MATRIX METALLOPROTEINASES - NOVEL TARGETS FOR DIRECTED CANCER-THERAPY

Matrix metalloproteinases (MMPs), or matrixins, are a family of zinc e ndopeptidases that play a key role in both physiological and pathologi cal tissue degradation. Normally, there is a careful balance between c ell division, matrix synthesis and matrix degradation, which is under the control of cytokines, growth factors and cell matrix interactions. The MMPs are involved in remodelling during tissue morphogenesis and wound healing. Under pathological conditions, this balance is altered: in arthritis, there is uncontrolled destruction of cartilage; in canc er, increased matrix turnover is thought to promote tumour cell invasi on. The demonstration of a functional role of MMPs in arthritis and tu mour metastasis raises the possibility of therapeutic intervention usi ng synthetic MMP inhibitors with appropriate selectivity and pharmacok inetics. As the process of drug discovery focuses on structure-based d esign, efforts to resolve the 3-dimensional structures of the MMP fami ly have intensified. Several novel MMP inhibitors have been identified and are currently being investigated in clinical trials. The structur al information that is rapidly accumulating will be useful in refining the available inhibitors to selectively target specific MMP family me mbers. In this review, we focus on the role of MMPs and their inhibito rs in tumour metastasis and angiogenesis, and examine how MMPs may be targeted to prevent cancer progression.