中国肿瘤生物治疗杂志》2017年第5期472-477,共6页Chinese Journal of Cancer Biotherapy

基　　金：国家自然科学基金资助项目(No.81272525;No.81201792)~~

摘　　要：目的:观察溶瘤痘苗病毒VVΔTKΔN1L-RFP和VVΔTKΔN1L-m IL-21对小鼠乳腺癌细胞系JC、TUBO和4T1的体内外治疗效果。方法:采用MTT法比较VVΔTKΔN1L-RFP和VVΔTKΔN1L-m IL-21两种病毒在不同质量浓度下对乳腺癌JC、TUBO和4T1细胞的体外杀伤效果,用TCID_(50)法检测病毒在三株乳腺癌细胞株中的复制能力,用ELISA法检测两种病毒感染细胞后上清液中m IL-21的水平。建立三阴性乳腺癌4T1和Her-2扩增型乳腺癌TUBO细胞移植瘤模型,检测两种病毒的治疗作用。结果:VVΔTKΔN1L-RFP和VVΔTKΔN1L-m IL-21两种病毒在乳腺癌JC、TUBO和4T1细胞中均具有复制能力,低剂量的病毒就对乳腺癌细胞产生明显的杀伤效应;VVΔTKΔN1L-m IL-21感染的细胞上清中检测到高表达的m IL-21蛋白。在4T1乳腺癌细胞移植瘤模型中,病毒治疗无明显效果(P>0.05);在TUBO乳腺癌细胞移植瘤模型中,两种病毒均能显著抑制肿瘤生长(P<0.05或P<0.01),延长荷瘤小鼠生存期(P<0.01)。结论:VVΔTKΔN1L-RFP和VVΔTKΔN1L-m IL-21两种病毒在乳腺癌细胞中具有特异性增殖并杀伤肿瘤细胞的能力,在体内两种病毒对Her-2扩增型和三阴性乳腺癌具有不同的治疗效果。Objective：To evaluate the in vitro and in vivo efficacy of tumor-targeted oncolytic vaccinia virus （VV） vectors, VVΔTKΔN1L-RFP and VVΔTKΔN1L-mIL-21, on murine breast cancer cell lines （JC, TUBO and 4T1）.Methods： The cytotoxicity of the viruses （VVΔTKΔN1L-RFP and VVΔTKΔN1L-mIL-21） at different mass concentrations on JC, TUBO and 4T1 cells was compared by MTT assay. The replication ability of the two viruses in the three cell lines was tested by TCID50. ELISA assay was performed to detect mIL-21 expression in the supernatants of the culture medium of three cell lines after virus infection. Orthotopic models of triple negative breast cancer （4T1） and Her-2 amplified breast cancer （TUBO） in the BALB/c mice were established to investigate the antitumor efficacy of the two VVs. Results：The two viruses were all able to replicate in breast cancer JC, TUBO and 4T1 cell lines, and low dose of VV caused significant cytotoxicity against breast cancer cell lines. High level of mIL-21 protein was detected in the cell culture supernatants after VVΔTKΔN1L-mIL-21 infection. In the orthotopic 4T1 breast cancer model, the viruses did not show significant anti-tumor effect （P〉0.05）; however, in the orthotopic TUBO breast cancer model, tumor growth was significantly inhibited by both viruses （P〈0.05,P〈0.01）, and the survival time（P〈0.01） of tumor bearing mouse was prolonged in both VVΔTKΔN1L-RFP and VVΔTKΔN1L-mIL-21 treatment group. Conclusion： Both VVΔTKΔN1L-RFP and VVΔTKΔN1L-mIL-21viruses could specifically replicate and showed cell killing effect on breast cancer cells. The two viruses have different in vivo therapeutic effects on Her-2 gene amplified breast cancer and triple negative breast cancer.

关 键 词：痘苗病毒 乳腺癌 白细胞介素-21 

分 类 号：R730.51[医药卫生—肿瘤] R737.9[医药卫生—临床医学]