携带mIL-12基因的增生型腺病毒对小鼠移植胃癌的治疗作用  

Therapeutic effect of replication-competent adenovirus-mediated transfer of interleukin-12 gene on the mouse transplanted gastric cancer in vivo

作　　者：薛绪潮 方国恩[1] 王星华[2] 刘芳[3] 毕建威[1] 曹贵松[1] 钱其军[2] 

机构地区：[1]中国人民解放军第二军医大学附属长海医院普外科,上海市200433 [2]中国人民解放军第二军医大学附属东方肝胆医院病毒-基因治疗实验室,上海市200438 [3]济南军区联勤部药材仓库门诊部,山东省济南市250022

出　　处：《世界华人消化杂志》2004年第7期1522-1526,共5页World Chinese Journal of Digestology

基　　金：国家自然科学基金国际合作重大项目资助;No.30120160823国家"863"高技术研究发展计划基金资助;No.2001AA217031~~

摘　　要：目的:研究携带mIL-12基因的增生型腺病毒对小鼠移植胃癌的治疗效果及其作用机制,探讨胃癌治疗的新思路及途径. 方法:以E1B55KDa缺失的增生型腺病毒ONYX-015、带有小鼠IL-12(mIL-12)基因的增生型腺病毒CNHK200- mIL-12以及非增生型腺病毒Ad-mIL-12治疗SGC-7901 BALB/C裸鼠及MFC 615小鼠胃癌移植模型,从肿瘤大小及动物生存期等方面评价治疗效果;并检测各治疗组的CD4+和CD8+淋巴细胞水平及NK和CTL细胞的杀伤活性, 探讨其免疫学作用机制. 结果:实验证实增生型腺病毒(ONYX-015,CNHK200- mIL-12)可以有效地杀伤裸鼠体内的SGC-7901胃癌细胞,但是不足以使其完全消退,仅起到延缓生长的作用. 荷瘤615小鼠在注射Ad-mIL-12后部分(3/10)肿瘤消退, 余者(7/10)生长明显减慢,肿瘤无破溃,生存期明显延长; CNHK200-mIL-12治疗组部分肿瘤(4/10)停止生长,1 wk 后开始缩小,10—14 d完全消退,其余小鼠肿瘤(6/10)生长明显减慢,肿瘤无破溃,生存期明显延长.免疫学检测发现各腺病毒治疗组的CD4+和CD8+细胞水平以及NK、CTL细胞的杀伤活性均高于对照组,尤以携带IL-12基因者明显(P<0.001). 结论:以增生型腺病毒为载体携带IL-12基因可大量杀伤肿瘤细胞并与增生型腺病毒协同发挥抗肿瘤活性.AIM: To study the treatment of the replication-competent adenovirus-mediated transfer of interleukin-12 gene in the mouse transplanted with gastric cancer in vivo, and to explore the new therapeutic approach of gastric cancer. METHODS: The efficacy of CNHK200-mIL-12, ONYX-015, Ad-mIL-12 was tested in nude mice and 615 mice with subcutaneous human SGC-7901 and MFC 615 mice carcinomas. The immunological mechanism in xenografts gastric tumor of mice was further analyzed. RESULTS: The replication-competent adenovirus-mediated transfer of interleukin-12 gene slowed down the tumor progress. This might be caused by the proliferation of the replication-competent adenovirus. Ad-mIL-12 had little effect on the transplanted tumor in nude mice. While 615 mice bearing MFC gastric cancer presented the best anti-cancer effects. Administration of Ad-mIL-12 was showed to delay the growth of transplanted MFC tumor markedly (P<0.001), and mediate complete regression of 3/10 established tumor. In the setting of CNHK200-mIL-12, the regression ratio was 4/10. Significantly prolonged survival was observed in both Ad-mIL-12 and CNHK200-mIL-12 experimental groups of MFC gastric tumor bearing mice. The analysis of the immunological mechanism in xenografts gastric tumor of mice 615 showed that the expression of IL-12 by CNHK200-mIL-12 and Ad-mIL-12 could greatly stimulate the immune response against the transplanted gastric tumor. It was found that these therapies could enhance the natural killer cell activity and specific cytotoxic T cell activity. The CD4+ and CD8+ T cell infiltrated into the tumor more significantly than that in the group of ONYX-015 and control (P<0.001). CONCLUSION: The replication-competent adenovirus can specifically replicate in tumor cells and kill the tumor cells. IL-12 is an effective cytokine stimulating anticancer immune responses. When combined, it is complementary resulting in a significantly improved treatment outcome.

关 键 词：MIL-12基因 增生型腺病毒 小鼠 移植 胃癌 治疗 

分 类 号：R735.2[医药卫生—肿瘤]