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Antimetastatic activity of a novel mechanism-based gelatinase inhibitor.

Abstract
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.
AuthorsAchim Krüger, Matthias J E Arlt, Michael Gerg, Charlotte Kopitz, M Margarida Bernardo, Mayland Chang, Shahriar Mobashery, Rafael Fridman
JournalCancer research (Cancer Res) Vol. 65 Issue 9 Pg. 3523-6 (May 01 2005) ISSN: 0008-5472 [Print] United States
PMID15867341 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Heterocyclic Compounds, 1-Ring
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • SB 3CT compound
  • Sulfones
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Heterocyclic Compounds, 1-Ring (pharmacology)
  • Liver Neoplasms, Experimental (enzymology, prevention & control, secondary)
  • Lymphoma, T-Cell (drug therapy, enzymology, prevention & control)
  • Matrix Metalloproteinase Inhibitors
  • Mice
  • Mice, Inbred DBA
  • Protease Inhibitors (pharmacology)
  • Sulfones (pharmacology)

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