Rapid up-regulation of cyclooxygenase-2 by 5-fluorouracil in human solid tumors.
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.
Mercer
Stuart J
SJ
Translational Oncology Research Centre, Department of Histopathology, Queen Alexandra Hospital, Portsmouth PO6 3LY, UK.
Di Nicolantonio
Federica
F
Knight
Louise A
LA
Gabriel
Francis G
FG
Whitehouse
Pauline A
PA
Sharma
Sanjay
S
Fernando
Augusta
A
Bhandari
Pradeep
P
Somers
Shaw S
SS
Toh
Simon K
SK
Cree
Ian A
IA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D004790:Enzyme Induction; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000964:Antimetabolites, Antineoplastic; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D005472:Fluorouracil