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Synergy between expression of fusogenic membrane proteins, chemotherapy and facultative virotherapy in colorectal cancer

Gene Therapy volume 13, pages 1534–1544 (2006)Cite this article

A Corrigendum to this article was published on 18 December 2007

Abstract

Using Chou–Talalay median effect analysis, we demonstrated in permanent and short-term cultures of colorectal cancer cells that the expression of measles virus fusogenic membrane glycoproteins (FMGs) in combination with chemotherapy often causes over most of the cytotoxic dose range synergistic cell killing. In this combined treatment, we observed strongly enhanced annexin V binding and caspase-3/7 activity when compared to single-agent treatment. Furthermore, we showed increased expression of heat-shock protein (Hsp)70 and Hsp90α, but not of Hsp60. In a subcutaneous HT-29 colorectal xenograft model, we demonstrated that the administration of a replication-defective adenoviral or herpes simplex virus (HSV) amplicon vector (Ad.H/F or HSV.H/F) encoding tumor-restricted FMG in combination with FOLFOX significantly enhanced treatment outcome when compared to treatment with each compound individually. To increase the fraction of tumor cells expressing the FMG, we trans-complemented the Ad.H/F and HSV.H/F vector with the respective oncolytic replication-restricted adenovirus Ad.COXΔMK or HSV-1 G47Δ vector. At the end of the observation period (day 100), eight out of 10 animals that received G47Δ, HSV.H/F and FOLFOX were alive and tumor free. Administration of the analogous adenovirus-based regimen resulted in four out of 10 long-term survivors. We demonstrated that the expression of FMG in combination with chemotherapy can significantly enhance treatment outcome, which is further enhanced by combination with trans-complementing oncolytic vectors.

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Acknowledgements

We thank Professor Klaus Überla for creating an inspiring environment and providing constant support. Furthermore, we are grateful to Professor Andrea Frilling (Klinik für Allgemeine und Transplantationschirurgie). Furthermore, we thank Dr Cathrin Walter ((Innere Klinik – Tumorforschung) Universitätsklinikum Essen, Germany) for critical review of this manuscript and Professor Matthias Dobbelstein and Dr German P Horn, Institute of Virology, Philipps-Universität Marburg, for helpful discussions and advice. This work was supported by grants from Deutsche Forschungsgemeinschaft and Wilhelm Sander-Stiftung to OW.

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  1. Department of Molecular and Medical Virology, Institute of Microbiology and Hygiene, Ruhr-University Bochum, Bochum, Germany

    D Hoffmann, W Bayer & O Wildner

  2. Department of Trauma Surgery, University of Duisburg-Essen, University Hospital Essen, Essen, Germany

    J-M Bangen

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Hoffmann, D., Bangen, JM., Bayer, W. et al. Synergy between expression of fusogenic membrane proteins, chemotherapy and facultative virotherapy in colorectal cancer. Gene Ther 13, 1534–1544 (2006). https://doi.org/10.1038/sj.gt.3302806

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