Studies in vitro and in animal models of colorectal and hepatocellular cancers suggest that curcumin is an effective chemopreventive agent. In this pilot trial, we investigated whether oral administration of curcumin results in concentrations of the agent in normal and malignant human liver tissue, which are sufficient to elicit pharmacological activity. In total, 12 patients with hepatic metastases from colorectal cancer received 450 -3600 mg of curcumin daily, for 1 week prior to surgery. Levels of curcumin and its metabolites were measured by HPLC in portal and peripheral blood, bile and liver tissue. Curcumin was poorly available, following oral administration, with low nanomolar levels of the parent compound and its glucuronide and sulphate conjugates found in the peripheral or portal circulation. While curcumin was not found in liver tissue, trace levels of products of its metabolic reduction were detected. In patients who had received curcumin, levels of malondialdehyde-DNA (M 1 G) adduct, which reflect oxidative DNA changes, were not decreased in post-treatment normal and malignant liver tissue when compared to pretreatment samples. The results suggest that doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans.
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...
Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I.Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M 1 dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 Amol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M 1 dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.
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