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 E 2 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 E 2 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]

Resistance of cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells against γδ T cell cytotoxicity

“…1,28,29 While anti-Cox-2 therapy has been consistently shown to inhibit PGE2 synthesis in xenografted pancreatic tumors and in pancreatic cancer patients, conflicting findings have been reported in regards to the antitumor, antiproliferative and anti-angiogenic effect of Cox-2 inhibitors in xenografted pancreatic carcinomas, a result that may be due to the usage of PDAC cell lines versus primary PDAC cells in these two contradictory reports. 11,13 In our experiments, we did not focus on the direct toxic effect of Cox-2 inhibitors on PDAC cells but on the effect on gd T cell-mediated cytotoxicity. Based on previous titration results, we used Cox-2 inhibitors at concentrations that were not toxic for PDAC cells but potently inhibited their PGE2 release.…”

“…26 However, such an enhanced PGE2 synthesis could be potently decreased by the Cox-2 inhibitor celecoxib in a pancreatic cancer xenograft mouse model. 11 Although selective Cox-2 inhibitors such as celecoxib and DuP697 showed anti-proliferative activity toward different tumor entities and against several PDAC cell lines in vitro as well as in vivo, celecoxib as a single agent failed to exert anti-proliferative or antitumor effects toward pancreatic adenocarcinomas resected from patients and implanted in nude mice in a xenograft model, despite a decrease in PGE2 synthesis. [11][12][13] Nevertheless, selective Cox-2 inhibitors have been included in clinical trials (Phase II) as combinatorial therapies, such as to increase the efficiency of the topoisomerase I inhibitor irinotecan or chemotherapy for the treatment of patients with advanced or metastatic pancreatic adenocarcinoma.…”

“…11 Although selective Cox-2 inhibitors such as celecoxib and DuP697 showed anti-proliferative activity toward different tumor entities and against several PDAC cell lines in vitro as well as in vivo, celecoxib as a single agent failed to exert anti-proliferative or antitumor effects toward pancreatic adenocarcinomas resected from patients and implanted in nude mice in a xenograft model, despite a decrease in PGE2 synthesis. [11][12][13] Nevertheless, selective Cox-2 inhibitors have been included in clinical trials (Phase II) as combinatorial therapies, such as to increase the efficiency of the topoisomerase I inhibitor irinotecan or chemotherapy for the treatment of patients with advanced or metastatic pancreatic adenocarcinoma. 12,14,15 PDAC is a highly malignant gastrointestinal tumor characterized by the presence of a dense desmoplastic stroma composed of extracellular matrix and diverse non-neoplastic inflammatory cells mostly displaying an immunosuppressive phenotype.…”

Effects of Capecitabine and Celecoxib in Experimental Pancreatic Cancer

“…Cox 2 inhibitory therapy reduces tumor growth and metastasis in colon cancer [14]. The regulation of Cox 2 expression may be a promising antitumoral treatment in pancreatic cancer [15]. The administration of Cox 2 inhibitor (celecoxib) has been shown to reduce the tissue expression of VEGF, tumor angiogenesis and metastasis in an experimental model of pancreatic cancer [11].…”

Pancreatic cancer: from molecular pathogenesis to targeted therapy

“…In the same study, tumors from other pancreatic cancer patients were transplanted in nude mice and subsequently treated with celecoxib or vehicle. Unfortunately no growth inhibition or antitumor effect was seen in the resected specimens or in the xenograft tumors after treatment with single agent celecoxib, though synthesis of prostaglandin E2 was sufficiently inhibited [162].…”