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Research Articles: Therapeutics, Targets, and Development

Assessment of celecoxib pharmacodynamics in pancreatic cancer

¹ The Sol Goldman Pancreatic Cancer Research Center at The Sidney Kimmel Comprehensive Cancer Center, Departments of ² Pathology and ³ Surgery, and ⁴ Division of Clinical Pharmacy, Johns Hopkins University School of Medicine, Baltimore, Maryland; ⁵ University of Southern California; ⁶ Response Genetics, Inc., Los Angeles, California; ⁷ Department of Pathology, Wallace Tumor Institute, University of Alabama at Birmingham, Alabama; and ⁸ Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania

Requests for reprints: Manuel Hidalgo, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 1650 Orleans Street, Room 1M89, Baltimore, MD 21231. E-mail: mhidalg1{at}jhmi.edu

Abstract

Cyclooxygenase-2 (COX-2) inhibitors are being developed as chemopreventive and anticancer agents. This study aimed to determine the biological effect of the COX-2 inhibitor celecoxib in pancreatic cancer as an early step to the further development of the agent in this disease. Eight patients scheduled for resection of an infiltrating adenocarcinoma of the pancreas were randomized to receive celecoxib at a dose of 400 mg twice daily or placebo for 5 to 15 days before the surgery. In addition, carcinomas from nine additional patients were xenografted in nude mice, expanded, and treated with vehicle or celecoxib for 28 days. Celecoxib markedly decreased the intra-tumor levels of prostaglandin E₂ in patient carcinomas and in the heterotransplanted xenografts. However, this effect did not result in inhibition of cell proliferation or microvessel density (as assessed by Ki67 and CD31 staining). In addition, a panel of markers, including bcl-2, COX-1, COX-2, and VEGF, did not change with treatment in a significant manner. Furthermore, there was no evidence of antitumor effects in the xenografted carcinomas. In summary, celecoxib efficiently inhibited the synthesis of prostaglandin E₂ both in pancreatic cancer surgical specimens and in xenografted carcinomas but did not exert evident antitumor, antiproliferative, or antiangiogenic effect as a single agent. The direct pancreatic cancer xenograft model proved to be a valuable tool for drug evaluation and biological studies and showed similar results to those observed in resected pancreatic cancer specimens. [Mol Cancer Ther 2006;5(12):3240–7]

Grant support: National Comprehensive Cancer Network.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/13/06; revised 10/ 8/06; accepted 11/ 1/06.