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Celecoxib Treatment Alters the Gene Expression Profile of Normal Colonic Mucosa

¹ Genetics Branch, Center for Cancer Research; ² Division of Cancer Prevention, National Cancer Institute; ³ Surgery Department, National Naval Medical Center, Bethesda, Maryland; ⁴ University of Texas M.D. Anderson Cancer Center, Houston, Texas; ⁵ Creighton University, Omaha, Nebraska; ⁶ University of Toronto, Toronto, Ontario, Canada; ⁷ Pharmacia, Peapack, New Jersey; and ⁸ Ovation Pharma, Lincolnshire, Illinois

Requests for reprints: Ilan R. Kirsch, Oncology Research, Amgen, 1201 Amgen Court West, AW1-J4144, Seattle, WA 98119-3105. Phone: 206-265-7316; Fax: 206-216-5930. E-mail: lkirsch{at}amgen.com

A clinical trial was recently conducted to evaluate the safety and efficacy of a selective inhibitor of cyclooxygenase-2 (celecoxib) in hereditary nonpolyposis colon cancer patients. In a randomized, placebo-controlled phase I/II multicenter trial, hereditary nonpolyposis colon cancer patients and gene carriers received either celecoxib at one of two doses or placebo. The goal was to evaluate the effects of these treatment arms on a number of endoscopic and tissue-based biomarker end points after 12 months of treatment. As part of this trial, we analyzed gene expression by cDNA array technology in normal descending (rectal) colonic mucosa of patients before and after treatment with celecoxib or placebo. We found that treatment of patients with celecoxib at recommended clinical doses (200 and 400 mg p.o. bid), in contrast to treatment with placebo, leads to changes in expression of >1,400 genes in the healthy colon, although in general, the magnitude of changes is <2-fold. Twenty-three of 25 pairs of colon biopsies taken before and after celecoxib treatment can be classified correctly by the pattern of gene expression in a leave-one-out cross-validation. Immune response, particularly T- and B-lymphocyte activation and early steps of inflammatory reaction, cell signaling and cell adhesion, response to stress, transforming growth factor-ß signaling, and regulation of apoptosis, are the main biological processes targeted by celecoxib as shown by overrepresentation analysis of the distribution of celecoxib-affected genes across Gene Ontology categories. Analysis of possible cumulative effects of celecoxib-induced changes in gene expression indicates that in healthy colon, celecoxib may suppress the immune response and early steps of inflammation, inhibit formation of focal contacts, and stimulate transforming growth factor-ß signaling. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1382–91)

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