NSAIDS PROVOKE A SPECIFIC PORTFOLIO OF DIFFERENTIALLY EXPRESSED GENES IN HEALTHY COLON OF HNPCC PATIENTS
16 July 2006 - American Association for Cancer Research (AACR)

Taking celecoxib, a COX-2 inhibitor better known as Celebrex, has been found to alter a specific "signature" set of genes in the colons of patients at high risk for a hereditary form of colon cancer, according to a new study reported here at the 96th Annual Meeting of the American Association for Cancer Research.

The scientists further reported that many of the genes, whose expression is changed by celecoxib, were tied to the immune system and the inflammatory response.

Together, the results offer specific molecular evidence for how this drug may suppress the formation of colon polyps, which often serve as a marker for early colon cancer.

"Analysis of these celecoxib-induced changes in gene expression suggests that in the 'normal' colon, this COX-2 inhibitor may act directly or indirectly to suppress the immune response and early steps of inflammation," said Oleg Glebov, Ph.D., a cancer genetics researcher at the National Cancer Institute.

As described by the scientists, a portfolio of 173 genes isolated in the normal mucosal lining of the colon is differentially expressed in patients genetically at risk for hereditary nonpolyposis colon cancer. Also known as Lynch Syndrome, patients with this inherited disorder are at higher risk of developing colorectal cancer and certain other types of cancer, such as ovarian or endometrial cancers. Only about three percent of all cases of colon cancer stem from this condition.

Glebov and his colleagues noted that patients taking higher doses of celecoxib (800 mg twice a day) experienced more dramatic effects than those on lower doses (200 mg twice a day). Specifically, the drug affected genes involved with cell signaling, cell adhesion, response to stress, TGF-beta signaling, and the regulation of cell death, or apoptosis.

"We found that treatment of patients with celecoxib led to changes in more than 1,400 genes in the healthy colon," Glebov said. "Of those genes, a specific set of 173 forms a signature portfolio that accurately identifies the colonic biopsies from patients taking the nonsteroidal anti-inflammatory drug celecoxib."

Joining Glebov in pursuit of these studies were Luz Rodriguez, Kenneth Nakahara, Jean Jenkins, Casey-Jo Humbyrd, Janet Cliatt, Ernest Hawk and Ilan Kirsch, NCI, Bethesda, Md.; Patrick Lynch, Sherry Patterson, UT M. D. Anderson Cancer Center, Houston, Texas; Henry Lynch, Creighton University, Omaha, Neb.; Peter Soballe, John DeNobile National Naval Medical Center, Bethesda, Md.; Steven Gallinger, University of Toronto, Toronto, ON; Aby Buchbinder, Pharmacia, Peapack, N.J.; and Gary Gordon, Ovation Pharma, Lincolnshire, Ill.

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