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Fiber-chimeric adenoviruses expressing fibers from serotype 16 and 50 improve gene transfer to human pancreatic adenocarcinoma

Cancer Gene Therapy volume 16, pages 585–597 (2009)Cite this article

Abstract

Survival of patients with pancreatic cancer is poor. Adenoviral (Ad) gene therapy employing the commonly used serotype 5 reveals limited transduction efficiency due to the low amount of coxsackie-adenovirus receptor on pancreatic cancer cells. To identify fiber-chimeric adenoviruses with improved gene transfer, a library of Ad vectors based on Ad5 and carrying fiber molecules consisting of 16 other serotypes were transduced to human pancreatic carcinoma cell lines. Adenoviruses containing fibers from serotype 16 and 50 showed increased gene transfer and were further analyzed. In a gene-directed prodrug activation system using cytosine deaminase, these adenoviruses proved to be effective in eradicating primary pancreatic tumor cells. Fiber-chimeric Ad5 containing fiber 16 and wild-type Ad5 were also transduced ex vivo to slices of normal human pancreatic tissue and pancreatic carcinoma tissue obtained during surgery. It was shown that fiber-chimeric Ad5 with fiber 16 revealed an improved gene delivery to primary pancreatic tumor tissue compared to Ad5. In conclusion, fiber-chimeric adenoviruses carrying fiber 16 and 50 reveal a significantly enhanced gene transfer and an increased specificity to human pancreatic adenocarcinoma compared to Ad5, whereas transduction to normal pancreatic tissue was decreased. These findings expand the therapeutic window of Ad gene therapy for pancreatic cancer.

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Acknowledgements

We thank Jerome Custers (Crucell BV, Leiden) for providing the various virus batches. This work was supported by the Dutch Cancer Society (grant UVA2002-2604 to M van Geer).

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  1. J G Wesseling

    Present address: 4Current address: Corning BV, Schiphol-Rijk, The Netherlands.,

Authors and Affiliations

  1. Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    K F D Kuhlmann & D J Gouma

  2. Liver Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    M A van Geer, C T Bakker, J E M Dekker, R P J Oude Elferink, P J Bosma & J G Wesseling

  3. TNO Biosciences, Leiden, The Netherlands

    M J E Havenga

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  1. K F D Kuhlmann
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Kuhlmann, K., van Geer, M., Bakker, C. et al. Fiber-chimeric adenoviruses expressing fibers from serotype 16 and 50 improve gene transfer to human pancreatic adenocarcinoma. Cancer Gene Ther 16, 585–597 (2009). https://doi.org/10.1038/cgt.2009.4

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