Evaluation of cyclooxygenase-2 inhibition in an orthotopic murine model of lung cancer for dose-dependent effect.
OBJECTIVE
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 E 2 in unstimulated and interleukin 1beta-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 mm 3 (control group), 41.4 +/- 54.0 mm 3 (low-dose group), 34.5 +/- 39.3 mm 3 (medium-dose group), and 27.3 +/- 53.6 mm 3 (high-dose group). In vitro celecoxib was effective at inhibiting production of prostaglandin E 2 , 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.


CONCLUSIONS
Inhibition of cyclooxygenase-2 with low-dose celecoxib restricted the growth of lung cancer in this model. This might be mediated by prostaglandin E 2 . 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.
Sievers
Eric M
EM
Department of Cardiothoracic Surgery, University of Southern California, Keck School of Medicine, the Hastings Thoracic Oncology Laboratory, Los Angeles, Calif, USA.
Bart
Robert D
RD
Backhus
Leah M
LM
Lin
Yuanguang
Y
Starnes
Margaret
M
Castanos
Roberto
R
Starnes
Vaughn A
VA
Bremner
Ross M
RM
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000068579:Celecoxib; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*
D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib