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|Title:||Pre Clinical and Clinical Studies of the Effects of Resveratrol, a Phytochemical With Potential Chemopreventive Efficacy|
|Authors:||Brown, Victoria Alison|
|Supervisors:||Steward, Will P.|
|Presented at:||University of Leicester|
|Abstract:||Resveratrol, found in grape skins and red wine, has potential chemopreventive activity in vitro at concentrations ≥5μM. This project explored the tolerability, pharmacokinetics and pharmacodynamics of resveratrol in two clinical phase 1 studies. In vivo data were supported by in vitro studies designed to mimic the daily dosing protocol, using concentrations observed clinically. Forty healthy volunteers received 29 oral daily doses of 0.5, 1.0, 2.5 and 5.0g resveratrol and 20 colorectal cancer patients 8 oral daily doses of 0.5 and 1.0g prior to surgical resection. The pharmacodynamics of resveratrol were assessed by measuring changes in plasma levels of proteins involved in the IGF system, oxidative DNA damage in whole blood and colorectal tissue (M1dG), effects on inflammatory pathways in plasma (PGE2) and colorectal tissue (COX-2), as well as colorectal tissue proliferation (Ki-67). No serious adverse events were reported. In volunteers, mean peak plasma levels of resveratrol across the dose groups ranged from 44.7-954ng/mL (0.20-4.20μM), and for the main metabolite, resveratrol-3-sulfate, were 4-13 fold-higher. Despite low systemic bioavailability, resveratrol concentrations associated with potential chemopreventive efficacy were observed in colorectal tumour tissue with a mean of 44.0nmol/g detected in patients receiving the 1.0g dose (range 0.30-195nmol/g). Post dosing, IGF-1 levels were reduced by 8% (P=0.03) in volunteers and by 33% (P<0.001) in colorectal cancer patients. In tissue, a reduction in cell proliferation of 5.5% (P=0.05) was observed, whilst there was an increase in COX-2 staining (P=0.004). Apart from the 2.5g dose in volunteers, where a significant increase was observed in blood M1dG (21.6%, P=0.02), resveratrol did not significantly affect plasma PGE2 or markers of DNA damage in either study. In cultured colon cancer cells, daily exposure to resveratrol was associated with increased antiproliferative activity compared to an equivalent single dose, supporting the indication that chronic administration may cause pharmacodynamic changes in humans. The work presented here suggests resveratrol has potential as a cancer chemopreventive agent and controlled clinical trials are now warranted.|
|Appears in Collections:||Theses, Dept. of Cancer Studies & Molecular Medicine|
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