Journal Article

Anatomical site-specific response to DNA damage is related to later tumor development in the rat azoxymethane colon carcinogenesis model

Mee Young Hong, Robert S. Chapkin, Jeffrey S. Morris, Naisyin Wang, Raymond J. Carroll, Nancy D. Turner, Wen Chi L. Chang, Laurie A. Davidson and Joanne R. Lupton

in Carcinogenesis

Volume 22, issue 11, pages 1831-1835
Published in print November 2001 | ISSN: 0143-3334
Published online November 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.11.1831
Anatomical site-specific response to DNA damage is related to later tumor development in the rat azoxymethane colon carcinogenesis model

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There is now general agreement that the etiology of proximal and distal colon cancers may differ, thus prompting renewed interest in understanding anatomical site-specific molecular mechanisms of tumor development. Using a 2×2×2 factorial design with male Sprague–Dawley rats (corn oil, fish oil; pectin, cellulose; plus or minus azoxymethane injection) we found a greater than 2-fold difference (P < 0.001) in tumor incidence proximally versus distally (prox/dist ratio: corn oil, 2.25; fish oil, 2.61). The purpose of the present study was to determine if the higher degree of proximal versus distal tumors in our model system could be accounted for by differences between these two sites in initial DNA damage, response to that damage or an effect of diet at one site but not the other. DNA damage was assessed by quantitative immunohistochemistry of O6-methylguanine adducts; repair by measurement of O6-methylguanine-DNA alkyltransferase and removal was determined by measurement of targeted apoptosis. Although overall initial DNA damage was similar at both sites, in the distal colon there was a greater expression of repair protein (P < 0.001) and a greater degree of targeted apoptosis (P < 0.0001). There was also a reduction in DNA damage in the distal colon of rats consuming fish oil. Together, these results suggest that the lower tumor incidence in the distal colon may be a result of the capacity to deal with initial DNA damage by the distal colon, as compared with the proximal colon. Therefore, the determination of site-specific mechanisms in tumor development is important because distinct strategies may be required to protect against cancer at different sites.

Keywords: AOM, azoxymethane; ATase, O6-methylguanine-DNA-alkyltransferase; O6-dmetG, O6-deoxymethylguanine.

Journal Article.  4167 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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