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Increase in Gelatinase-specificity of Matrix Metalloproteinase Inhibitors Correlates with Antimetastatic Efficacy in a T-Cell Lymphoma Model¹

Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, D-81675 München, Germany (M. A., C. K., B. G., A. K.); University of East Anglia, School of Biological Sciences, Norwich, Norfolk NR4 7TJ, United Kingdom (C. P., D. R. E.); University of Toronto, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada (K. L. M. W., R. K.); Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany (W. B.); and Roche Diagnostics GmbH, D-82377 Penzberg, Germany (H. W. K.)

The recognition that matrix metalloproteinases (MMPs) facilitate tumor cell invasion and metastasis has led to the development of synthetic MMP inhibitors (MMPIs) as cancer therapeutic agents. Because several Phase III trials failed recently to show efficacy of broad-spectrum MMPIs in advanced cancer, the feasibility of MMPs as therapeutic targets has been challenged. However, it has not yet been determined whether MMPIs that have increased specificity may have greater benefit. We show that MMP-9 expression closely correlates with the progression of liver metastasis in a T-cell lymphoma model. MMPIs with greater selectivity/specificity for MMP-9 in vitro showed greater efficacy against liver metastasis in vivo. These data demonstrate a link between increased specificity of MMPIs and enhanced anticancer activity.