Carcinogenesis Advance Access originally published online on April 7, 2005
Carcinogenesis 2005 26(7):1256-1262; doi:10.1093/carcin/bgi077
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Carcinogenesis vol.26 no.7 © Oxford University Press 2005; all rights reserved.
Prostate cancer risk and DNA damage: translational significance of selenium supplementation in a canine model
1 Department of Veterinary Clinical Sciences and 2 Department of Veterinary Pathobiology, Purdue University, West Lafayette, IN 47907, USA, 3 Bostwick Laboratories, Richmond, VA 23294, USA, 4 Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA, 5 University of Missouri-Columbia Research Reactor Center, Columbia, MO 65211, USA and 6 Gerald P.Murphy Cancer Foundation, West Lafayette, IN 47906, USA
* To whom correspondence should be addressed at: Gerald P.Murphy Cancer Foundation, 3000 Kent Avenue, Suite E2100, West Lafayette, IN 47906, USA. Tel: +1 765 494 9271; Fax: +1 765 775 1006; Email: dwaters{at}gpmcf.org
Daily supplementation with the essential trace mineral selenium significantly reduced prostate cancer risk in men in the Nutritional Prevention of Cancer Trial. However, the optimal intake of selenium for prostate cancer prevention is unknown. We hypothesized that selenium significantly regulates the extent of genotoxic damage within the aging prostate and that the relationship between dietary selenium intake and DNA damage is non-linear, i.e. more selenium is not necessarily better. To test this hypothesis, we conducted a randomized feeding trial in which 49 elderly beagle dogs (physiologically equivalent to 62–69-year-old men) received nutritionally adequate or supranutritional levels of selenium for 7 months, in order to mimic the range of dietary selenium intake of men in the United States. Our results demonstrate an intriguing U-shaped dose–response relationship between selenium status (toenail selenium concentration) and the extent of DNA damage (alkaline Comet assay) within the prostate. Further, we demonstrate that the concentration of selenium that minimizes DNA damage in the aging dog prostate remarkably parallels the selenium concentration in men that minimizes prostate cancer risk. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a new approach to bridge the gap between laboratory and human studies that can be used to select the appropriate dose of anticancer agents for large-scale human cancer prevention trials. From the U-shaped dose–response, it follows that not all men will necessarily benefit from increasing their selenium intake and that measurement of baseline nutrient status should be required for all individuals in prevention trials to avoid oversupplementation.
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