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Treatment of Colorectal Liver Metastases by Adenoviral Transfer of Tissue Inhibitor of Metalloproteinases-2 into the Liver Tissue

Institute for Molecular and Cellular Biology, Humboldt University Berlin, Max Delbrück Center of Molecular Medicine, 13122 Berlin, Germany [K. B., A. P., M. S., M. G.]; Department of Medicine and Therapeutics, University of Glasgow, Western Infirmary, Glasgow G11 6NT, United Kingdom [A. H. B.]; Institute for Pathology, University Clinic Benjamin Franklin, Free University Berlin, 12200 Berlin, Germany [A. P-C.]; and Biomedical Research Campus Berlin-Buch, 13122 Berlin, Germany [W. A.]

Metastatic disease is the leading cause of death in cancer patients. Here, we describe a novel gene therapeutic strategy for prevention of metastatic spread by providing a suitable defense mechanism for the target organ. The production of metalloproteinase (MMP) enzymes by cancer cells is critical for local invasion and for infiltration of metastatic cells into distant sites. Using a nude mouse model of colorectal liver metastasis, we have overexpressed the MMP inhibitor, tissue inhibitor of MMP-2 (TIMP-2) in the liver prior to, or following, tumor challenge by metastatic LS174T cells in vivo. Transduction of 50% of hepatocytes resulted in 95% reduction in metastasis after tumor challenge compared with controls. Furthermore, TIMP-2 gene transfer into livers with preexisting metastatic spread resulted in a 77% reduction in tumor cell growth. Our data imply that MMP activity of metastatic cancer cells is required for spread and subsequent tumor growth and that enhancing antiproteolytic defense mechanisms in target organs represents a novel form of cancer gene therapy.

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