SCF或(和)GM-CSF体内基因转染对“自杀基因”疗法抗肿瘤作用的增强效应及其相关机理的研究

Enhanced antitumor effect of suicide gene therapy by SCF, GM CSF gene transfer in vivo and its immunological mechanism

目的通过增强体内抗原提呈功能提高“自杀基因”疗法疗效，探讨其相关免疫学机理。方法采用腺病毒介导的ＳＣＦ、ＧＭＣＳＦ基因体内转染联合ＣＤ／５ＦＣ“自杀基因”疗法治疗小鼠的ＣＴ２６结肠腺癌，观察肿瘤的生长和荷瘤小鼠的存活期、不同方法所诱导的ＣＴＬ杀伤活性及肿瘤局部的细胞因子表达。结果一次性低剂量腺病毒介导的ｍＧＭＣＳＦ或（和）ｍＳＣＦ基因的体内转染，能增强“自杀基因”疗法的疗效。在肿瘤局部出现新的细胞因子表达，包括ｍＩＬ４、ｍＩＬ２、ｍＩＦＮγ和ｍＴＮＦα。脾细胞对ＣＴ２６细胞的杀伤作用增强。结论ｍＧＭＣＳＦ或（和）ｍＳＣＦ基因的联合转染对“自杀基因”系统的疗效具有明显的增强作用，其与机体特异抗肿瘤免疫功能以及肿瘤局部分泌的细胞因子有关。

Objective To explore an efficient approach to enhance antitumor effect of suicide gene therapy by improving in vivo antigen presenting function and their immunological mechanisms. Methods The CT26 colon adenocarcinoma was treated with CD/5FC system combined with the mGM CSF or/and mSCF gene transfection, and the antitumor effects were evaluated by the tumor growth, tumor free mouse rate, splenic CTL activity and cytokine expression of tumor milieu. Results The tumor burden was reduced significantly and higher survival rate was obtained after the combined treatment. It was found that some cytokines(including mIL 4, mIL 2, mIFN γ and mTNF α) were expressed in the tumor milieu after mGM CSF or/and mSCF gene transfection following CD/5FC treatment but not in the control groups. The cytotoxic activity against CT26 cells of spleen cells of the treated mice was significanthy incressed. Conclusion The combination of mSCF or/and mGM CSF gene transfection enhances the antitumor effect of the suicide gene therapy. Such an enhancement is associated with the induction of specific antitumor immune response and secretion of cytokines in tumor milieu.