Antitumor enhancement of celecoxib, a selective Cyclooxygenase-2 inhibitor, in a Lewis lung carcinoma expressing Cyclooxygenase-2

Won Park, Young Taek Oh, Jae Ho Han, Hongryull Pyo

The goal of this study was to determine the effects of a selective Cyclooxygenase (COX)-2 inhibitor on the inhibition of tumor growth and pulmonary metastasis in a Lewis Lung Carcinoma (LLC) animal model. For immunoblot analysis of COX-2 and PGE2, cells were treated with irradiation in the presence or absence of celecoxib. The right thighs of male, 6-week old C57/BL mice were subcutaneously injected with 1 x 106 LLC cells. The animals were randomized into one of six groups: (1) no treatment, (2) 25 mg/kg celecoxib daily, (3) 75 mg/kg celecoxib daily, (4) 10 Gy irradiation, (5) 10 Gy irradiation plus 25 mg/kg celecoxib daily, and (6) 10 Gy irradiation plus 75 mg/kg celecoxib daily. Mice were irradiated only once, and celecoxib was administered orally. Mice were irradiated with 4-MV photons once the tumor volume of the control group reached 500 mm3. All mice were sacrificed when the mean tumor volume of control animals grew to 4000 mm3. The left lobes of the lungs were extracted for the measurement of metastatic nodules. Irradiation resulted in a dose-dependent increase in PGE2 production. PGE2 synthesis decreased markedly after treatment with celecoxib alone or in combination with irradiation. Compared to mice treated with low dose celecoxib, mean tumor volume decreased significantly in mice treated with a high dose of celecoxib with or without irradiation. Mice treated with a high dose celecoxib alone, with irradiation alone, or with irradiation plus celecoxib had markedly fewer metastatic lung nodules than controls. The mean metastatic area was the smallest for mice treated with irradiation plus a high dose celecoxib. Oral administration of high dose celecoxib significantly inhibited tumor growth, as compared to a low dose treatment. Radiotherapy in combination with high dose celecoxib delayed tumor growth and reduced the number of pulmonary metastases to a greater extent than celecoxib or radiotherapy alone.