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The use of tissue inhibitors of matrix metalloproteinases to increase the efficacy of a tumor necrosis factor/interferonγ antitumor therapy

Cancer Gene Therapy volume 14, pages 372–379 (2007)Cite this article

Abstract

Owing to its impressive ability to kill tumor cells, especially in combination with interferon-γ (IFNγ), tumor necrosis factor (TNF) is widely appreciated as being a potential systemic therapeutic for the treatment of cancer. On the other hand, owing to its proinflammatory activities, administration of TNF leads to many systemic side effects and eventually to a potentially lethal systemic inflammatory response syndrome (SIRS). However, systemic treatment of tumor-bearing mice with TNF/IFNγ in combination with BB-94 (a broad-spectrum metalloproteinase inhibitor) confers protection against TNF/IFNγ-induced mortality, whereas preserving the antitumor activity. In this study, we investigated the effect of the adenoviral delivery of human tissue inhibitors of matrix metalloproteinase (hTIMP)-1 and hTIMP-2 genes on the outcome of TNF/IFNγ antitumor therapy. The dose of adenovirus was limited to 108 PFU per mouse owing to the additive toxicity of combining it with TNF/IFNγ therapy. Nevertheless, this dose was sufficient to achieve highly efficient adenoviral transfer and expression of hTIMP-1 and hTIMP-2 in the liver, but not the tumor. Treatment with this low dose of AdhTIMP-1 or AdhTIMP-2 was not enough to protect the host against the toxic effects of TNF/IFNγ. However, it was sufficient to show a synergistic effect of hTIMPs with TNF/IFNγ such that tumors regressed significantly faster. Interestingly, only AdTIMP-2 was able to prevent relapses after treatment.

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Acknowledgements

We thank Leen Puimege and Joke Vanden Berghe for excellent technical assistance. Amin Bredan is acknowledged for editorial help. Research was supported by grants from the Fund for Scientific Research (FWO)-Flanders, Interuniversity Attraction Poles (IUAP) Program of the Belgian Science Policy, Vereniging voor Kankerbestrijding, Belgium.

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  1. B Wielockx

    Present address: 3Current address: Technical University of Dresden, Dresden, Germany.,

Authors and Affiliations

  1. Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Zwijnaarde, Ghent, Belgium

    M Van Roy, B Wielockx & C Libert

  2. Department of Medicine and Therapeutics, University of Glasgow, Glasgow, UK

    A Baker

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Correspondence to C Libert.

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Van Roy, M., Wielockx, B., Baker, A. et al. The use of tissue inhibitors of matrix metalloproteinases to increase the efficacy of a tumor necrosis factor/interferonγ antitumor therapy. Cancer Gene Ther 14, 372–379 (2007). https://doi.org/10.1038/sj.cgt.7701020

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