Cancer Prevention/Risk Assessments from DNA Modification Levels

Roswell Park Cancer Institute Corp, Buffalo NY

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Abstract

DESCRIPTION (provided by applicant): Recent epidemiological studies have shown that moderate supplementation of the diet by antioxidants reduces the risk of cancer. These results contrast with the results of earlier studies involving much larger doses of antioxidants that produced adverse effects. The history of antioxidant usage in the prevention of cancer shows that a better indicator of oxidative DNA damage is needed to judge the efficacy of antioxidants. Recently an assay was developed at RPCI that provides a more comprehensive and rational assessment of oxidative DNA damage. The assay measures 5 base modifications, at least two of which are clearly related to hydroxyl radical activity. An intervention study is proposed in which non-melanoma dermatology patients/healthy volunteer will take the same combination of antioxidants and minerals for 8 weeks that has been shown to reduce cancer in men by 31%. It is anticipated 40 participants will be recruited to the study. The RPCI assay will be used to measure oxidative DNA damage pre and post intervention. The amount of supplement and individual base-line levels appear to be key factors in determining whether antioxidants can be efficacious. The goal of our research is to establish a molecular basis for the effects of antioxidant intervention. To this end the assay developed at RPCI provides a much more comprehensive and rational assessment of oxidative stress than the measurement of 8-oxo-7,8-dihydroguanine. The five most prominent DNA modifications detected by this methodology contain: (a) nucleosides that have lost their base constituent, (b) pyrimidine nucleosides having the base degraded to a formamide remnant, (c) an imidazolidene modification of deoxycytosine, (d) a formamide modification derived from deoxyguanosine (Fapy G) and (e) a hydroxyhydroperoxy derivative of thymidine. The 8-oxo-7, 8-dihydroguanine lesion, although observed, was not among the most prominent modifcations observed in the RPCI comprehensive survey.