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Science 29 March 2002:
Vol. 295. no. 5564, pp. 2387 - 2392
DOI: 10.1126/science.1067100
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Review

Matrix Metalloproteinase Inhibitors and Cancer—Trials and Tribulations

Lisa M. Coussens,1 Barbara Fingleton,2 Lynn M. Matrisian2*

For at least 30 years, matrix metalloproteinases (MMPs) have been heralded as promising targets for cancer therapy on the basis of their massive up-regulation in malignant tissues and their unique ability to degrade all components of the extracellular matrix. Preclinical studies testing the efficacy of MMP suppression in tumor models were so compelling that synthetic metalloproteinase inhibitors (MPIs) were rapidly developed and routed into human clinical trials. The results of these trials have been disappointing. Here we review the studies that brought MPIs into clinical testing and discuss the design and outcome of the trials in light of new information about the cellular source, substrates, and mode of action of MMPs at different stages of tumor progression. The important lessons learned from the MPI experience may be of great value for future studies of MPIs and for cancer drug development in general.

1 Department of Pathology and Cancer Research Institute, University of California, 2340 Sutter Street, San Francisco, CA 94143, USA.
2 Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
*   To whom correspondence should be addressed. E-mail: lynn.matrisian{at}vanderbilt.edu

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Cell-surface association between matrix metalloproteinases and integrins: role of the complexes in leukocyte migration and cancer progression.
M. Stefanidakis and E. Koivunen (2006)
Blood 108, 1441-1450
   Abstract »    Full Text »    PDF »
Oncolytic efficacy and enhanced safety of measles virus activated by tumor-secreted matrix metalloproteinases..
C. Springfeld, V. von Messling, M. Frenzke, G. Ungerechts, C. J. Buchholz, and R. Cattaneo (2006)
Cancer Res. 66, 7694-7700
   Abstract »    Full Text »    PDF »
Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor 1 promoting endothelial cell activation..
T. Goerge, A. Barg, E.-M. Schnaeker, B. Poppelmann, V. Shpacovitch, A. Rattenholl, C. Maaser, T. A. Luger, M. Steinhoff, and S. W. Schneider (2006)
Cancer Res. 66, 7766-7774
   Abstract »    Full Text »    PDF »
Interaction of HIV Tat and matrix metalloproteinase in HIV neuropathogenesis: a new host defense mechanism.
J. Rumbaugh, J. Turchan-Cholewo, D. Galey, C. St. Hillaire, C. Anderson, K. Conant, and A. Nath (2006)
FASEB J 20, 1736-1738
   Abstract »    Full Text »    PDF »
An MMP liberates the Ninjurin A ectodomain to signal a lossof cell adhesion.
S. Zhang, G. M. Dailey, E. Kwan, B. M. Glasheen, G. E. Sroga, and A. Page-McCaw (2006)
Genes & Dev. 20, 1899-1910
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Proteomic Identification of Desmoglein 2 and Activated Leukocyte Cell Adhesion Molecule as Substrates of ADAM17 and ADAM10 by Difference Gel Electrophoresis..
J. J. Bech-Serra, B. Santiago-Josefat, C. Esselens, P. Saftig, J. Baselga, J. Arribas, and F. Canals (2006)
Mol. Cell. Biol. 26, 5086-5095
   Abstract »    Full Text »    PDF »
Conditional Activation of RET/PTC3 and BRAFV600E in Thyroid Cells Is Associated with Gene Expression Profiles that Predict a Preferential Role of BRAF in Extracellular Matrix Remodeling..
C. Mesa Jr., M. Mirza, N. Mitsutake, M. Sartor, M. Medvedovic, C. Tomlinson, J. A Knauf, G. F. Weber, and J. A. Fagin (2006)
Cancer Res. 66, 6521-6529
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Macrophage elastase (matrix metalloproteinase-12) suppresses growth of lung metastases..
A. M. Houghton, J. L. Grisolano, M. L. Baumann, D. K. Kobayashi, R. D. Hautamaki, L. C. Nehring, L. A. Cornelius, and S. D. Shapiro (2006)
Cancer Res. 66, 6149-6155
   Abstract »    Full Text »    PDF »
Conflicting results from clinical observations and murine models: what is the role of plasminogen activators in tumor growth?.
M. Narazaki and G. Tosato (2006)
J Natl Cancer Inst 98, 726-727
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Protease specificity determination by using cellular libraries of peptide substrates (CLiPS).
K. T. Boulware and P. S. Daugherty (2006)
PNAS 103, 7583-7588
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Development of Selective Inhibitors and Substrate of Matrix Metalloproteinase-12.
L. Devel, V. Rogakos, A. David, A. Makaritis, F. Beau, P. Cuniasse, A. Yiotakis, and V. Dive (2006)
J. Biol. Chem. 281, 11152-11160
   Abstract »    Full Text »    PDF »
Pericellular Proteases in Angiogenesis and Vasculogenesis.
V. W.M. van Hinsbergh, M. A. Engelse, and P. H.A. Quax (2006)
Arterioscler Thromb Vasc Biol 26, 716-728
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Tumor epithelial cell matrix metalloproteinase 9 is a target for antimetastatic therapy in colorectal cancer..
W. J. Lubbe, Z. Y. Zhou, W. Fu, D. Zuzga, S. Schulz, R. Fridman, R. J. Muschel, S. A. Waldman, and G. M. Pitari (2006)
Clin. Cancer Res. 12, 1876-1882
   Abstract »    Full Text »    PDF »
Inhibitory Effects of Lycopene on the Adhesion, Invasion, and Migration of SK-Hep1 Human Hepatoma Cells..
E.-S. Hwang and H. J. Lee (2006)
Experimental Biology and Medicine 231, 322-327
   Abstract »    Full Text »    PDF »


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