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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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A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Laminin from Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischemia.
Z. Gu, J. Cui, S. Brown, R. Fridman, S. Mobashery, A. Y. Strongin, and S. A. Lipton (2005)
J. Neurosci. 25, 6401-6408
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{alpha}v{beta}3-dependent cross-presentation of matrix metalloproteinase-2 by melanoma cells gives rise to a new tumor antigen.
E. Godefroy, A. Moreau-Aubry, E. Diez, B. Dreno, F. Jotereau, and Y. Guilloux (2005)
J. Exp. Med. 202, 61-72
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Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases.
M. Xu, E. Bruno, J. Chao, S. Huang, G. Finazzi, S. M. Fruchtman, U. Popat, J. T. Prchal, G. Barosi, R. Hoffman, et al. (2005)
Blood 105, 4508-4515
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