MATRIX METALLOPROTEINASES AND THEIR INHIBITORS

Tumor invasion and metastasis represent key events in the natural history of cancer. To complete the different steps involved in the metastatic cascade of events, a malignant cell has to overcome a number of natural barriers, including extracellular matrix and basement membranes. This can be partly achieved through excess production of proteolytic enzymes either by the tumor cells themselves, or through stimulation of surrounding stromal cells to secrete such enzymes (151). The matrix metalloproteinases (MMPs) are a large family (23 in humans) of extracellular zinc enzymes that mediate a number of tissue-remodeling processes, and have been strongly associated with cancer invasion and metastasis because of their capacity to degrade the extracellular matrix. A number of malignancies including prostate cancer have been shown to differentially express MMPs that correlated strongly with aggressive disease (152-154). MMPs are tightly regulated by their inhibitors called tissue inhibitors of metalloproteinases that bind in a 1:1 stoichiometry to inactivate the MMPs. Past clinical evaluation of small molecule inhibitors of the MMPs has been unrewarding, partly a consequence of treating patients with advanced, metastatic disease. However, several novel inhibitors of MMPs have been synthesized and they may still provide a useful therapeutic approach for prostate tumors that have not metastasized (155).

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