Tumor-specific transcriptional targeting of suicide gene therapy Journal Article
| 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. |
| Article Title: | Tumor-specific transcriptional targeting of suicide gene therapy |
| 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 ([131I]-FIAU) serving as a substrate for HSV-tk. [131I]-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. |
| Keywords: | imaging; adenovirus; liver metastases; suicide gene therapy; transcriptional targeting |
| Journal Title: | Gene Therapy |
| Volume: | 9 |
| Issue: | 3 |
| ISSN: | 0969-7128 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2002-02-01 |
| Start Page: | 168 |
| End Page: | 175 |
| Language: | English |
| DOI: | 10.1038/sj.gt.3301618 |
| PROVIDER: | scopus |
| PUBMED: | 11859419 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 July 2018 -- Source: Scopus |
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