Melanoma Research Today is a free monthly online journal that collates and summarizes the latest research about Melanoma, including details on identification, causes, prevention, treatment.

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

Van Roy M, Wielockx B, Baker A, Libert C

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

Owing to its impressive ability to kill tumor cells, especially in combination with interferon-gamma (IFNgamma), 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/IFNgamma in combination with BB-94 (a broad-spectrum metalloproteinase inhibitor) confers protection against TNF/IFNgamma-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/IFNgamma antitumor therapy. The dose of adenovirus was limited to 10(8) PFU per mouse owing to the additive toxicity of combining it with TNF/IFNgamma 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/IFNgamma. However, it was sufficient to show a synergistic effect of hTIMPs with TNF/IFNgamma such that tumors regressed significantly faster. Interestingly, only AdTIMP-2 was able to prevent relapses after treatment.

Published 14 March 2007 in Cancer Gene Ther, 14(4): 372-9.
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