Evaluating COX-2 inhibition in an orthotopic murine model of lung cancer for dose-dependent effect
E. M. Sievers, R. D. Bart, L. M. Backhus, C. A. DiPerna, R. Costanos, V. A. Starnes, R. M. Bremner. ,
Keck School of Medicine, Univerisity of Southern California, Los Angeles, CA
Objectives: Cyclooxygenase-2 (COX-2) is expressed in most lung cancers and plays a role in growth, apoptosis, angiogenesis, and metastases. Inhibition of COX-2 with celecoxib has been shown to inhibit tumor growth. It is not known whether this effect is dose-dependent. We evaluated the efficacy 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 SCID mice (2x106cells). Mice were randomly assigned to 4 groups at implantation (n=10/group); control, 25mg celecoxib/kg body weight/day, 100mg celecoxib/kg body weight/day, 200mg celecoxib/kg body weight/day. After 3-weeks, mice were killed and a blinded observer measured total tumor volume. COX-2 expression of orthotopic tumors was established by PCR and immunohistochemistry.
Results: All 40 mice survived 3-weeks with no observed toxicities. Total tumor volume was inhibited in each celecoxib group. The mean tumor volumes are shown in Figure 1. Tumors from all treatment groups express COX-2.
Conclusion: Inhibition of COX-2 with low dose celecoxib retarded the growth of cancer in this model using this cell line. Higher doses of celecoxib afforded no additional benefit and may be unnecessary. Chronic therapy with low dose COX-2 inhibition has the potential to influence tumor progression in NSCLC.
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