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Rapid up-regulation of cyclooxygenase-2 by 5-fluorouracil in human solid tumors

Mercer, Stuart J.a; Di Nicolantonio, Federicaa; Knight, Louise A.a; Gabriel, Francis G.a; Whitehouse, Pauline A.a; Sharma, Sanjaya; Fernando, Augustaa; Bhandari, Pradeepb; Somers, Shaw S.b; Toh, Simon K.b; Cree, Ian A.bfor the NHS Collaborative Research Programme on Predictive Oncology

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Inhibition of cyclooxygenase (COX)-2 has been associated with reduced growth of malignant cells. Current therapy of gastrointestinal carcinomas involves the use of 5-fluorouracil (5-FU)-based chemotherapy and we have therefore studied the effect of this agent on the expression of COX-2. COX-2 expression was measured by quantitative RT-PCR in biopsies from a series of 14 esophageal carcinomas, six of which had paired samples taken before and after chemotherapy, and in tumor-derived cells exposed to 5-FU in vitro from a series of 44 tumors, including breast, ovarian, esophageal and colonic carcinomas. COX-2 expression was increased by exposure to 5-FU or 5-FU combination chemotherapy in all the tumor types studied, whether measured in biopsies taken before and after 5-FU-based chemotherapy (4-fold increase, p<0.015) or in primary cells exposed to drugs in vitro (24-fold increase, p<0.001). A modest increase of COX-2 mRNA was also seen after in vitro treatment of cells with cisplatin. In contrast, doxorubicin and paclitaxel caused no up-regulation in vitro, while irinotecan caused inhibition of COX-2 (2.7-fold decrease, p<0.01). These data provide a molecular rationale for clinical trials of combination chemotherapy with COX-2 inhibitors.

aTranslational Oncology Research Centre, Department of Histopathology

bSolent Centre for Digestive Diseases, Queen Alexandra Hospital, Portsmouth, UK

Sponsorship: This study was funded by CanTech Ltd, the Royal Navy (S. J. M), the BBSRC (31/ABY14513), the European Commission (BMH4-CT98-9522), and was supported by a donation from Schering Plough Ltd.

Conflict of interest: I. A. C. is a Director of two University spin-off companies, one of which (CanTech Ltd) provided financial assistance for this study.

The first two authors contributed equally to this work.

Correspondence to I. A. Cree, Translational Oncology Research Centre, Michael Darmady Laboratory, Department of Histopathology, E Level, Queen Alexandra Hospital, Portsmouth PO6 3LY, UK

Tel: +44 23 9228 6378; fax: +44 23 9228 6379;

E-mail: ian.cree@port.ac.uk

Received 7 February 2005 Accepted 1 March 2005

© 2005 Lippincott Williams & Wilkins, Inc.