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Cytosine deaminase/5-fluorocytosine gene therapy and Apo2L/TRAIL cooperate to kill TRAIL-resistant tumor cells

Cancer Gene Therapy volume 14, pages 640–651 (2007)Cite this article

Abstract

The death ligand Apo2L/TRAIL (Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand) eradicates many tumor types while sparing most normal tissues. However, some tumors are resistant to TRAIL. We therefore determined if TRAIL cooperates with cytosine deaminase/5-fluorocytosine (CD/5-FC) gene therapy and investigated the mechanisms involved. Transfection of human LAN-5 neuroblastoma cells with CD rendered the cells (LAN-5-CD) sensitive to 5-FC-induced, caspase-dependent apoptosis. Mediated by caspase-3, CD/5-FC and TRAIL cooperated to induce apoptosis in these TRAIL-resistant cells and to cleave X-linked inhibitor of apoptosis protein (XIAP). In established LAN-5-CD tumors growing subcutaneously in mice, intratumorally applied TRAIL did not decrease tumor growth and systemically administered 5-FC only attenuated tumor growth. In contrast, 5-FC together with TRAIL dramatically decreased tumor growth and eradicated a tumor. Assuming sufficient gene transfer of CD in situ, CD/5-FC with TRAIL may be useful for the therapy of tumors resistant to TRAIL.

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Acknowledgements

We thank M Schwab for LAN-5 cells, R Reisfeld for NXS2 cells, H Bujard for the pUHD 10-1vector, P Krammer for FLIPL antibody, HR Rodewald for a breeding colony of RAG2−/−/cγ−/− mice and advice on their properties, and W Uckert for discussion. This work has been supported by grants to CB and KMD from the Deutsche Krebshilfe.

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  1. G Jarmy

    Present address: 4Present address: Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.,

  2. J Wei and J Wahl: These authors contributed equally to this work.

Authors and Affiliations

  1. University Children's Hospital, Ulm, Germany

    J Wei, J Wahl, H Knauss, S Zeller, G Jarmy, K-M Debatin & C Beltinger

  2. Department of Surgical Research, Technische Universität, Dresden, Germany

    G Fitze

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Wei, J., Wahl, J., Knauss, H. et al. Cytosine deaminase/5-fluorocytosine gene therapy and Apo2L/TRAIL cooperate to kill TRAIL-resistant tumor cells. Cancer Gene Ther 14, 640–651 (2007). https://doi.org/10.1038/sj.cgt.7701051

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