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Tumor-specific transcriptional targeting of suicide gene therapy

Gene Therapy volume 9, pages 168–175 (2002)Cite this article

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.

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Acknowledgements

The authors wish to thank Dr Manuel Caruso for the helpful discussions and Dr Olivier Martinet for the editing of this manuscript. This research was supported in part by NIH grants R29 CA-70337; R01 CA-75175; R01 CA84404 to SH Chen. The work performed at MSKCC was partially supported by funding from NIH RO1 CA69769, NIH RO1 CA76177, NIH RO24 CA98023 and DOE 86ER60407.

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Authors and Affiliations

  1. Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY, USA

    J Qiao, BV Sauter, Y Huang, ZS Guo, S-H Chen & SLC Woo

  2. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    M Doubrovin, J Balatoni, T Akhurst, RG Blasberg & JG Tjuvajev

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  1. J Qiao
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Qiao, J., Doubrovin, M., Sauter, B. et al. Tumor-specific transcriptional targeting of suicide gene therapy. Gene Ther 9, 168–175 (2002). https://doi.org/10.1038/sj.gt.3301618

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