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

H. Pyo, H. Choy, G. P. Amorino, J. S. Kim, Q. Cao, S. K. Hercules, R. N. DuBois

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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 μM 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.

Original languageEnglish (US)
Pages (from-to)2998-3005
Number of pages8
JournalClinical Cancer Research
Volume7
Issue number10
StatePublished - 2001
Externally publishedYes

Fingerprint

Cyclooxygenase 2 Inhibitors
Radiation Effects
Cyclooxygenase 2
Radiation Tolerance
HCT116 Cells
Radiation
Neoplasms
Apoptosis
Radiation-Sensitizing Agents
N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
In Vitro Techniques
Colonic Neoplasms
Lung Neoplasms
Flow Cytometry
Complementary DNA
Epithelial Cells
Survival
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Pyo, H.; Choy, H.; Amorino, G. P.; Kim, J. S.; Cao, Q.; Hercules, S. K.; DuBois, R. N.

In: Clinical Cancer Research, Vol. 7, No. 10, 2001, p. 2998-3005.

Research output: Contribution to journalArticle

Pyo, H. ; Choy, H. ; Amorino, G. P. ; Kim, J. S. ; Cao, Q. ; Hercules, S. K. ; DuBois, R. N. / 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. In: Clinical Cancer Research. 2001 ; Vol. 7, No. 10. pp. 2998-3005.
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AU - DuBois, R. N.

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