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. They received a single dose of 1.88 g standardized bilberry extract (mirtoselect) via either nasogastric or nasojejunal tube intra-operatively during liver resection. HPLC-MS/MS and HPLC-UV analysis showed there were more anthocyanins and metabolites in the urine of the patient who received mirtoselect via the stomach than via the jejunum. This result is consistent with information obtained in rodents which suggests the stomach is the predominant site for anthocyanin absorption.

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 1.4, 2.8, or 5.6 grams (containing 0.5-2.0 grams anthocyanins) daily for 7 days before surgery. Bilberry anthocyanins were analyzed by high performance liquid chromatography (HPLC) with visible or mass spectrometric detection. Proliferation was determined by immunohistochemistry of Ki-67 in colorectal tumor. Concentrations of insulin-like growth factor (IGF)-I were measured in plasma. Mirtocyan anthocyanins and methyl and glucuronide metabolites were identified in plasma, colorectal tissue, and urine, but not in liver. Anthocyanin concentrations in plasma and urine were roughly dose-dependent, reaching approximately 179 ng/gram in tumor tissue at the highest dose. In tumor tissue from all patients on mirtocyan, proliferation was decreased by 7% compared with preintervention values. The low dose caused a small but nonsignificant reduction in circulating IGF-I concentrations. In conclusion, repeated administration of bilberry anthocyanins exerts pharmacodynamic effects and generates concentrations of anthocyanins in humans resembling those seen in Apc(Min) mice, a model of FAP adenomas sensitive to the chemopreventive properties of anthocyanins. Studies of doses containing <0.5 gram bilberry anthocyanins are necessary to adjudge whether they may be appropriate for development as colorectal cancer chemopreventive agents.

Do anthocyanins and anthocyanidins, cancer chemopreventive pigments in the diet, merit development as potential drugs?

Anthocyanins, plant pigments in fruits and berries, have been shown to delay cancer development in rodent models of carcinogenesis, especially those of the colorectal tract. Anthocyanins and anthocyanidins, their aglycons, especially cyanidin and delphinidin, have been subjected to extensive mechanistic studies. In cells in vitro, both glycosides and aglycons engage an array of anti-oncogenic mechanisms including anti-proliferation, induction of apoptosis and inhibition of activities of oncogenic transcription factors and protein tyrosine kinases. Anthocyanins and anthocyanidins exist as four isomers, interconversion between which depends on pH, temperature and access to light. Anthocyanidins are much more prone to avid chemical decomposition than the glycosides, and they only survive for minutes in the biophase. These pharmaceutical issues are very important determinants of the suitability of these flavonoids for potential development as cancer chemopreventive drugs, and they have hitherto not received adequate attention. In the light of their robust cancer chemopreventive efficacy in experimental models and their superior stability as compared to that of the aglycons, the anthocyanins seem much more suitable for further drug development than their anthocyanidin counterparts.

Dietary polyphenolic phytochemicals--promising cancer chemopreventive agents in humans? A review of their clinical properties.

Epidemiological and preclinical evidence suggests that polyphenolic phytochemicals exemplified by epigallocatechin gallate from tea, curcumin from curry and soya isoflavones possess cancer chemopreventive properties. Whilst such naturally occurring polyphenols have been the subject of numerous mechanistic studies in cells, information on their clinical properties, which might help assess their promise as human cancer chemopreventive agents, is scarce. Therefore, we present a review of pilot studies and trials with a cancer chemoprevention-related rationale, in which either healthy individuals or patients with premalignant conditions or cancer received polyphenolic phytochemicals. The review identifies trial design elements specifically applicable to polyphenolic phytochemicals. The available evidence for tea polyphenols tentatively supports their advancement into phase III clinical intervention trials aimed at the prevention of progression of prostate intraepithelial neoplasia, leukoplakia or premalignant cervical disease. In the case of curcumin and soya isoflavones more studies in premalignacies seem appropriate to optimise the nature and design of suitable phase III trials. The abundance of flavonoids and related polyphenols in the plant kingdom makes it possible that several hitherto uncharacterised agents with chemopreventive efficacy are still to be identified, which may constitute attractive alternatives to currently used chemopreventive drugs.