Matrix metalloproteinase inhibitors: a review

The matrix metalloproteinases (MMPs) are a family of closely related, zinc-dependent proteolytic enzymes. Collectively, they are capable of degrading all the components of the extracellular matrix and as such are involved in a number of physiological and pathological processes. The extracellular matrix is the principal barrier to tumour growth and spread, and there is evidence that MMPs play a role in the processes of tumour growth and metastasis. Therefore, inhibitors of MMPs may be of value in the treatment of malignant disease. There exist naturally occurring inhibitors of these enzymes known as 'tissue inhibitors of MMPs', or TIMPs. Although there have been considerable preclinical studies on these inhibitors, they are as yet unavailable for use as therapeutic drugs. Research in this field has focused largely on the development of low molecular weight (<500D) synthetic inhibitors of MMPs. In this review we focus on the various subgroups of MMP inhibitors now available, their preclinical evaluation and the limited information available from preliminary clinical trials. We comment on the suitability of the preclinical models used and the difficulty in designing clinical trials of these drugs. We focus on future developments which may involve the use of these drugs in combination with existing chemotherapeutic regimens to achieve a synergistic effect.