Abstract 1854: Effects of supplemental antioxidant micronutrients on oxidative DNA damage marker in normal colorectal mucosa: A randomized clinical trial

Abstract

Abstract Background: Basic science and animal studies suggests that oxidative stress plays a role in colorectal oncogenesis. Smokers are reported to have increased oxidative DNA lesions in transformed colorectal epithelial cells and increased colorectal cancer risk; however, the majority of observational and clinical studies report weak or null associations between oxidative stress and risk of colorectal neoplasia. To address this we conducted, a pilot, randomized, double blinded, placebo controlled clinical trial to test the effects of an antioxidant micronutrient combination on a marker of oxidative DNA damage, 8-hydroxy-2’-deoxyguanosine (8-OH-dG), in the normal colorectal mucosa. Methods: Forty-seven patients diagnosed with at least one pathology confirmed sporadic colorectal adenoma were given a daily antioxidant micronutrient combination (800mg dl-alpha-tocopherol acetate, 24 mg beta carotene, 1.0 g vitamin C, 200µg l-selenomethionine, 7.2 mg riboflavin, 80 mg niacin, 60 mg zinc, 5 mg manganese) or placebo for 4 months. A subset of patients (n=33) for whom tissue was available pre- and post supplementation was used in this analysis. 8-OH-dG was detected in biopsies of normal-appearing colorectal mucosa using standardized automated immunohistochemistry. Overall labeling and distribution of 8-OH-dG within the colon crypts were quantified by novel image analysis methods. Treatment effects were assessed using a MIXED effects model as implemented in SAS v9.2. Results: Relative to the placebo group, in the antioxidant group 8-OH-dG labeling decreased 13% (p=0.87) along the full length of crypts, 27% (p=0.49) in the upper third of crypts, 27 % (p=0.53) in the middle third of crypts, and 8% (p=0.92) in the bottom third of crypts. Among smokers (n=14), relative to the placebo group, in the antioxidant group 8-OH-dG labeling increased 6% (p=0.82) in the upper third of crypts, 28% (p=0.65) in the middle third of crypts, and 51% (p=0.50) in the bottom third of crypts. In non-smokers (n=18), relative to the placebo group, in the antioxidant group 8-OH-dG expression decreased 23% (p=0.55) in the upper third of crypts, 34% (p=0.44) in the middle third of crypts, and 24% (p=0.57) in the bottom third of crypts. Discussion: These preliminary findings, while not statistically significant 1) suggest that antioxidants may modulate oxidative DNA damage in the normal-appearing human colorectal epithelium – potentially modified by smoking status; 2) provide support for the use of 8-OH-dG as a potential treatable biomarker of risk for colorectal neoplasms; and 3) provide support for extending this investigation in a larger, more definitive trial. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1854. doi:10.1158/1538-7445.AM2011-1854