Matrix metalloproteinase inhibitors and cancer: trials and tribulations.
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.
Coussens
Lisa M
LM
Department of Pathology and Cancer Research Institute, University of California, 2340 Sutter Street, San Francisco, CA 94143, USA.
Fingleton
Barbara
B
Matrisian
Lynn M
LM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases