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Adenovirus-based virotherapy enabled by cellular YB-1 expression in vitro and in vivo

Cancer Gene Therapy volume 16, pages 753–763 (2009)Cite this article

Abstract

We have earlier described the oncolytic adenovirus vector dl520 that was rendered cancer-specific by deletion of the transactivation domain CR3 of the adenoviral E1A13S protein; this deletion causes antitumor activity in drug-resistant cells displaying nuclear YB-1 expression. We hypothesized that the anticancer activity of dl520 could be further improved by introducing the RGD motif in the fiber knob and by deletion of the adenoviral E1B19K protein (Ad-Delo3-RGD). In this study, the in vitro and in vivo antitumor activity of Ad-Delo3-RGD was investigated focussing on two pancreatic cancer cell lines MiaPaCa-2 and BxPC3 alone and in combination with cytotoxic drugs. Furthermore, luciferin-based bioluminescence imaging was established to study the therapeutic response in vivo. In addition, to confirm the specificity of Ad-Delo3-RGD for YB-1 a tetracycline-inducible anti-YB-1 shRNA-expressing cell variant EPG85-257RDB/tetR/YB-1 was used. This TetON regulatable expression system allows us to measure adenoviral replication by real-time PCR in the absence of YB-1 expression. The results confirmed the YB-1 dependency of Ad-Delo3-RGD and showed that Ad-Delo3-RGD has potent activity against human pancreatic cancer cells in vitro and in vivo, which was augmented by the addition of paclitaxel. However, although high replication capacity was measured in vitro and in vivo, complete tumor regression was not achieved, indicating the need for further improvements to treat pancreatic cancer effectively.

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Acknowledgements

We thank Hildegard Kalvelage and Sava Michailidou for technical assistance. This work was supported by grants from BMBF ‘Innovative Therapies of molecular Basis’ to PSH.

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Authors and Affiliations

  1. Institute of Experimental Oncology and Therapeutics, Klinikum Rechts der Isar, Technische Universitaet Muenchen, Muenchen, Germany

    E Rognoni, M Widmaier, C Haczek, K Mantwill, R Holzmüller, B Gansbacher & P S Holm

  2. Department of Oral and Maxillofacial Surgery, Klinikum Rechts der Isar, Technische Universitaet Muenchen, Muenchen, Germany

    A Kolk

  3. Institute of Medical Statistics and Epidemiology, Klinikum Rechts der Isar, Technische Universitaet Muenchen,, Muenchen, Germany

    T Schuster

  4. Department of Medicine II, Klinikum Rechts der Isar, Technische Universitaet Muenchen, Muenchen, Germany

    R M Schmid & D Saur

  5. Institute of Pathology, Charité Campus Mitte, Berlin, Germany

    A Kaszubiak & H Lage

  6. XVir Therapeutics GmbH, Munich, Germany

    P S Holm

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  1. E Rognoni
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Correspondence to P S Holm.

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Rognoni, E., Widmaier, M., Haczek, C. et al. Adenovirus-based virotherapy enabled by cellular YB-1 expression in vitro and in vivo. Cancer Gene Ther 16, 753–763 (2009). https://doi.org/10.1038/cgt.2009.20

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  • DOI: https://doi.org/10.1038/cgt.2009.20

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