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- Title
Tumor-specific transciptional targeting of suicide gene therapy.
- Authors
Qiao, J.; Doubrovin, M.; Sauter, B.V.; Huang, Y.; Guo, Z.S.; Balatoni, J.; Akhurst, T.; Blasberg, R.G.; Tjuvajev, J.G.; Chen, S.-H.; Woo, S.L.C.
- Abstract
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 ([¹311]-FIAU) serving as a substrate for HSV-tk. [¹311]-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 CEAdriven 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.
- Subjects
TRANSCRIPTION factors; TUMORS; TISSUE-specific antigens; GENE therapy
- Publication
Gene Therapy, 2002, Vol 9, Issue 3, p168
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/sj.gt.3301618