Sequence-dependent effect of a cyclooxygenase-2 inhibitor on topoisomerase I inhibitor and 5-fluorouracil-induced cytotoxicity of colon cancer cells.
Selective cyclooxygenase-2 (COX-2) inhibitors have been found to induce anti-proliferative and apoptotic activity in many cancer cells. However, interaction between COX-2 inhibitors and other chemotherapeutic agents remains to be determined. We investigated the interactive effects of a selective COX-2 inhibitor, etodolac, in combination with 5-fluorouracil (5-FU) or SN-38 (active metabolite of irinotecan) on colon cancer cell lines, HT29 and SW620, in simultaneous and sequential administration schedules. Isobologram analysis demonstrated that etodolac in combination with 5-FU or SN-38 according to a simultaneous schedule resulted in only an additive effect; however, synergism was achieved in a sequential schedule. Apoptosis induction in both cell lines was also significantly increased after sequential treatment with etodolac followed by either 5-FU or SN-38 compared to that after simultaneous treatment with etodolac and either 5-FU or SN-38. Our study suggests apoptosis-inducing synergism resulted from administration of etodolac and either 5-FU or SN-38 sequentially, but not simultaneously.
Chen
Wei-Shone
WS
Division of Colorectal Surgery, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan. wschen@vghtpe.gov.tw
Liu
Jin-Hwang
JH
Liu
Jacqueline Ming
JM
Lin
Jen-Kou
JK
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity; D017308:Etodolac / Q000633:toxicity; D005472:Fluorouracil / Q000633:toxicity*; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D059004:Topoisomerase I Inhibitors
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D059004:Topoisomerase I Inhibitors; D017308:Etodolac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D004264:DNA Topoisomerases, Type I; D005472:Fluorouracil