Co-inhibition of cyclooxygenase-2 and dihydropyrimidine dehydrogenase by non-steroidal anti-inflammatory drugs in tumor cells and xenografts.
BACKGROUND
Non-steroidal anti-inflammatory drugs (NSAIDs) may be able to enhance the antitumor effect of cancer drugs. Cyclooxygenase-2 (COX-2) is the best characterized target of NSAIDs. It was demonstrated that elevated dihydropyrimidine dehydrogenase (DPD) and COX-2 activities influence the response to 5-fluorouracil (5-FU). We previously showed that NSAIDs increased 5-FU sensitivity only in high COX-2-expressing cancer cells.


METHODS
The effect of indomethacin and NS-398 on DPD activity and mRNA expression in a high COX-2-expressing (determined by Western blotting, immunoflourescence and immunohistochemistry) cell line (24-, 48-hour, 10-day treatment) and xenograft (3-week treatment) was investigated.


RESULTS
The coexistence of high COX-2 and DPD activity or low activities of both enzymes were detected. After treatment with NSAIDs, a simultaneous and significant decrease of both activities was also demonstrated.


CONCLUSIONS
NSAIDs could be promising modulators of fluorouracil-based chemotherapy, especially in high COX-2-expressing tumours.
Réti
Andrea
A
National Institute of Oncology, Rath Gy. str. 7-9, Budapest H-1122, Hungary.
Pap
Eva
E
Zalatnai
Attila
A
Jeney
András
A
Kralovánszky
Judit
J
Budai
Barna
B
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007213:Indomethacin / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D009578:Nitrobenzenes / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D042943:Dihydrouracil Dehydrogenase (NADP); D007213:Indomethacin