title: Assessment of celecoxib pharmacodynamics in pancreatic cancer.
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.
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 1650 Orleans Street, Room 1M89, Baltimore, MD 21231, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: Amador
authors.forename: Peter
authors.initials: P
authors.lastname: Kulesza
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.forename: Belen
authors.initials: B
authors.lastname: Rubio-Viqueira
authors.forename: Xiangfeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Audrey
authors.initials: A
authors.lastname: Chan
authors.forename: Jenna
authors.initials: J
authors.lastname: Wheelhouse
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kuramochi
authors.forename: Koji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Kathleen
authors.initials: K
authors.lastname: Danenberg
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Virna
authors.initials: V
authors.lastname: Almuete
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000818:Animals; D000068579:Celecoxib; D051545:Cyclooxygenase 1 / Q000096:biosynthesis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D000068579:Celecoxib; D015232:Dinoprostone