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Development of new tumor specific gene therapy in gastrointestinal carcinoma

胃肠癌新肿瘤特异性基因治疗的进展

基本信息

批准号：
11671180
负责人：
IWAHASHI Makoto
金额：
$ 2.24万
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 (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671180/
关键词：
gene therapy Cre loxP system CEA promoter adenovirus vector orthotopic model CD 5-FC suicide gene therapy loxP system adenovirus Vector 大腸癌同所移植モデル胃癌同所移植モデル tissue specific expression

项目摘要

Tumor-specific gene delivery is crucial to achieving successful effects in suicide gene therapy. Carcinoembryonic antigen (CEA) promoter has been widely used for this purpose, but the expression level of tumor-specific promoters such as CEA promoter is generally low. In this study, we employed the Cre/loxP system, and showed that LacZ expression by CEA promoter was remarkably enhanced while maintaining its specificity using Cre/loxP regulation system. And, the Cre/loxP system was first applied to augmentation of selective expression of cytosine deaminase (CD) gene as a suicide gene therapy in CEA-producing cells. The double infection with AxCEANCre expressing Cre recombinase under control of CEA promoter and AxCALNLCD expressing CD gene under control of CAG promoter by the Cre-switching ststem rendered CEA-producing tumor cells 13-fold more sensitive to 5-FC (5-fluorocytosine) compared with the single infection with AxCEACD expressing CD gene driven by CEA promoter. The therapeutic eff … More icacy of the enhanced CD/5-F Csuicide gene therapy was evaluated in orthotopic models of human gastric carcinoma. Adenovirus vectors (1 × 10^9 pfu) were administered i. p. into mice three times, and then 5-FC was administered i. p. for the next 10 days. Tumor volume and weight in mice treated with AxCEANCre and AxCALNLCD were significantly reduced as compared with those in mice treated not only with Mock but also with AxCEACD (p < 0.0001). The survival periods of the mice treated with AxCEANCre and AxCALNLCD /5-FC were longer than those in mice treated with Mock or AxCEACD/5-FC (p < 0.01). Moreover, in orthotopic models of human colon carcinoma, the double administration of AxCEANCre and AxCALNLCD completely inhibited liver metastases, and significantly reduced primary tumor volume compared to the administration of Mock or AxCEACD. These results suggested that the application of Cre/loxP system could provide a new approach for enhanced selective suicide gene therapy of CD/5-FC for the treatment of human gastrointestinal carcinoma. Less

肿瘤特异性基因递送是自杀基因治疗取得成功的关键。癌胚抗原（CEA）启动子已被广泛用于此目的，但肿瘤特异性启动子如CEA启动子的表达水平通常较低。在这项研究中，我们采用了Cre/loxP系统，并表明CEA启动子的LacZ表达显着增强，同时保持其特异性使用Cre/loxP调节系统。而且，Cre/loxP系统首次被应用于增强胞嘧啶脱氨酶（CD）基因的选择性表达，作为CEA生产细胞中的自杀基因治疗。Cre转换系统将表达Cre重组酶的AxCEANCre和表达CD基因的AxCALNLCD双重感染CEA产生细胞，使CEA产生细胞对5-氟胞嘧啶（5-fluorocytosine，5-FC）的敏感性提高13倍。治疗效果 ...更多信息在原位人胃癌模型中评价CD/5-FC自杀基因治疗的敏感性。腺病毒载体（1 × 10^9 pfu）i. p.给药3次，然后i. P未来10天用AxCEANCre和AxCALNLCD处理的小鼠中的肿瘤体积和重量与不仅用Mock而且用AxCEACD处理的小鼠中的肿瘤体积和重量相比显著降低（p < 0.0001）。AxCEANCre和AxCALNLCD /5-FC治疗组小鼠的生存期明显长于Mock和AxCEACD/5-FC治疗组（p < 0.01）。此外，在人结肠癌的原位模型中，AxCEANCre和AxCALNLCD的双重施用与Mock或AxCEACD的施用相比完全抑制了肝转移，并且显著减小了原发性肿瘤体积。提示Cre/loxP系统的应用为CD/5-FC增强选择性自杀基因治疗胃肠道肿瘤提供了新的途径。少