Matrix metalloproteinases. Novel targets for directed cancer therapy.
Matrix metalloproteinases (MMPs), or matrixins, are a family of zinc endopeptidases that play a key role in both physiological and pathological tissue degradation. Normally, there is a careful balance between cell 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 cancer, increased matrix turnover is thought to promote tumour cell invasion. The demonstration of a functional role of MMPs in arthritis and tumour metastasis raises the possibility of therapeutic intervention using synthetic MMP inhibitors with appropriate selectivity and pharmacokinetics. As the process of drug discovery focuses on structure-based design, efforts to resolve the 3-dimensional structures of the MMP family have intensified. Several novel MMP inhibitors have been identified and are currently being investigated in clinical trials. The structural information that is rapidly accumulating will be useful in refining the available inhibitors to selectively target specific MMP family members. In this review, we focus on the role of MMPs and their inhibitors in tumour invasion, metastasis and angiogenesis, and examine how MMPs may be targeted to prevent cancer progression.
Yu
A E
AE
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Hewitt
R E
RE
Connor
E W
EW
Stetler-Stevenson
W G
WG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005109:Extracellular Matrix / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000145:classification; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000627:therapeutic use; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000627:therapeutic use
D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2; D008666:Metalloendopeptidases