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

Abstract

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.

• Authors: M Van Roy, B Wielockx, A Baker, C Libert
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 14 Issue 4 Pg. 372-9 (Apr 2007) ISSN: 0929-1903 [Print] England
• PMID: 17218947 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tissue Inhibitor of Metalloproteinase-1
• Tumor Necrosis Factors
• Tissue Inhibitor of Metalloproteinase-2
• Interferon-gamma

Topics

• Adenoviridae (genetics)
• Animals
• Combined Modality Therapy
• Genetic Therapy
• Genetic Vectors
• Interferon-gamma (therapeutic use)
• Melanoma, Experimental (drug therapy, therapy)
• Mice
• Skin Neoplasms (drug therapy, therapy)
• Tissue Inhibitor of Metalloproteinase-1 (genetics)
• Tissue Inhibitor of Metalloproteinase-2 (genetics)
• Treatment Outcome
• Tumor Necrosis Factors (therapeutic use)