MATRIX METALLOPROTEINASE INHIBITORS

The matrix metalloproteinases (MMPs) are a family of at least fifteen secreted and membrane-bound zinc-endopeptidases. Collectively, these e nzymes can degrade all of the components of the extracellular matrix, including fibrallar and non-fibrallar collagens, fibronectin, laminin and basement membrane glycoproteins. MMPs are thought to be essential for the diverse invasive processes of angiogenesis and tumor metastasi s. Numerous studies have shown that there is a close association betwe en expression of various members of the MMP family by tumors and their proliferative and invasive behavior and metastatic potential. In some of human cancers a positive correlation has also been demonstrated be tween the intensity of new blood vessel growth (angiogenesis) and the likelihood of developing metastases. Thus, control of MMP activity in these two different contexts has generated considerable interest as a possible therapeutic target. The tissue inhibitors of metalloproteinas es (TIMPs) are naturally occurring proteins that specifically inhibit matrix metalloproteinases, thus maintaining balance between matrix des truction and formation. An imbalance between MMPs and the associated T IMPs may play a significant role in the invasive phenotype of malignan t tumors. TIMP-1 has been shown to inhibit tumor-induced angiogenesis in experimental systems. These findings raised the possibility of usin g an agent that affects expression or activity of MMPs as an anti-canc er therapy. TIMPs are probably not suitable for pharmacologic applicat ions due to their short half-life in vivo. Batimastat (BB-94) and mari mastat (BB-2516) are synthetic, low-molecular weight MMP inhibitors. T hey have a collagen-mimicking hydroxamate structure, which facilitates chelation of the zinc ion in the active site of the MMPs. These compo unds inhibit MMPs potently and specifically. Batimastat was the first synthetic MMP inhibitor studied in humans with advanced malignancies, but its usefulness has been limited by extremely poor water solubility , which required intraperitoneal administration of the drug as a deter gent emulsion. Marimastat belongs to a second generation of MMP inhibi tors. In contrast to batimastat, marimastat is orally available. Both of these agents are currently in Phase I/II trials in US, Europe and C anada. Some other new agents, currently in clinical trials, have been shown to inhibit MMP production. Bryostatins, naturally occurring macr ocyclic lactones, have both in vitro and in vivo activity in numerous murine and human tumors. In culture, bryostatin-l has been shown to in duce differentiation and halt the growth of several malignant cell lin es. While the exact mechanism responsible for anti-tumor activity is u nclear, an initial event in the action of bryostatin-l is activation o f protein kinase C (PKC), followed by its down regulation. Bryostatin- l does not directly affect the activity of MMPs, but it can inhibit th e production of MMP-1, 3, 9, 10 and 1 1 by inhibiting PKC. TIMP-1 leve ls could also be modulated by bryostatin-l, as it is encoded by a PKC responsive gene.