Journal
CANCER PREVENTION RESEARCH
Volume 10, Issue 12, Pages 729-737Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1940-6207.CAPR-17-0091
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Funding
- NIH: the Gastro-Intestinal SPORE [P50 CA130810]
- University of Michigan Comprehensive Cancer Center [P30 CA046592]
- University of Michigan Clinical Research Center [UL1RR024986]
- University of Pittsburgh Cancer Institute [P30 CA047904]
- University of Michigan Clinical Translational Resource Allocation Committee (CTRAC)
- Kutsche Family Memorial Endowment
- Rose and Lawrence C. Page Foundation
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This clinical trial developed a personalized dosing model for reducing prostaglandin E2 (PGE2) in colonic mucosa using w-3 fatty acid supplementation. The model utilized serum eicosapentaenoic acid (EPA, w-3): arachidonic acid (AA, w-6) ratios as biomarkers of colonic mucosal PGE2 concentration. Normal human volunteers were given low and high w-3 fatty acid test doses for 2 weeks. This established a slope and intercept of the line for dose versus serum EPA: AA ratio in each individual. The slope and intercept was utilized to calculate a personalized target dose that was given for 12 weeks. This target dose was calculated on the basis of a model, initially derived from lean rodents, showing a log-linear relationship between serum EPA: AA ratios and colonic mucosal PGE2 reduction. Bayesian methods allowed addition of human data to the rodent model as the trial progressed. The dosing model aimed to achieve a serum EPA: AA ratio that is associated with a 50% reduction in colonic PGE2. Mean colonic mucosal PGE2 concentrations were 6.55 ng/mg protein (SD, 5.78) before any supplementation and 3.59 ng/mg protein (SD, 3.29) after 12 weeks of target dosing. In secondary analyses, the decreases in PGE2 were significantly attenuated in overweight and obese participants. This occurred despite a higher target dose for the obese versus normal weight participants, as generated by the pharmacodynamic predictive model. Large decreases also were observed in 12-hydroxyicosatetraenoic acids, and PGE3 increased substantially. Future biomarker-driven dosing models for cancer prevention therefore should consider energy balance as well as overall eicosanoid homeostasis in normal tissue. (C) 2017 AACR.
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