Development of matrix metalloproteinase inhibitors in cancer therapy

The matrix metalloproteinases (MMPs) are a family of zinc-dependent protein ases 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 associate d with an aggressive malignant phenotype and adverse prognosis in patients with cancer, A number of MMP inhibitors are being developed for the treatme nt of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP activ e site, tetracycline derivatives, and bisphosphonates. The hydroxamate pept idomimetic inhibitor batimastat and its orally bioavailable analogue marima stat, which bind covalently to the zinc atom at the MMP-active site, were t he first MMP inhibitors to be studied in detail. Marimastat is currently be ing studied in randomized clinical trials. The nonpeptidic MMP inhibitors w ere synthesized in an attempt to improve the oral bioavailability and pharm aceutical properties of the peptidic inhibitors. Several members of this cl ass of compounds are undergoing evaluation in phase III clinical trials. Th e tetracyclines and, particularly, the nonantibiotic chemically modified te tracyclines, interfere with several aspects of MMP expression and activatio n and inhibit tumor growth and metastases in preclinical models. A represen tative 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 t he 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 mechanis m of action, will require novel clinical trial design strategies.