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Carbamoylphosphonate Matrix Metalloproteinase Inhibitors 3: In vivo Evaluation of Cyclopentylcarbamoylphosphonic Acid in Experimental Metastasis and Angiogenesis

Authors' Affiliations: Departments of ¹ Pharmacology and ² Medicinal Chemistry, and ³ David R. Bloom Center of Pharmacy, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

Requests for reprints: Reuven Reich, Department of Pharmacology, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, P.O. Box 12065, 91120 Jerusalem, Israel. Phone: 972-2-6757505; Fax: 972-2-6758741; E-mail: reich{at}cc.huji.ac.il.

The spread of malignant tumor cells from a primary neoplasm to distant organs where they multiply and form new foci is the major cause of death from cancer. Despite the different modalities of cancer treatment, no effective curative therapy of metastatic lesions is available. To possess metastatic potential, a cell has to be able to invade the surrounding tissue, spread via lymphatics and/or the bloodstream, extravasate, and multiply at secondary sites. There is increasing evidence for a positive correlation between matrix metalloproteinase-2 (MMP-2) activity and tumor cell invasion. Agents blocking MMP-2 have been shown to prevent tumor cell invasion in vitro and in vivo. Inhibition of MMPs has, therefore, become the focus of considerable interest in connection with a variety of potential therapeutic applications. We have discovered a nontoxic MMP-2–selective inhibitor effective at nanomolar range on recombinant MMP. This compound, cyclopentylcarbamoylphosphonic acid, significantly inhibited cellular invasion and capillary formation in vitro. Further, i.p. or oral administration of the compound significantly reduced lung metastasis formation and s.c. tumor growth in a murine melanoma model. The effect of this novel compound on lung colonization, capillary formation, and s.c. tumor growth indicates that the compound might also be effective in treatment of primary tumor growth in reduction, or at least in prevention, of further tumor growth, thereby reducing the tumor burden of the patient by a nontoxic approach.

Key Words: MMP-2 • metastasis • MMPI • cancer • angiogenesis • melanoma • phosphonate