Matrix-buster inhibitor has second way to throttle angiogenesis

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Findings represent latest insight into motley tribe of proteins

Matrix metalloproteinases (MMPs) and their regulators, the tissue inhibitors of metalloproteinases (TIMPs), form an intriguing partnership. MMPs work by breaking down the dense matrix surrounding cells, freeing them to wander the body during processes like metastasis and angiogenesis. TIMPs rein in the MMPs, essentially cutting off the supply of migrating cancer or endothelial cells. Given the TIMPs’ anti-angiogenic action, it is no wonder that pharmaceutical companies have been rushing to develop synthetic MMP-inhibiting agents. Yet in clinical trials, these manmade versions have often performed poorly, producing serious side-effects while failing to stop angiogenesis in cancer patients. It now appears that inhibiting the MMPs is not enough to arrest the new blood vessel growth that accompanies tumors. Working in a mouse model, Marsha Moses, Cecilia Fernandez, and their colleagues found that TIMP-2, a variant known to stifle angiogenesis in vivo, owes its power to stop cancer-related angiogenesis to its unique ability to inhibit endothelial cells from proliferating, rather than its ability to bind MMP. What is more, TIMP-2’s anti-proliferative power appears to be restricted to a small, easily synthesized region of the molecule, Loop 6. ” “It is a new angiogenesis inhibitor, it is small, and it is bioavailable,” said Moses, Harvard Medical School associate professor of surgery at Children’s Hospital. The study appears in the Oct. 17, 2003 Journal of Biological Chemistry.