糖化重组生存素腺病毒疫苗抗肿瘤作用的实验研究  

Mannan-modified recombinant adenovirus encoding survivin as a vaccine to induce anti-tumor activity

作　　者：李秋[1] 文艳君[1] 吴扬[1] 罗彦[1] 卢铀[1] 

机构地区：[1]四川大学华西医院人类疾病生物治疗国家重点实验室.肿瘤中心,四川成都610041

出　　处：《中国癌症杂志》2007年第5期369-373,共5页China Oncology

基　　金：国家973计划(2004CB518706);国家自然科学基金(30470672)

摘　　要：背景与目的:生存素在调控细胞凋亡和有丝分裂过程中起着重要作用,在正常分化的组织中不表达或表达极低,而在胚胎组织和大部分肿瘤组织中广泛表达,而这一特点为恶性肿瘤的基因治疗提供了很好的靶标。本研究制备糖化重组生存素腺病毒疫苗,观察其抗肿瘤作用并探讨其作用机制。方法:将重组生存素腺病毒和甘露聚糖在氧化条件下偶联,同时建立小鼠结肠癌和Lewis肺癌模型,以糖化重组生存素腺病毒疫苗治疗荷瘤小鼠,观察肿瘤体积和小鼠生存时间。对小鼠肿瘤组织作TUNEL染色观察肿瘤细胞凋亡。为了检测疫苗的保护作用,预先以糖化重组生存素腺病毒疫苗免疫接种小鼠,或合用抗CD4、CD8和NK单克隆抗体阻断相应的淋巴细胞亚群,再接种肿瘤,观察小鼠肿瘤生长情况。结果:糖化重组生存素腺病毒疫苗治疗组小鼠肿瘤生长受到明显抑制,无明显不良反应发生,小鼠的生存时间明显延长,肿瘤细胞凋亡明显增加。同时,糖化重组生存素腺病毒疫苗能诱导小鼠产生抗肿瘤免疫,这一免疫反应依赖于CD4和CD8淋巴细胞,也部分依赖于NK细胞。结论:糖化重组生存素腺病毒疫苗能诱导机体产生特异性的主动免疫反应,诱导肿瘤细胞凋亡,具有明确的抗肿瘤作用,值得进一步研究。Background and purpose： Survivin plays an important role in apoptosis and mitosis. It is abundantly expressed in fetal tissues and a variety of cancer, while undetectable in most normal, terminally differentiated adult tissues. Thus it may serve as universal tumor antigen candidate for immunotherapy of cancer. In this study, recombinant adenovirus encoding survivin was conjugated with mannan as a vaccine. Then the anti-tumor efficacy and the underlying mechanism of the vaccine were studied. Methods： Recombinant adenovirus encoding survivin was conjugated with mannan by using oxidizing conditions as a vaccine. Meanwhile, CT-26 colon cancer and Lewis lung cancer were established in BALB/c and C57BL/6 mice, respectively. Tumor bearing mice were treated with the vaccine. At the same time, recombinant adenovirus, mannan-modified null adenovirus, and PBS were used as controls. Tumor volumes and survival times of treated mice were recorded. Apoptosis of tumor cells from treated mice were checked by using TVNEL staining. In addition to study the protective effect of the vaccine, mice were first inoculated with the vaccine, with or without the monoclonal antibody of CD4, CD8, NK, and then mice were challenged with tumor cells. Again, the growth of tumor was investigated. Results： The tumor growth of mice treated with mannan-modified recombinant adenovirus were heavily inhibited without marked adverse effects. The survival of vaccine treated mice was also prolonged compared with the controls. TUNEL staining showed augmented apoptosis of tumor cells of vaccine treated mice. Meanwhile, mannan-modified recombinant adenovirus could induce anti-tumor activity, which was dependent on CD4 and CD8 T cells, and partially dependent on NK cells. Conclusions： Mannan-modified recombinant adenovirus encoding survivin could induce special active anti-tumor immune response and apoptosis of tumor cells. The vaccine may be of importance for the future exploration.

关 键 词：生存素 疫苗 肿瘤 

分 类 号：R730.3[医药卫生—肿瘤]