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TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells

Cancer Gene Therapy volume 9, pages 372–381 (2002)Cite this article

Abstract

The clinical benefit of suicide gene therapy of tumors has been marginal, mostly due to the low gene transfer efficiency in vivo. The death-inducing ligand, TRAIL, effectively kills many tumor cell types, while sparing most normal tissues. We hypothesized that TRAIL may enhance HSV thymidine kinase/ganciclovir (TK/GCV) gene therapy of tumor cells by augmenting both target and bystander cell kill. Human SH-EP neuroblastoma cells expressing TK as well as bystander cells were effectively killed by apoptosis, and their clonogenicity was ablated following GCV. Human TRAIL enhanced TK/GCV–induced cell death and decreased clonogenicity of TK-expressing cells and also of bystander cells. Cooperation between TRAIL and TK/GCV depended both on caspase activation and on mitochondrial apoptogenic function because both the broad-spectrum caspase inhibitor zVAD.fmk and overexpression of Bcl-2 decreased enhancement of cell kill by TRAIL. Facilitation of TRAIL signalling by up-regulation of TRAIL receptors did not contribute to enhancement because cell surface expression of the agonistic TRAIL receptors 1 and 2 was not increased by TK/GCV. In conclusion, the concerted activation of caspases and the mitochondrial amplification of caspase activation by TK/GCV may explain the cooperative effect of TK/GCV and TRAIL on the kill of neuroblastoma cells. Because combined treatment also augmented the bystander cell kill, the addition of TRAIL may increase the efficacy of TK/GCV gene therapy of neuroblastoma.

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Acknowledgements

We thank W Uckert for advice. The skillful technical assistance of H Knauss is appreciated. This work has been partially supported by grants to CB and KMD from the Deutsche Krebshilfe. Presented, in part, at the 92nd annual meeting of the American Association for Cancer Research, New Orleans, 2001.

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Authors and Affiliations

  1. University Children's Hospital, Ulm, 89075, Germany

    Christian Beltinger, Simone Fulda & Klaus-Michael Debatin

  2. German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany

    Henning Walczak

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  1. Christian Beltinger
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  4. Klaus-Michael Debatin
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Correspondence to Christian Beltinger.

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Beltinger, C., Fulda, S., Walczak, H. et al. TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells. Cancer Gene Ther 9, 372–381 (2002). https://doi.org/10.1038/sj.cgt.7700448

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