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.

使用同基因小鼠模型，我们研究了使用表达小鼠白细胞介素2（AdmIL-2）和大肠杆菌胞嘧啶脱氨酶（AdCD）的腺病毒载体联合基因治疗的治疗效果。在皮下肿瘤模型中，对荷瘤小鼠进行瘤内注射腺病毒载体治疗，并腹膜内注射5-氟胞嘧啶（5-FC）。只有用AdCD(2x10^8 pfu)和中等剂量的AdmIL-2(1x10^6 pfu)治疗的小鼠比单独用AdCD治疗的小鼠存活时间显着更长(p<0.01)。此外，40% 的接受治疗的小鼠的肿瘤状态得到完全缓解。从处理小鼠获得的脾细胞的细胞毒性与存活期相关。冷靶竞争测定表明，细胞介导的细胞毒性反应对亲代肿瘤细胞具有特异性。在肝转移模型中，静脉注射 AdCD (2x10^8 pfu) 和中等剂量 AdmIL-2 (1x10^6 pfu) 治疗的小鼠表现出最显着的转移灶减少和最长的生存期 (5 年后)。 -FC管理。这些结果表明，与 AdmIL-2 和 AdCD 相结合的基因治疗可能是一种有前途的临床应用策略，此外，将联合基因治疗从小鼠模型转化为临床环境需要仔细注意细胞因子表达水平的变量。临床试验的设计和治疗效果的评估。