1. ¹Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Zwijnaarde, Ghent, Belgium
2. ²Department of Medicine and Therapeutics, University of Glasgow, Glasgow, UK

Correspondence: Dr C Libert, VIB – Ghent University, FSVM Building, Technologiepark 927, B-9052 Zwijnaarde (Ghent), Belgium. E-mail: Claude.Libert@dmbr.ugent.be

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

Received 21 April 2006; Revised 31 July 2006; Accepted 8 October 2006; Published online 12 January 2007.

Abstract

Owing to its impressive ability to kill tumor cells, especially in combination with interferon- (IFN), 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/IFN in combination with BB-94 (a broad-spectrum metalloproteinase inhibitor) confers protection against TNF/IFN-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/IFN antitumor therapy. The dose of adenovirus was limited to 10⁸ PFU per mouse owing to the additive toxicity of combining it with TNF/IFN 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/IFN. However, it was sufficient to show a synergistic effect of hTIMPs with TNF/IFN such that tumors regressed significantly faster. Interestingly, only AdTIMP-2 was able to prevent relapses after treatment.