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New findings point to new target to block angiogenesis

NASHVILLE, Tenn. - Cutting off supply lines is a sure way to strangle and defeat an enemy army. The strategy is being applied to the war against tumors, which require supply lines-new blood vessels-to support their growth and metastasis. Scientists at the Vanderbilt-Ingram Cancer Center have identified an unexpected participant in the process of blood vessel development. Reported in the Sept. 15 issue of the journal Cancer Research, their findings point to a new target for drugs that inhibit this process, angiogenesis.

Previous work from multiple laboratories had suggested that the enzyme cyclooxygenase-2 (COX-2) contributes to the blood vessel development associated with tumors. To determine which of many COX-2 products participate in angiogenesis, Dr. Thomas Daniel, director of Vanderbilt's Vascular Biology Center, took advantage of a cultured endothelial cell system developed in his laboratory. The cultured cells migrate in response to angiogenic signals, just as they would in order to form new blood vessels in vivo.

Collaborator Dr. Jason D. Morrow, a professor of Medicine and Pharmacology, used a technique called mass spectrometry to establish that the activated endothelial cells generate the COX-2 products PGE2, thromboxane A2, and PGF2alpha. COX-2 inhibitors developed by biochemist Lawrence J. Marnett, Ph.D., associate director of research programs at the Vanderbilt-Ingram Cancer Center, prevented the formation of all of these products and blocked the cell migration response. Of the three products, only thromboxane A2 turned out to have a functional role in endothelial cell migration.

"Adding back thromboxane A2 under COX-2-inhibited conditions reconstituted cell migration," Daniel said.

Drugs that block the thromboxane A2 receptor also halted endothelial cell migration.

Using a model of angiogenesis in the mouse cornea, Daniel showed that the findings were not limited to cultured cells. "All of our in vitro observations implicating throm
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Contact: Cynthia Manley
cynthia.manley@mcmail.vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
15-Sep-1999


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