title: Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11.
abstract: Combining anticancer drugs with different mechanisms of action has the potential to enhance antitumor effect. CPT-11 (Camptosar, irinotecan), a topoisomerase I inhibitor, has been shown to be highly effective in the treatment of a variety of cancers. However, its clinical usage is often complicated by late diarrhea. A number of studies have shown that cyclooxygenase (COX)-2 is overexpressed in many forms of human tumors, suggesting that COX-2 inhibition may be useful in the treatment of cancer. In this study, we used two mouse tumor models (HT-29 and colon-26 cells) to evaluate the effect of combining CPT-11 with celecoxib on tumor growth. We also assessed the involvement of COX-2 in the pathogenesis of CPT-11-induced late diarrhea using a rat model. Results indicate that celecoxib enhances the antitumor effect of CPT-11 and reduces the severity of late diarrhea in a dose-dependent manner. The extended benefits of combining celecoxib with CPT-11 may significantly improve the outcome of cancer patients.
authors.affiliation: Oncology Pharmacology, Pharmacia Corp., Chesterfield, Missouri 63198, USA. ovidiu.c.trifan@pharmacia.com
authors.forename: Ovidiu C
authors.initials: OC
authors.lastname: Trifan
authors.forename: William F
authors.initials: WF
authors.lastname: Durham
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Salazar
authors.forename: Jennifer
authors.initials: J
authors.lastname: Horton
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Levine
authors.forename: Ben S
authors.initials: BS
authors.lastname: Zweifel
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Davis
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Masferrer
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000068579:Celecoxib; D003106:Colon / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control*; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology; D004334:Drug Administration Schedule; D004357:Drug Synergism; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D000077146:Irinotecan; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D015232:Dinoprostone; D002166:Camptothecin