自杀基因
胸苷激酶
遗传增强
癌胚抗原
生物
交易激励
单纯疱疹病毒
基因传递
分子生物学
癌症研究
体内
基因表达
病毒载体
腺病毒科
病毒学
基因
病毒
重组DNA
癌症
遗传学
作者
Jian Qiao,Mikhail Doubrovin,Bv V. Sauter,Yong Huang,Guo Zs,Julius Balatoni,Timothy Akhurst,Ron G. Blasberg,Jg G. Tjuvajev,S.-H. Chen,S. L. C. Woo
出处
期刊:Gene Therapy
[Springer Nature]
日期:2002-02-01
卷期号:9 (3): 168-175
被引量:117
标识
DOI:10.1038/sj.gt.3301618
摘要
Transcriptional targeting of gene expression has been plagued by the weakness of tissue-specific promoters. Thus, to increase promoter strength while maintaining tissue specificity, we constructed a recombinant adenovirus containing a binary promoter system with a tumor-specific promoter (CEA; carcinoembryonic antigen) driving a transcription transactivator, which then activates a minimal promoter to express a suicide gene (HSV-tk; herpes simplex virus thymidine kinase). This ADV/binary-tk induced equal or greater cell killing in a CEA-specific manner in vitro compared with the CEA-independent killing of a vector with a constitutive viral promoter driving HSV-tk (ADV/RSV-tk). To monitor adenovirus-mediated HSV-tk gene expression in vivo, we employed noninvasive nuclear imaging using a radioiodinated nucleoside analog ([((1)31)I]-FIAU) serving as a substrate for HSV-tk. [((1)31)I]-FIAU-derived radioactivity accumulated after intratumoral injection of ADV/binary-tk only in the area of CEA-positive tumors with significantly less spread to the adjacent liver tissue than after administration of the universally expressed ADV/RSV-tk. Both viruses exhibited similar antitumor efficacy upon injection of liver metastases. Importantly, in vivo dose escalation studies demonstrated significantly reduced toxicity after intravenous administration of ADV/binary-tk versus ADV/RSV-tk. In summary, the increased therapeutic index of this novel, amplified CEA-driven suicide gene therapy vector is a proof of principle for the powerful enhancement of a weak tissue-specific promoter for effective tumor restricted gene expression.
科研通智能强力驱动
Strongly Powered by AbleSci AI