title: A selective cyclooxygenase-2 inhibitor, NS-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cyclooxygenase-2.
abstract: It has been proposed that Cyclooxygenase (COX)-2 inhibitors may be able to enhance the effects of chemotherapeutic or radiation treatment; however, currently few studies have been reported that define the radiation-enhancing effect of COX-2 inhibitors. We conducted in vitro radiation survival experiments using rat intestinal epithelial cells which were stably transfected with COX-2 cDNA in the sense (RIE-S) and antisense (RIE-AS) orientations to investigate the potential radiosensitizing effect of the selective COX-2 inhibitor, NS-398. Apoptosis was measured using 7-aminoactinomycin-D with flow cytometry to investigate underlying mechanisms for the effect of NS-398 on radiosensitivity. The same experiments were repeated with NCI-H460 human lung cancer cells, which express COX-2 constitutively, and HCT-116 human colon cancer cells, which lack COX-2 expression. In vivo tumor growth delay assays were also performed with tumors formed by H460 and HCT-116 cells. No difference was observed in the intrinsic radiation sensitivity of RIE-S and RIE-AS cells exposed to radiation alone. However, 150-400 microM of NS-398 enhanced radiosensitivity in a concentration-dependent manner in RIE-S cells with dose enhancement ratios of 1.2-1.9 at a surviving fraction of 0.25. However, this effect was not shown in RIE-AS cells. NS-398 enhanced radiosensitivity in H460 cells with a dose enhancement ratio of 1.8 but protected HCT-116 cells from the effects of radiation. Radiation-induced apoptosis was enhanced by NS-398 in RIE-S and H460 cells but not in RIE-AS and HCT-116 cells. Additionally, this radiation-enhancing effect in RIE-S cells seemed to be attributable to some mechanisms other than the reversal of radioresistance induced by COX-2. NS-398 (36 mg/kg) enhanced the effect of radiation on H460 tumors in vivo by an enhancement factor of 2.5; however, it did not enhance the radiosensitivity of HCT-116 tumors (enhancement factor = 1.04). These in vitro and in vivo results suggest that selective COX-2 inhibitors enhance the effect of radiation on tumors that express COX-2 but not on COX-2-lacking tumors. This effect may be attributable to enhancement of radiation-induced apoptosis. Thus, selective COX-2 inhibitors may have potential as radiosensitizers for treatment of human cancers.
authors.affiliation: Department of Radiation Oncology, Vanderbilt University Medical Center, 22nd Avenue at Pierce, Nashville, TN 37232-5671, USA.
authors.forename: H
authors.initials: H
authors.lastname: Pyo
authors.forename: H
authors.initials: H
authors.lastname: Choy
authors.forename: G P
authors.initials: GP
authors.lastname: Amorino
authors.forename: J S
authors.initials: JS
authors.lastname: Kim
authors.forename: Q
authors.initials: Q
authors.lastname: Cao
authors.forename: S K
authors.initials: SK
authors.lastname: Hercules
authors.forename: R N
authors.initials: RN
authors.lastname: DuBois
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016373:DNA, Antisense / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D009578:Nitrobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016373:DNA, Antisense; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases