Acute changes in colonic PGE2 levels as a biomarker of efficacy after treatment of the Pirc (F344/NTac-Apc am1137) rat with celecoxib
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This study sought to evaluate short-term treatment with COX-2 inhibitors and acute changes in colonic PGE2 levels as predictors of long-term efficacy in a genetic model of colorectal cancer.
Celecoxib oral suspension (40 mg/kg BID) was dosed to Apc-mutant Pirc (F344/NTac-Apcam1137) rats for 4 days (short-term group), or the equivalent dose of 1500 ppm celecoxib was administered in the diet for 4 months (long-term group). Percent inhibition of colonic PGE2 was calculated, and the reduction in colonic PGE2 was assessed in relation to suppression of adenomatous colon polyps.
Colonic mucosa PGE2 was fourfold higher in Pirc than in F344 wild-type rats (21 vs. 5.6 pg/mg epithelial tissue), due at least in part to higher COX-2 expression, and this was confirmed by elevated PGE2-d11 levels in Pirc colonic S9 incubations. In the 4-day study, dose-dependent reductions in PGE2 were observed in colonic epithelium (-33% (P>0.05) and -57% (P=0.0012)), after low- and high-dose celecoxib treatments of 4 mg/kg and 40 mg/kg (bid), respectively. In the 4-month study, 1500 ppm celecoxib suppressed colonic epithelium PGE2 by 43.5%, and tumor multiplicity by 80% (P<0.0015). Suppression of plasma 6-keto PGF1α also was corroborated following long-term treatment with 1500 ppm celecoxib (P<0.05).
Acute changes in colonic mucosa PGE2 provided a rapid means of predicting long-term chemopreventive effects from celecoxib, and might be useful for screening of new COX-2 inhibitor compounds.
KeywordsPirc rat FAP Prostaglandin E2 Chemoprevention COX-2 inhibitor Celecoxib
Adenomatous polyposis coli
Familial adenomatous polyposis
Food and Drug Administration
- Pirc rat
Polyposis in the rat colon rat (F344/NTac-Apcam1137)
Half-maximal inhibitory concentration
Liquid chromatography–mass spectrometry
Non-steroidal anti-inflammatory drug
- 6-keto PGF1α
6-Keto prostaglandin F1α
We sincerely appreciate Dr. Roderick H. Dashwood (Texas A&M University) for the manuscript reviewing, Dr. Vincent H. Tam (University of Houston) and Lawrence N. Kwong (University of Texas MD Anderson Cancer Center) for the professional advice. We thank our lab mates including Rashim Singh, Lijun Xie, Yifan Tu, Dinh Bui, Zuoxu Xie, and Lu Wang who helped us to collect the rat tissue. The work is supported by a CPRIT Grant (RP180863) and NIGMS Grant (GM-070737) to Hu.
Compliance with ethical standards
Conflict of interest
The authors declare no potential conflicts of interest.
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