Matrix metalloproteinase inhibitors.

The matrix metalloproteinases (MMPs) are a family of at least fifteen secreted and membrane-bound zinc-endopeptidases. Collectively, these enzymes 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 metastasis. Numerous studies have shown that there is a close association between 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 between 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 metalloproteinases (TIMPs) are naturally occurring proteins that specifically inhibit matrix metalloproteinases, thus maintaining balance between matrix destruction and formation. An imbalance between MMPs and the associated TIMPs may play a significant role in the invasive phenotype of malignant tumors. TIMP-1 has been shown to inhibit tumor-induced angiogenesis in experimental systems. These findings raised the possibility of using an agent that affects expression or activity of MMPs as an anti-cancer therapy. TIMPs are probably not suitable for pharmacologic applications due to their short half-life in vivo. Batimastat (BB-94) and marimastat (BB-2516) are synthetic, low-molecular weight MMP inhibitors. They have a collagen-mimicking hydroxamate structure, which facilitates chelation of the zinc ion in the active site of the MMPs. These compounds 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 detergent emulsion. Marimastat belongs to a second generation of MMP inhibitors. In contrast to batimastat, marimastat is orally available. Both of these agents are currently in Phase I/II trials in US, Europe and Canada. Some other new agents, currently in clinical trials, have been shown to inhibit MMP production. Bryostatins, naturally occurring macrocyclic lactones, have both in vitro and in vivo activity in numerous murine and human tumors. In culture, bryostatin-1 has been shown to induce differentiation and halt the growth of several malignant cell lines. While the exact mechanism responsible for anti-tumor activity is unclear, an initial event in the action of bryostatin-1 is activation of protein kinase C (PKC), followed by its down regulation. Bryostatin-1 does not directly affect the activity of MMPs, but it can inhibit the production of MMP-1, 3, 9, 10 and 11 by inhibiting PKC. TIMP-1 levels could also be modulated by bryostatin-1, as it is encoded by a PKC responsive gene.