TY - JOUR
T1 - Inhibition of cyclooxygenase-2 with NS-398 and the prevention of radiation-induced transformation, micronuclei formation and clonogenic cell death in C3H 10T1/2 cells
AU - Bisht, K. S.
AU - Bradbury, C. M.
AU - Zoberi, I.
AU - Curry, H. A.
AU - Kaushal, A.
AU - Roti Roti, J. L.
AU - Gius, D.
N1 - Funding Information:
D. G. was supported by grants from the National Institutes of Health (1 K08 CA72602-01), and the American Cancer Society (RPG TBE-100674 and PO1 CA75556). I. Z. was supported by a fellowship from the American Society of Therapeutic Radiology and Oncology. J. L. R. R. was supported by grants from the National Institute of Health (RO1 CA43198 and PO1 CA75556).
PY - 2003/11
Y1 - 2003/11
N2 - Purpose. Abnormally high levels of the cyclooxygenase (COX)-2 isozyme as well as the prostaglandin metabolites produced by the COX pathway have been observed in a variety of malignancies, including cancers of the skin, pancreas, colon, breast, cervix, prostate, and head and neck. Furthermore, exogenous genotoxic agents, including ionizing radiation (IR), have been shown to induce cellular transformation and to elevate COX-2 activity, whereas exposure to agents that specifically inhibit COX-2 activity have been shown to inhibit transformation. These data suggest a possible role of COX-2 both in IR-mediated cellular transformation processes and cell death. Materials and methods: C3H 10T1/2 and/or HeLa cells were treated with N-[2-(cyclohexyloxy)-4-nitrophenyl]- methanesulfonamide (NS-398) and/or exposed to IR. Following treatment, cells were assayed for neoplastic transformation, clonogenicity, growth rates, cell cycle distribution, micronuclei formation and DNA damage by established methodologies. Statistical tests were performed on data as described. Results: In the present study, experiments in normal murine fibroblast C3H 10T1/2 cells demonstrated that the chemical inhibition of COX-2 activity with moderate closes of NS-398 abrogated IR-incluced transformation events by fourfold and protected irradiated C3H 10T1/2 cells from clonogenic cell death. Considering that these doses of NS-398 had no significant effect on cellular proliferation or cell cycle distribution in C3H 10T1/2 cells, the results suggest that inhibition of COX-2 either increases DNA repair or prevents the accumulation of DNA damage. In supplemental experiments, treatment with NS-398 caused a 1. 5-fold reduction in IR-induced micronuclei formation and a significant decrease in DNA damage. Conclusions: These results suggest a role for COX-2 inhibitors in the normal tissue response to IR when administered at therapeutically achievable doses and therefore may have clinical implications for radiation oncology patients in the prevention of IR-induced malignancy.
AB - Purpose. Abnormally high levels of the cyclooxygenase (COX)-2 isozyme as well as the prostaglandin metabolites produced by the COX pathway have been observed in a variety of malignancies, including cancers of the skin, pancreas, colon, breast, cervix, prostate, and head and neck. Furthermore, exogenous genotoxic agents, including ionizing radiation (IR), have been shown to induce cellular transformation and to elevate COX-2 activity, whereas exposure to agents that specifically inhibit COX-2 activity have been shown to inhibit transformation. These data suggest a possible role of COX-2 both in IR-mediated cellular transformation processes and cell death. Materials and methods: C3H 10T1/2 and/or HeLa cells were treated with N-[2-(cyclohexyloxy)-4-nitrophenyl]- methanesulfonamide (NS-398) and/or exposed to IR. Following treatment, cells were assayed for neoplastic transformation, clonogenicity, growth rates, cell cycle distribution, micronuclei formation and DNA damage by established methodologies. Statistical tests were performed on data as described. Results: In the present study, experiments in normal murine fibroblast C3H 10T1/2 cells demonstrated that the chemical inhibition of COX-2 activity with moderate closes of NS-398 abrogated IR-incluced transformation events by fourfold and protected irradiated C3H 10T1/2 cells from clonogenic cell death. Considering that these doses of NS-398 had no significant effect on cellular proliferation or cell cycle distribution in C3H 10T1/2 cells, the results suggest that inhibition of COX-2 either increases DNA repair or prevents the accumulation of DNA damage. In supplemental experiments, treatment with NS-398 caused a 1. 5-fold reduction in IR-induced micronuclei formation and a significant decrease in DNA damage. Conclusions: These results suggest a role for COX-2 inhibitors in the normal tissue response to IR when administered at therapeutically achievable doses and therefore may have clinical implications for radiation oncology patients in the prevention of IR-induced malignancy.
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U2 - 10.1080/09553000310001621400
DO - 10.1080/09553000310001621400
M3 - Article
C2 - 14698956
AN - SCOPUS:0347949519
SN - 0955-3002
VL - 79
SP - 879
EP - 888
JO - International Journal of Radiation Biology
JF - International Journal of Radiation Biology
IS - 11
ER -