Introduction: Colorectal cancer (CRCA) is the second leading cause of cancer deaths in the U.S. Of the patients who die, most will succumb with metastatic disease to the liver. An impact on the early progression of metastatic disease could be important in the treatment of CRCA. COX-2 is an enzyme that is important regulator of prostaglandin synthesis and is involved in pathways such as angiogenesis during the progression of adenoma to carcinoima in the colon. The purpose of this study is to examine the hypothesis that early inhibition of COX-2 prior to the establishment of large metastases can decrease proliferation of metastatic disease in the liver from CRCA. Methods: C57BL/6 mice were separated into WT untreated controls and those treated with celecoxib (1000mg/kg diet). Both groups underwent orthotopic splenic injection of 1X105 syngeneic murine colon carcinoma cells that had been transfected with a luciferase reporter gene. To model treatment of patients at risk for the development of metastases, the celecoxib treated group was begun on drug 72 hours prior to orthotopic splenic injection. Mice were continued on therapeutic levels for the duration of the 14 day study. Liver metastases in both groups were followed using bioluminescence imaging for 14 days. Results: At the end of this period, animals were sacrificed and examined. Comparison of liver weights (in grams) in the two groups at the end of 14 days showed WT controls 4.63g (± 0.76) and the celecoxib treated group 2.7g (± 0.74), reflecting increased gross metastases in the liver in controls. Quantitation of photon counts from bioluminescence data (average total flux) acquired at 14 days post tumor cell injection, corroborated the increased burden of metastases in the WT animals 12.9x106 (± 1.5x106) vs. 2.0x106 (± 0.7x106) in celecoxib treated animals. Conclusions: Treatment with the COX-2 inhibitor celecoxib significantly decreased the metastatic burden of CRCA in the liver in an orthotopic murine model. Further study to understand the mechanism of this effect is warranted. COX-2 inhibition in patients at risk for developing metastatic colorectal cancer could be clinically beneficial.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]