June 9, 2000

Study probes role of COX-2 in tumor development

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Study probes role of COX-2 in tumor development

An enzyme implicated in colon cancer may also play a role in other cancers by promoting development of blood vessels to feed tumors, a Vanderbilt-Ingram Cancer Center scientist and his colleagues report.

Writing in the June 1 issue of the Journal of Clinical Investigation, the researchers report that lung tumors in animal models grew at a slower pace when the gene for this enzyme (cyclooxygenase-2 or COX-2) was deliberately eliminated. In addition, tumor growth was significantly reduced by treatment with a drug to block COX-2 in animals that had the active COX-2 gene.

Upon closer examination, they found that, in the absence of COX-2, the tumors developed about 30 percent fewer blood vessels than those in the animals whose COX-2 gene was present and active.

They also found that COX-2 levels were directly associated with levels of a growth factor that promotes the development of new blood vessels, a process called angiogenesis. In the cells missing the COX-2 gene, VEGF levels were substantially lower; with an active COX-2 gene, VEGF levels dropped after treatment with COX-2 inhibitors.

"It appears that the inhibition of tumor growth is due to lack of tumor-associated angiogenesis," said Raymond DuBois, MD, PhD, Mina Cobb Wallace Professor and Associate Director of Cancer Prevention at Vanderbilt-Ingram. "We are now examining exactly how that is controlled."

The link that is beginning to be established between COX-2 and angiogenesis — by these scientists and others — is important because it suggests selective COX-2 inhibitors might be useful as potential treatments for already established tumors.

Initially developed for arthritis, these drugs are similar to aspirin and non-steroidal anti-inflammatory drugs like ibuprofen. Aspirin and NSAIDs target both forms of the enzyme cyclooxygenase (1 and 2), both of which lead to the production of bio-active lipid hormones such as prostaglandins. Newer drugs, including the widely prescribed and marketed drug Celebrex, target only COX-2. This selectivity results in relief from pain and inflammation promoted by COX-2's prostaglandin products but leaves intact the stomach protection provided by COX-1's products.

Strong evidence over more than a decade has associated longterm use of aspirin and/or NSAIDs with a reduced risk for colon cancer. DuBois and his colleagues made the important link several years ago between elevated levels of COX-2 and the development of colon tumors. Now, DuBois is a national co-investigator in a multi-center study to test the ability of COX-2 inhibitors to prevent precancerous polyps in the colon.

In recent years, cancer researchers have turned to the field of angiogenesis as a hopeful avenue to fight cancer by more indirect means than traditional chemo- or radiation therapy.

Tumors produce growth factors, such as VEGF, to recruit new blood vessels to bring the oxygen and nutrients the tumors need to grow. These vessels also provide a route for metastasis (spread of cancer cells to other parts of the body).

A number of drugs that interfere with that process in various ways are being studied in the laboratory setting as well as in patients.

These drugs include an antibody that directly inhibits the action of VEGF. Scientists are also working to better understand the process of angiogenesis in order to develop more effective means of cutting off tumor supply lines.

DuBois' colleagues in the research reported in JCI were Christopher Williams, also of the VICC; Masahiko Tsujii of Osaka School of Medicine; and Jeff Reese and Sudhansu Dey of the University of Kansas Medical Center.

The work was supported by the T.J. Martell Foundation, which funds the Frances Williams Preston Laboratories at Vanderbilt-Ingram.