Matrix metalloproteinase inhibitors in the treatment of cancer

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Abstract
Matrix metalloproteinases are a family of zinc-containing proteolytic enzymes that break down extracellular matrix proteins in normal physiological processes such as embryogenesis, tissue growth, and wound healing. The family includes collagenases, gelatinases, stromelysins and metalloelastase. Observational and experimental data from studies of human malignancy indicate that these proteinases are induced by the tumour in order to reconstruct adjacent normal tissue to allow neovascularisation, tumour growth and spread. Tumours have been shown to overexpress certain matrix metalloproteinases relative to normal tissue and recent studies have shown an association between high levels of expression and poor prognosis. A large series of synthetic inhibitors have been developed using the structure of a principal substrate, collagen. The inhibitors contain a chemical group that binds the zinc atom in the active site of the metalloenzyme. Inhibition is specific for the known matrix metalloproteinase family and is reversible. Studies with these inhibitors and native tissue inhibitors of matrix metalloproteinases have shown that they can prevent the growth and spread of experimental tumours. In other studies, the inhibitors have been shown to be directly anti-angiogenic. Synthetic matrix metalloproteinase inhibitors have now reached the stage of clinical testing and preliminary results indicate that the compounds may be effective in slowing tumour growth. Trials currently underway should reveal whether this approach will become a standard part of anti-neoplastic therapy in the future.