The use of tissue inhibitors of matrix metalloproteinases to increase the efficacy of a tumor necrosis factor/interferon gamma antitumor therapy.
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.
Van Roy
M
M
Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Zwijnaarde, Ghent, Belgium.
Wielockx
B
B
Baker
A
A
Libert
C
C
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003131:Combined Modality Therapy; D015316:Genetic Therapy; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000628:therapy*; D051379:Mice; D012878:Skin Neoplasms / Q000188:drug therapy / Q000628:therapy*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*; D016896:Treatment Outcome; D048069:Tumor Necrosis Factors / Q000627:therapeutic use*
D019715:Tissue Inhibitor of Metalloproteinase-1; D048069:Tumor Necrosis Factors; D019716:Tissue Inhibitor of Metalloproteinase-2; D007371:Interferon-gamma