Effects of a Grapevine Shoot Extract Containing Resveratrol and Resveratrol Oligomers on Intestinal Adenoma Development in Mice: In Vitro and In Vivo Studies.

Scope: Evidence suggests that the dietary consumption of plant extracts containing polyphenols might help prevent the onset of cancers of the gastrointestinal tract. In the present study, the chemopreventive and antiproliferative efficacy of a grapevine shoot extract (Vineatrol®30) containing resveratrol and resveratrol oligomers is investigated in vivo and in vitro.

Methods And Results: The in vivo study is performed using Apc mice on a high-fat diet, which represents a model of human adenomatous polyposis, while the potential of the extract as well as some of its isolated constituents to inhibit intestinal adenoma cell proliferation in vitro is investigated using APC10.

Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice.

Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials to assess efficacy. To challenge the assumption that "more is better," we compared the pharmacokinetics and activity of a dietary dose with an intake 200 times higher. The dose-response relationship for concentrations generated and the metabolite profile of [(14)C]-resveratrol in colorectal tissue of cancer patients helped us to define clinically achievable levels.

Search for novel circulating cancer chemopreventive biomarkers of dietary rice bran intervention in Apc(Min) mice model of colorectal carcinogenesis, using proteomic and metabolic profiling strategies.

Scope: There is strong epidemiological evidence indicating that consumption by humans of whole-grain foods including rice bran may be associated with a low incidence of cancer, especially in the colorectum. Molecular processes associated with cancer development may be retarded by fiber consumption. Consequently, intervention with dietary fiber might be suitable as a cancer chemoprevention strategy in high-risk populations.

Inhibition of prostate cancer cell growth by 3',4',5'-trimethoxyflavonol (TMFol).

Purpose: TMFol (3',4',5'-trimethoxyflavonol) is a synthetic analogue of the naturally occurring flavonol fisetin and quercetin, which have been considered of potential usefulness in the management of prostate cancer. We investigated whether TMFol may have preclinical features superior to those of its two flavonol congeners.

Methods: The ability of the three flavonols to compromise prostate cancer cell survival was tested in four prostate cancer cell types 22Rv1, TRAMP C2, PC-3 and LNCaP.

Prolonged biologically active colonic tissue levels of curcumin achieved after oral administration--a clinical pilot study including assessment of patient acceptability.

Curcumin, the main constituent of turmeric, is suspected to possess cancer chemopreventive properties. Pharmacokinetic and pharmacodynamic parameters have been reported, but few data exist describing whether methodologies are suitably robust for curcuminoid detection in colonic biopsy specimens. Information on the acceptability of prolonged administration of daily curcumin is not available.

Dietary intake of rosmarinic acid by Apc(Min) mice, a model of colorectal carcinogenesis: levels of parent agent in the target tissue and effect on adenoma development.

Scope: Rosmarinic acid (RA), a constituent of culinary herbs is considered to possess cancer chemopreventive properties. It has been shown to inhibit the development of cancer in preclinical models but data are conflicting and whether it can protect against gastrointestinal malignancies in vivo has not been examined. This study aimed to investigate the effect of RA on the development of intestinal adenomas in the Apc(Min) mouse model of colorectal carcinogenesis, and to correlate efficacy with levels of RA achieved in the plasma and gastrointestinal tract.

Tissue distribution and metabolism of the putative cancer chemopreventive agent 3',4',5'-trimethoxyflavonol (TMFol) in mice.

3',4',5'-Trimethoxyflavonol (TMFol) is a synthetic flavonol with preclinical cancer chemopreventive properties. The hypothesis was tested that, in mice, p.o.

Resveratrol in human cancer chemoprevention--choosing the 'right' dose.

There is now robust preclinical evidence to suggest that resveratrol possesses cancer chemopreventive properties. A series of clinical pilot studies has provided insights into its pharmacokinetics, and data on its human antineoplastic pharmacodynamics start to emerge. It is likely that resveratrol will be developed further in the clinic as a putative cancer chemopreventive agent.

Evaluation of urinary ribonucleoside profiling for clinical biomarker discovery using constant neutral loss scanning liquid chromatography/tandem mass spectrometry.

The patterns and levels of urinary excreted ribonucleosides which reflect RNA turnover and metabolism in humans offer the potential for early detection of disease and monitoring of therapeutic intervention. A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method employing constant neutral loss (CNL) scanning for the loss of the ribose moiety (132 u) was used to detect ribonucleosides in human urine and to evaluate this analytical platform for biomarker research in clinical trials. Ribonucleosides were stable and not influenced by the time spent at room temperature prior to freezing or long-term storage at -80 °C.

Anthocyanin-rich extracts suppress the DNA-damaging effects of topoisomerase poisons in human colon cancer cells.

Scope: The effect of two anthocyanin-rich berry extracts (A, bilberry; B, red grape) on topoisomerases was investigated in a cell-free system and in human HT29 colon carcinoma cells. In parallel, their impact on DNA integrity was determined.

Methods And Results: The berry extracts suppressed the activity of topoisomerase I at concentrations ≥50 μg/mL.

Clinical trials of resveratrol.

