Carcinogenesis Advance Access published online on June 17, 2004
Carcinogenesis, doi:10.1093/carcin/bgh209
© 2004 by Oxford University Press
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1 Department of Pathology, Medical College of Ohio, Toledo, OH 43614
* To whom correspondence should be addressed. E-mail: Pereira-1{at}medctr.osu.edu.
The ability of celecoxib and
Revised May 18, 2004
Accepted June 6, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Modulation of DNA methylation and the methylation of the estrogen receptor-
gene by celecoxib and difluoromethylornithine in rat colon tumors
2 Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892
Abstract 
-difluoromethylornithine (DFMO) to modulate the DNA hypomethylation and the hypermethylation of the estrogen receptor- gene in colon tumors was evaluated as potential biomarkers for chemoprevention. Colon tumors were induced in rats by azoxymethane. Celecoxib, (500 mg/kg), DFMO (100, 1,000, and 3,000 mg/kg), or celecoxib + 1,000 mg/kg DFMO were administered in the diet for 7 or 28 days prior to sacrifice at week 37. Relative to the normal colon mucosa, colon tumors contained hypomethylated DNA and hypermethylation of the promoter plus exon-1 region of the estrogen receptor- gene. Limited treatment with celecoxib and DFMO (1,000 and 3,000 mg/kg) reversed the DNA hypomethylation. Administering 1,000 and 3,000 mg/kg -difluoromethylornithine for 7-days decreased the number of methylated CpG sites from 5.00 ± 0.95 to 3.83 ± 0.75 and 1.75 ± 0.49 that was decreased to 0.50 ± 0.26 following administration of 1,000 mg/kg for 28 days. Celecoxib administered for 7 and 28 days reduced the number of methylated sites to 4.25 ± 0.48 and 1.5 ± 0.50. The combination of celecoxib and -difluoromethylornithine reduced the number to 0.20 ± 0.20 at both 7 and 28 days. In parallel with the hypermethylation of the estrogen receptor- gene, the mRNA expression of the gene was decreased in colon tumors and was increased by celecoxib, DFMO or the combination. Celecoxib and DFMO reversed DNA hypomethylation and the hypermethylation of the estrogen receptor- gene in colon tumors supporting the hypothesis that modulation of methylation is a biomarker of chemoprevention.
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