© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 3, 178-193,
February 7, 2001
© 2001 Oxford University Press
REVIEW |
Development of Matrix Metalloproteinase Inhibitors in Cancer Therapy
Affiliations of authors: M. Hidalgo, Institute for Drug Development, The University of Texas Health Science Center at San Antonio; S. G. Eckhardt, Division of Medical Oncology, University of Colorado Health Science Center, Denver.
Correspondence to: Manuel Hidalgo, M.D., The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., Mail code 7884, San Antonio, TX 78229 (e-mail: manuelh{at}oncology.uthscsa.edu).
The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.
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