Modulation of DNA hypomethylation as a surrogate endpoint biomarker for chemoprevention of colon cancer.
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.
Tao
Lianhui
L
Department of Pathology, Medical College of Ohio, Toledo, Ohio, USA.
Wang
Wei
W
Kramer
Paula M
PM
Lubet
Ronald A
RA
Steele
Vernon E
VE
Pereira
Michael A
MA
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
D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D044503:5-Methylcytosine; D004247:DNA