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 resp...

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Bibliographic Details
Published in:Anticancer research 2009-08, Vol.29 (8), p.3095-3101
Main Authors: RETI, Andrea, PAP, Eva, ZALATNA, Attila, JENEY, Andras, KRALOVANSZKY, Judit, BUDAI, Barna
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Biological and medical sciences
Blotting, Western
Colonic Neoplasms - drug therapy
Colonic Neoplasms - enzymology
Colonic Neoplasms - pathology
Cyclooxygenase 2 - genetics
Cyclooxygenase 2 - metabolism
Dihydrouracil Dehydrogenase (NADP) - genetics
Dihydrouracil Dehydrogenase (NADP) - metabolism
Female
Fluorescent Antibody Technique
Humans
Immunoenzyme Techniques
Indomethacin - pharmacology
Medical sciences
Mice
Mice, SCID
Nitrobenzenes - pharmacology
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
RNA, Messenger - metabolism
Sulfonamides - pharmacology
Transplantation, Heterologous
Tumor Cells, Cultured
Tumors
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Summary: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. Materials and 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. Conclusion: NSAIDs could be promising modulators of fluorouracil-based chemotherapy, especially in high COX-2-expressing tumours.
ISSN:0250-7005
1791-7530