title: Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients.
abstract: Resveratrol is a phytochemical with chemopreventive activity in preclinical rodent models of colorectal carcinogenesis. Antiproliferation is one of the many chemopreventive modes of action it has been shown to engage in. Concentrations of resveratrol, which can be achieved in human tissues after p.o. administration, have not yet been defined. The purpose of this study was to measure concentrations of resveratrol and its metabolites in the colorectal tissue of humans who ingested resveratrol. Twenty patients with histologically confirmed colorectal cancer consumed eight daily doses of resveratrol at 0.5 or 1.0 g before surgical resection. Resveratrol was found to be well tolerated. Normal and malignant biopsy tissue samples were obtained before dosing. Parent compound plus its metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-O-sulfate, resveratrol sulfate glucuronide, and resveratrol disulfate were identified by high-performance liquid chromatography (HPLC) with UV or mass spectrometric detection in colorectal resection tissue. Quantitation was achieved by HPLC/UV. Cell proliferation, as reflected by Ki-67 staining, was compared in preintervention and postintervention tissue samples. Resveratrol and resveratrol-3-O-glucuronide were recovered from tissues at maximal mean concentrations of 674 and 86.0 nmol/g, respectively. Levels of resveratrol and its metabolites were consistently higher in tissues originating in the right side of the colon compared with the left. Consumption of resveratrol reduced tumor cell proliferation by 5% (P = 0.05). The results suggest that daily p.o. doses of resveratrol at 0.5 or 1.0 g produce levels in the human gastrointestinal tract of an order of magnitude sufficient to elicit anticarcinogenic effects. Resveratrol merits further clinical evaluation as a potential colorectal cancer chemopreventive agent.
authors.affiliation: Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom. kp23@le.ac.uk
authors.forename: Ketan R
authors.initials: KR
authors.lastname: Patel
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Brown
authors.forename: Donald J L
authors.initials: DJ
authors.lastname: Jones
authors.forename: Robert G
authors.initials: RG
authors.lastname: Britton
authors.forename: David
authors.initials: D
authors.lastname: Hemingway
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Miller
authors.forename: Kevin P
authors.initials: KP
authors.lastname: West
authors.forename: Tristan D
authors.initials: TD
authors.lastname: Booth
authors.forename: Marjorie
authors.initials: M
authors.lastname: Perloff
authors.forename: James A
authors.initials: JA
authors.lastname: Crowell
authors.forename: Dean E
authors.initials: DE
authors.lastname: Brenner
authors.forename: William P
authors.initials: WP
authors.lastname: Steward
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Gescher
authors.forename: Karen
authors.initials: K
authors.lastname: Brown
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D048708:Cell Growth Processes / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000077185:Resveratrol; D013267:Stilbenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019394:Ki-67 Antigen; D013267:Stilbenes; D000077185:Resveratrol