title: Modulation of DNA hypomethylation as a surrogate endpoint biomarker for chemoprevention of colon cancer.
abstract: Surrogate end-point biomarkers are being developed as indicators of the efficacy of chemopreventive agents. These biomarkers are molecular and biological end-points that can be modulated by chemopreventive agents in accordance with their efficacy to prevent cancer. DNA hypomethylation is a common alteration found in colon tumors that has the potential of being modulated by chemopreventive agents and thus being useful as a surrogate end-point biomarker. Agents that were either effective or ineffective in preventing colon cancer were evaluated for the ability to modulate DNA hypomethylation in azoxymethane-induced colon tumors in male F344 rats. DNA methylation was determined by Dot Blot Analysis using a mouse monoclonal anti-5-methylcytosine antibody. Colon tumors had a 70% reduction in DNA methylation relative to normal colonic mucosa. DNA methylation in the tumors was increased by 7 days of treatment with agents that have been shown to prevent colon cancer (calcium chloride, alpha-diflouromethylornithine [DFMO], piroxicam, and sulindac), whereas agents shown not to prevent colon cancer in rats (low dose aspirin, 2-carboxyphenyl retinamide [2-CPR], quercetin, 9-cis retinoic acid, and rutin) did not increase DNA methylation. The results suggest that the ability to reverse the DNA hypomethylation in colon tumors could be useful as a surrogate end-point biomarker for chemoprevention of colon cancer.
authors.affiliation: Department of Pathology, Medical College of Ohio, Toledo, Ohio, USA.
authors.forename: Lianhui
authors.initials: L
authors.lastname: Tao
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Paula M
authors.initials: PM
authors.lastname: Kramer
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pereira
mesh_terms: D044503:5-Methylcytosine / Q000032:analysis / Q000276:immunology; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004247:DNA / Q000187:drug effects; D019175:DNA Methylation; D015151:Immunoblotting; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D044503:5-Methylcytosine; D004247:DNA