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Antimetastatic Activity of a Novel Mechanism-Based Gelatinase Inhibitor

¹ Institut für Experimentelle Onkologie und Therapieforschung der Technischen Universität München, Munich, Germany; ² Department of Pathology and Proteases and Cancer Program, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan; and ³ Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, Indiana

Requests for reprints: Rafael Fridman, Department of Pathology, School of Medicine, Wayne State University, 540 East Canfield Avenue, Detroit, MI 48201. Phone: 313-577-1218; Fax: 313-577-8180; E-mail: rfridman{at}med.wayne.edu.

Matrix metalloproteinases (MMPs), and in particular gelatinases (MMP-2 and MMP-9), play a key role in cancer progression. However, clinical trials in which MMP inhibitors were tested in cancer patients have been disappointing. Whereas many reasons have been postulated to explain the failure of the clinical trials, lack of inhibitor selectivity was a major limitation. Thus, despite the consensus opinion that MMP-mediated proteolysis is essential for cancer progression and that certain MMPs represent important targets for intervention, effective and selective inhibition of those MMPs remains a major challenge in drug development. We previously reported the first mechanism-based MMP inhibitor, designated SB-3CT, which is a selective gelatinase inhibitor. Here we report that SB-3CT (5-50 mg/kg/d) is a potent inhibitor of liver metastasis and increases survival in an aggressive mouse model of T-cell lymphoma. This study shows that mechanism-based inhibition of gelatinases represents a novel approach to inhibitor design that promises to be a successful anticancer therapy.

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