A pharmacological study of celecoxib and gemcitabine in patients with advanced pancreatic cancer
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To evaluate whether celecoxib alters the conversion of gemcitabine into its active metabolite, difluorodeoxycytidine triphosphate (dFdCTP), in peripheral blood mononuclear cells (PBMCs).
Patients with advanced pancreatic cancer who had not received chemotherapy and had acceptable organ function were eligible for the study. The initial dose of gemcitabine was 750 mg/m2 administered intravenously at a rate of 10 mg/m2/min on days 1, 8, and 15 every 4 weeks. Celecoxib was administered orally at 400 mg twice a day starting 2 days after the first dose of gemcitabine. Serial blood samples were taken during the first and second gemcitabine infusions and the cellular dFdCTP levels from PBMCs were analyzed.
Five patients received gemcitabine at 750 mg/m2 and six patients received it at 650 mg/m2. Severe adverse events included neutropenia, thrombocytopenia, enteritis, and gastric perforation. Two patient died early during treatment. Cellular pharmacology studies showed that the conversion of gemcitabine into dFdCTP was not affected by celecoxib.
Despite the increased clinical toxicities encountered with the combination, celecoxib did not alter the conversion of gemcitabine into its active metabolites in PBMCs. Gemcitabine 650 mg/m2 infusion over 65 min on days 1, 8, and 15 every 4 weeks in combination with celecoxib at 400 mg twice a day was the dose recommended for further study.
KeywordsPancreatic cancer Celecoxib Gemcitabine Cellular pharmacology
The study was funded in part by a research grant from Pfizer. The authors thank Pamela Dumas for excellent research nursing support and Gail Bland for administrative support and editorial comments.
- 1.Grunewald R, Kantarjian H, Keating MJ, Abbruzzese J, Tarassoff P, Plunkett W (1990) Pharmacologically directed design of the dose rate and schedule of 2′,2′-difluorodeoxycytidine (gemcitabine) administration in leukemia. Cancer Res 50(21):6823–6826Google Scholar
- 4.Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413PubMedGoogle Scholar
- 5.Kokawa A, Kondo H, Gotoda T, Ono H, Saito D, Nakadaira S, Kosuge T, Yoshida S (2001) Increased expression of cyclooxygenase-2 in human pancreatic neoplasms and potential for chemoprevention by cyclooxygenase inhibitors. Cancer 91:333–338Google Scholar
- 6.Koshiba T, Hosotani R, Miyamoto Y, Wada M, Lee JU, Fujimoto K, Tsuji S, Nakajima S, Doi R, Imamura M (1999) Immunohistochemical analysis of cyclooxygenase-2 expression in pancreatic tumors. Int J Pancreatol 26:69–76Google Scholar
- 7.Merati K, said Siadaty M, Andea A, Sarkar F, Ben-Josef E, Mohammed R, Philip P, Shields AF, Vaitkevicius V, Grignon DJ, Adsay NV (2001) Expression of inflammatory modulator COX-2 in pancreatic ductal adenocarcinoma and its relationship to pathologic and clinical parameters. Am J Clin Oncol 24:447–452Google Scholar
- 8.Okami J, Yamamoto H, Fujiwara Y, Tsujie M, Kondo M, Noura S, Oshima S, Nagano H, Dono K, Umeshita K, Ishikawa O, Sakon M, Matsuura N, Nakamori S, Monden M (1999) Overexpression of cyclooxygenase-2 in carcinoma of the pancreas. Clin Cancer Res 5:2018–2024Google Scholar
- 11.Maitra A, Ashfaq R, Gunn CR, Rahman A, Yeo CJ, Sohn TA, Cameron JL, Hruban RH, Wilentz RE (2002) Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging. Am J Clin Pathol 118(2):194–201Google Scholar
- 18.Plunkett W, Hug V, Keating MJ, Chubb S (1980) Quantitation of 1-b-D-arabinofuranosylcytosine 5′- triphosphate in the leukemic cells from bone marrow and peripheral blood of patients receiving 1-β-D-arabinofuranosylcytosine therapy. Cancer Res 40:588–591Google Scholar
- 19.Gandhi V, Plunkett W (1990) Modulatory activity of 2′,2′-difluorodeoxycytidine on the phosphorylation and cytotoxicity of arabinosyl nucleosides. Cancer Res 50:3675–3680Google Scholar
- 20.Lorenz M, Slaughter HS, Wescott DM, Carter SI, Schnyder B, Dinchuk JE, Car BD (1999) Cyclooxygenase-2 is essential for normal recovery from 5-fluorouracil-induced myelotoxicity in mice. Exp Hematol 27:1494–1502Google Scholar
- 21.Altorki NK, Keresztes RS, Port JL, Libby DM, Korst RJ, Flieder DB, Ferrara CA, Yankelevitz DF, Subbaramaiah K, Pasmantier MW, Dannenberg AJ (2003) Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer. J Clin Oncol 21(14):2645–2650Google Scholar
- 22.Tempero M, Plunkett W, Ruiz Van Haperen V, Hainsworth J, Hochster H, Lenzi R, Abbruzzese JL (2003) Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21(18):3402–3408Google Scholar
- 23.Wolff RA, Evans DB, Gravel DM, Lenzi R, Pisters PW, Lee JE, Janjan NA, Charnsangavej C, Abbruzzese JL (2001) Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma. Clin Cancer Res 7(8):2246–2253Google Scholar