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Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

Cancer Gene Therapy volume 13, pages 686–695 (2006)Cite this article

Abstract

Clinical efficacy of adenovirus-mediated cancer gene therapy has been limited thus far. To improve its oncolytic effect, a replication-competent adenoviral vector was previously constructed to express high levels of p53 at a late time point in the viral life cycle. p53 expression from this vector improved tumor cell killing and viral spread in vitro. However, p53 function is antagonized by cellular mdm2 and adenoviral E1b-55kD, both of which are known to bind to and inactivate p53. Therefore, a new vector (Adp53W23S) that expresses a modified p53 transgene, which does not bind to E1b-55kD and mdm2, was constructed. The modified p53 protein was demonstrated to have a substantially prolonged half-life, and its localization was predominantly nuclear. Viral replication was unaffected by expression of the modified p53 and cancer cell killing was improved in vitro. However, in a xenograft model, efficacy was not significantly different from control virus. In conclusion, expression of a degradation-resistant p53 transgene late in the life cycle of a replication-competent adenovirus improves p53 stability and cancer cell killing in vitro. However, other factors, such as the adenoviral E1b-19kD and E1a proteins, which oppose p53 function, and limitations to viral spread need to be addressed to further improve in vivo efficacy.

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Acknowledgements

We thank Robert Norman for statistical advice and Hal Rosenblatt for careful reading of the manuscript. This work was supported by NIH-NCI R01CA89086, NIH-NCI R01CA102053, NIH-NCRR grant MO1RR-00096, Stony Wold-Herbert Fund, Goldring Clinical Scholars Fund, DVA Advanced Research Career Development Award.

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Authors and Affiliations

  1. Department of Medicine, Division of Pulmonary & Critical Care Medicine, New York University School of Medicine, New York, USA

    H Sauthoff, T Pipiya, S Chen, S Heitner, J Cheng, Y Q Huang, W N Rom & J G Hay

  2. Department of Environmental Medicine, New York University School of Medicine, New York, USA

    H Sauthoff

  3. Department of Veterans Affairs, New York Harbor Healthcare System, New York University School of Medicine, New York, USA

    H Sauthoff & J G Hay

  4. Department of Pathology, New York University School of Medicine, New York, USA

    J G Hay

  5. NYU Cancer Institute, New York University School of Medicine, New York, USA

    J G Hay

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  1. H Sauthoff
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Correspondence to J G Hay.

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Sauthoff, H., Pipiya, T., Chen, S. et al. Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53. Cancer Gene Ther 13, 686–695 (2006). https://doi.org/10.1038/sj.cgt.7700936

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