An expanding body of preclinical evidence suggests resveratrol has the potential to impact a variety of human diseases. To translate encouraging experimental findings into human benefits, information is first needed on the safety, pharmacokinetics, pharmacodynamics, and, ultimately, clinical efficacy of resveratrol. Published clinical trials have largely focused on characterizing the pharmacokinetics and metabolism of resveratrol.

Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis.

Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing.

Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients.

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.

Determination of anthocyanins in the urine of patients with colorectal liver metastases after administration of bilberry extract.

Anthocyanins possess cancer chemopreventive properties in preclinical models. Their clinical pharmacology is only poorly understood. In this pilot study, anthocyanins and their metabolites were analysed in the urine of two patients with colorectal liver metastases.

Preclinical colorectal cancer chemopreventive efficacy and p53-modulating activity of 3',4',5'-trimethoxyflavonol, a quercetin analogue.

Some naturally occurring flavonols, exemplified by quercetin, seem to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3',4',5'-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, Apc(Min) mice and human-derived HCT116 adenocarcinoma-bearing nude mice.

Plasma metabolic profiling reveals age-dependency of systemic effects of green tea polyphenols in mice with and without prostate cancer.

Green tea polyphenols (GTP) have been widely investigated for their potential to prevent prostate cancer. However, results from epidemiological and clinical studies are equivocal. Studies in the TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mouse suggest that the chemopreventive efficacy of GTP is higher in young animals with early stages of carcinogenesis than in old ones.

Pharmacokinetics in mice and metabolism in murine and human liver fractions of the putative cancer chemopreventive agents 3',4',5',5,7-pentamethoxyflavone and tricin (4',5,7-trihydroxy-3',5'-dimethoxyflavone).

Purpose: The flavones tricin (4',5,7-trihydroxy-3',5'-dimethoxyflavone) and 3',4',5',5,7-pentamethoxyflavone (PMF) are under development as potential colorectal cancer chemopreventive agents as they reduced adenoma development in the Apc(Min) mouse model of intestinal carcinogenesis. Here, the pharmacokinetic properties and metabolism of these flavones after oral administration were compared in mice.

Methods: C57BL/6 J mice received an oral bolus of PMF or tricin (807 μmol/kg).

Anthocyanin-rich red grape extract impedes adenoma development in the Apc(Min) mouse: pharmacodynamic changes and anthocyanin levels in the murine biophase.

Purpose: Red grape pomace extract (oenocyanin) is a cheap and rich source of anthocyanins, the agents suggested to possess cancer chemopreventive properties. Here the hypothesis was tested that oenocyanin added to the diet can interfere with intestinal adenoma development in the Apc(Min) mouse, a model of intestinal carcinogenesis linked to an Apc mutation.

Methods: Mice received oenocyanin (0.

APC10.1 cells as a model for assessing the efficacy of potential chemopreventive agents in the Apc(Min) mouse model in vivo.

Apc(Min) mice are widely used for mechanism and efficacy studies associated with the development of chemopreventive agents. APC10.1 cells have been derived from Apc(Min) mouse adenomas and retain the heterozygous Apc genotype.

Flavones as colorectal cancer chemopreventive agents--phenol-o-methylation enhances efficacy.

Flavonoids occur ubiquitously in plants, and some possess preclinical cancer chemopreventive activity. Little is known about molecular features that mediate chemopreventive efficacy of flavonoids. Here, three related flavones, apigenin (4',5,7-trihydroxyflavone), tricin (4',5,7-trihydroxy-3',5'-dimethoxyflavone), and 3',4',5',5,7-pentamethoxyflavone (PMF), were compared in terms of their effects on (a) adenoma development in Apc(Min) mice, a model of human gastrointestinal malignancies; (b) growth of APC10.

Pilot study of oral anthocyanins for colorectal cancer chemoprevention.

Naturally occurring anthocyanins possess colorectal cancer chemopreventive properties in rodent models. We investigated whether mirtocyan, an anthocyanin-rich standardized bilberry extract, causes pharmacodynamic changes consistent with chemopreventive efficacy and generates measurable levels of anthocyanins in blood, urine, and target tissue. Twenty-five colorectal cancer patients scheduled to undergo resection of primary tumor or liver metastases received mirtocyan 1.

Development of dietary phytochemical chemopreventive agents: biomarkers and choice of dose for early clinical trials.

In view of safety concerns surrounding the use of pharmaceuticals such as nonsteroidal anti-inflammatory drugs and tamoxifen as cancer chemopreventive agents, potentially innocuous phytochemicals derived from the diet are considered attractive alternatives. However, results from cancer chemoprevention trials of dietary agents have been disappointing to date, as promising activities observed in rodent models and cells in vitro have not translated into clinical success. This may be partly due to the development process for these agents, which is complex for a number of reasons; the definitive end point, inhibition of carcinogenesis, requires large numbers of individuals followed-up over many years.

Pharmacokinetics and metabolism of the putative cancer chemopreventive agent cyanidin-3-glucoside in mice.

Purpose: Cyanidin-3-glucoside (C3G), an anthocyanin component of fruits and berries, possesses cancer chemopreventive properties in mouse models of carcinogenesis. Its pharmacokinetics and metabolism in mice have hitherto not been studied.

Methods: C57BL6J mice received C3G by either gavage at 500 mg/kg or tail vein injection at 1 mg/kg.