Sep. 17, 1999 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 thromboxane A2 in a COX-2 mediated response were borne out in vivo," Daniel said. "Whether this will be true in other neovascularization contexts still needs to be determined."
The studies suggest that thromboxane A2 receptor antagonists will function as angiogenesis inhibitors. A number of such drugs have been developed as anti-thrombotics.
"Drugs that were developed and tested, but didn't make it as better anti-thrombotics might have applicability in the context of angiogenesis," Daniel said. "It's an idea that we will explore with commercial partners." Thromboxane A2 receptor-directed drugs may offer advantages over COX-2 inhibitors alone in blocking tumor angiogenesis.
"There are other ways to produce thromboxane A2 in tumors that don't express a lot of COX-2. Blockers of the thromboxane A2 receptor might be effective in situations when COX-2 inhibitors are not," Daniel said.
Combinations of drugs attacking different parts of the angiogenesis process, such as thromboxane A2 receptor antagonists and COX-2 inhibitors, may have fewer side effects and be more effective than standard chemotherapy.
Anti-angiogenesis agents offer the additional hope for less risk of drug resistance since they target normal endothelial cells rather than genetically unstable tumor cells.
Other colleagues important to the studies were research associate Hua Liu and senior research associate Brenda Crews. The work was supported by the National Institutes of Health, the National Cancer Institute, and the T.J. Martell Foundation.
As one of a select group of National Cancer Institute-designated cancer centers, the Vanderbilt-Ingram Cancer Center is a recognized leader in cancer research, treatment and prevention. The VICC is one of only a few NCI-designated centers in the southeast and the only one in Tennessee dedicated to providing the most promising therapies and advancing research in all types of cancer in adults and children. For more information, visit the VICC website at http://www.vanderbiltcancer.org .
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