Establishment of combined gene therapy with immunogene and suicide gene for gastrointestinal cancer

免疫基因与自杀基因联合治疗胃肠癌基因治疗的建立

基本信息

批准号：
10470263
负责人：
YAMAUE Hiroki
金额：
$ 0.7万
依托单位：
Wakayama Medical University, School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470263/
关键词：
gastrointestinal cancer gene therapy adenoviral vector immunogene suicide gene

项目摘要

Using a syngeneic murine model, we investigated the therapeutic efficacy of combined gene therapy using adenoviral vectors expressing murine interleukin-2(AdmIL-2)and Escherichia coli cytosine deaminase(AdCD). In a subcutaneous tumor model, tumor-bearing mice were treated with an intratumoral injection of adenoviral vectors and received an intraperitoneal administration of 5-fluorocytosine(5-FC). Only the mice treated with AdCD(2x10^8 pfu)and an intermediate dose of AdmIL-2(1x10^6 pfu)survived significantly longer than mice treated with AdCD alone(p<0.01). Moreover, 40% of these treated mice obtained complete remission from tumor-bearing status. The cytotoxicity of splenocytes obtained from the treated mice was related to the survival period. A cold target competition assay showed that the cell-mediated cytotoxic response was specific for parental tumor cells. In a hepatic metastasis model, mice treated with an intravenous administration of both AdCD(2x10^8 pfu)and an intermediate dose of AdmIL-2(1x10^6 pfu)demonstrated the most significant reduction of metastatic foci and the longest survival following a 5-FC administration. These results suggest that gene therapy combined with AdmIL-2 and AdCD may be a promising strategy for a clinical application and in addition that translation of combined gene therapy from murine models into the clinical setting will require careful attention to the variables of cytokine expression levels in the design of clinical trials and in the evaluation of treatment efficacy.

使用同基因鼠模型，我们使用表达鼠介毒素2（Ampil-2）和大肠杆菌胞嘧啶脱氨酶（ADCD）的腺病毒载体（ADCD）研究了联合基因治疗的治疗疗效。在皮下肿瘤模型中，用肿瘤内注射腺病毒载体治疗含有肿瘤的小鼠，并接受了5-氟细胞胞嘧啶（5-FC）的腹膜内给药。只有用ADCD（2x10^8 PFU）和中间剂量的Ampil-2（1x10^6 PFU）处理的小鼠的生存时间明显比单独使用ADCD治疗的小鼠（P <0.01）。此外，这些经过治疗的小鼠中有40％从肿瘤状态获得了完全缓解。从处理的小鼠获得的脾细胞的细胞毒性与生存期有关。冷目标竞争分析表明，细胞介导的细胞毒性反应是特定于亲本肿瘤细胞的。在肝转移模型中，用静脉内给药（2x10^8 PFU）和中间剂量的Ampil-2（1x10^6 PFU）治疗的小鼠表现出转移性灶和5-FC后最长的生存率的最显着降低。这些结果表明，与Ampil-2和ADCD结合使用的基因疗法可能是临床应用的有前途的策略，此外，在临床试验设计和评估治疗效率的评估中，将基因疗法从鼠模型转化为临床环境的组合疗法将需要仔细注意细胞因子表达水平的变量。