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The carcinoma-specific epithelial glycoprotein-2 promoter controls efficient and selective gene expression in an adenoviral context

Cancer Gene Therapy volume 13, pages 150–158 (2006)Cite this article

Abstract

Adenoviral vectors are widely used in cancer gene therapy. After systemic administration however, the majority of the virus homes to the liver and the expressed transgene may cause hepatotoxicity. To restrict transgene expression to tumor cells, tumor- or tissue-specific promoters are utilized. The tumor antigen epithelial glycoprotein-2 (EGP-2), also known as Ep-CAM, is expressed in many cancers from different epithelial origins. In this study, the EGP-2 promoter was shown to restrict the expression of luciferase and thymidine kinase in an adenoviral context in different cell lines. In vivo, the EGP-2 promoter mediated efficient expression of luciferase in tumors but showed a 3-log lower activity in liver tissue when compared with the cytomegalovirus (CMV) promoter. Similarly, the EGP-2 promoter mediated specific cell killing after ganciclovir treatment in EGP-2-positive cells. Moreover, in vivo, this treatment regiment did not cause any rise in the liver enzymes aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT), demonstrating absence of liver toxicity. In contrast, CMV-mediated expression of thymidine kinase in combination with ganciclovir treatment resulted in high ASAT and ALAT values. This study demonstrates the value of the EGP-2 promoter to restrict transgene expression to a broad range of tumor types, thereby preventing liver toxicity.

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Acknowledgements

This work was supported by NIH Grant R03 AR46864, NIH Grant R01 CA94084, NIH Grant R01 DK63615 (to MY) and by NIH Grant R01 CA86881 (to DTC). We are grateful to DAM Heideman from the VUMC, Amsterdam, The Netherlands for advice on RT-PCR and to B Dontje and A van Loenen-Weemaes from the RUG, Groningen, The Netherlands for their help with the animal experiments.

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Authors and Affiliations

  1. Department of Therapeutic Gene Modulation, University Center for Pharmacy, University Groningen, Groningen, The Netherlands

    W M Gommans, S J van Eert, H J Haisma & M G Rots

  2. Department of Pathology and Laboratory Medicine, Medical Biology Section, University Hospital Groningen, Groningen, The Netherlands

    P M J McLaughlin & M C Harmsen

  3. Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA

    M Yamamoto & D T Curiel

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  1. W M Gommans
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Correspondence to M G Rots.

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Gommans, W., van Eert, S., McLaughlin, P. et al. The carcinoma-specific epithelial glycoprotein-2 promoter controls efficient and selective gene expression in an adenoviral context. Cancer Gene Ther 13, 150–158 (2006). https://doi.org/10.1038/sj.cgt.7700882

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