Tumor-specific transcriptional targeting of suicide gene therapy

J. Qiao, M. Doubrovin, B. V. Sauter, Y. Huang, Z. S. Guo, J. Balatoni, T. Akhurst, R. G. Blasberg, J. G. Tjuvajev, S. H. Chen, S. L.C. Woo

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)168-175
Number of pages8
JournalGene Therapy
Volume9
Issue number3
DOIs
Publication statusPublished - Jan 1 2002

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Keywords

  • Adenovirus
  • Imaging
  • Liver metastases
  • Suicide gene therapy
  • Transcriptional targeting

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Qiao, J., Doubrovin, M., Sauter, B. V., Huang, Y., Guo, Z. S., Balatoni, J., ... Woo, S. L. C. (2002). Tumor-specific transcriptional targeting of suicide gene therapy. Gene Therapy, 9(3), 168-175. https://doi.org/10.1038/sj.gt.3301618