Evaluation of cyclooxygenase-2 inhibition in an orthotopic murine model of lung cancer for dose-dependent effect

Objectives: Cyclooxygenase-2 plays a role in growth, apoptosis, angiogenesis, and metastasis in lung cancer. Inhibition of cyclooxygenase-2 with celecoxib has been shown to inhibit tumor growth. We evaluated the effect of increasing doses of celecoxib in a murine model of human lung cancer. Methods: Human lung adenocarcinoma cells (A549) were implanted in the left lung upper lobe of mice with severe combined immunodeficiency syndrome. Mice were randomly assigned to 4 groups at implantation (n = 10 per group): control, 125 mg/kg chow, 500 mg/kg chow, 1000 mg/kg chow. After 3 weeks, mice were killed, and a blinded observer measured total tumor volume. The dose effect of celecoxib was examined in vitro by studying cell proliferation, expression of cyclooxygenase-2 (mRNA and protein), and production of prostaglandin E₂ in unstimulated and interleukin 1β-stimulated cells. Results: All 40 mice survived for 3 weeks with no observed toxicities. Total tumor volume was inhibited in each celecoxib group (P =. 0038, Welch analysis of variance): 206.7 ± 119.5 mm³ (control group), 41.4 ± 54.0 mm ³ (low-dose group), 34.5 ± 39.3 mm³ (medium-dose group), and 27.3 ± 53.6 mm³ (high-dose group). In vitro celecoxib was effective at inhibiting production of prostaglandin E₂, even in stimulated cells, although little effect was seen on cyclooxygenase-2 protein levels. Inhibition of proliferation was evident only at doses that exceeded those used in the animal model. Conclusion: Inhibition of cyclooxygenase-2 with low-dose celecoxib restricted the growth of lung cancer in this model. This might be mediated by prostaglandin E₂. Higher doses of celecoxib afforded no additional benefit. Chronic therapy with low-dose cyclooxygenase-2 inhibition has the potential to influence tumor progression in non-small cell lung cancer.