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. ' 2006 Wiley-Liss, Inc.Key words: cancer chemoprevention; clinical trial; curcumin; flavonoids; tea polyphenolsIn recent years there has been increasing interest in the potential cancer chemopreventive properties of diet-derived agents. This interest has been elicited by epidemiological research linking variations in geographical distribution of cancer incidence to intake of specific diets, and it has been supported by convincing evidence of chemopreventive efficacy of specific diet constituents in rodent models of carcinogenesis. The ultimate proof of efficacy of a putative cancer chemopreventive agent is provided by long-term phase III clinical intervention studies involving large numbers of individuals. Such studies are complex and expensive to conduct. Only relatively few dietary constituents have undergone, or are currently undergoing, phase III cancer chemoprevention studies. Prominent among them are folate, 1 b-carotene plus vitamins A and E, 2,3 calcium plus vitamin D 4 and selenium plus vitamin E. 5 Polyphenolic pytochemicals such as epigallocatechin gallate (EGCG) from tea, the flavonoids quercetin and genistein from onions and soya, respectively, curcumin in curry spice and resveratrol from red grapes (for structures see Fig. 1) constitute a class of diet constituents with notable efficacy in preclinical models of carcinogenesis, including those of the colorectum, breast and prostate. 6 To our knowledge, none of these species have to date been the subject of phase III clinical trials. A prominent feature rendering polyphenolic phytochemicals worthy of s...

Resection of duodenal adenocarcinoma in specialist centres is associated with good long-term survival. Lymphovascular invasion and nodal metastases are independent prognostic indicators.

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 ∼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.