Breast cancer prevention by green tea catechins and black tea theaflavins in the C3(1) SV40 T,t antigen transgenic mouse model is accompanied by increased apoptosis and a decrease in oxidative DNA adducts.

Tea consumption is associated with a reduced risk of mammary cancer as reflected by epidemiological studies and experiments in carcinogen-induced rodent models of mammary carcinogenesis. We tested the hypothesis that green tea catechins (GTC) or theaflavins from black tea (BTT) interfere with mammary carcinogenesis in C3(1) SV40 T,t antigen transgenic multiple mammary adenocarcinoma (TAg) mice and that GTC/BTT affect tumor survival or oxidation status. TAg mice received GTC/BTT (0.05%) in drinking water for their lifetime. As compared to control mice, they survived longer and had smaller tumors. On microscopic inspection, the size of the largest tumor per mouse was decreased by 40-42% (p<0.01). GTC (0.01%) and BTT (0.05%) increased levels of cleaved caspase 3 in tumor tissue by 67 and 38%, respectively (p<0.05), intimating increased apoptosis. Tumor levels of the malondialdehyde-DNA adduct M1dG in mice receiving GTC or BTT (0.05%) were reduced by 78 (p<0.001) or 63% (p<0.05), respectively, as compared to controls. The results render the exploration of the breast cancer chemopreventive properties of tea preparations in humans worthwhile.

Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine.

PURPOSE: Curcumin, a major constituent of the spice turmeric, suppresses expression of the enzyme cyclooxygenase 2 (Cox-2) and has cancer chemopreventive properties in rodents. It possesses poor systemic availability. We explored whether formulation with phosphatidylcholine increases the oral bioavailability or affects the metabolite profile of curcumin. METHODS: Male Wistar rats received 340 mg/kg of either unformulated curcumin or curcumin formulated with phosphatidylcholine (Meriva) by oral gavage. Rats were killed at 15, 30, 60 and 120 min post administration. Plasma, intestinal mucosa and liver were analysed for the presence of curcumin and metabolites using HPLC with UV detection. Identity of curcumin and metabolites was verified by negative ion electrospray liquid chromatography/tandem mass spectrometry. RESULTS: Curcumin, the accompanying curcuminoids desmethoxycurcumin and bisdesmethoxycurcumin, and the metabolites tetrahydrocurcumin, hexahydrocurcumin, curcumin glucuronide and curcumin sulfate were identified in plasma, intestinal mucosa and liver of rats which had received Meriva. Peak plasma levels and area under the plasma concentration time curve (AUC) values for parent curcumin after administration of Meriva were fivefold higher than the equivalent values seen after unformulated curcumin. Similarly, liver levels of curcumin were higher after administration of Meriva as compared to unformulated curcumin. In contrast, curcumin concentrations in the gastrointestinal mucosa after ingestion of Meriva were somewhat lower than those observed after administration of unformulated curcumin. Similar observations were made for curcumin metabolites as for parent compound. CONCLUSION: The results suggest that curcumin formulated with phosphatidylcholine furnishes higher systemic levels of parent agent than unformulated curcumin.

Development of analyses by high-performance liquid chromatography and liquid chromatography/tandem mass spectrometry of bilberry (Vaccinium myrtilus) anthocyanins in human plasma and urine.

Anthocyanins are potent antioxidants that may possess chronic disease preventive properties. Here, rapid, reliable, and reproducible solid-phase extraction, high-performance liquid chromatography (HPLC), and mass spectrometry techniques are described for the isolation, separation, and identification of anthocyanins in human plasma and urine. Recoveries of cyanidin-3-glucoside (C3G) were 91% from water, 71% from plasma, and 81% from urine. Intra- and interday variations for C3G extraction were 9 and 9.1% in plasma and 7.1 and 9.1% in urine and were less than 15% for all anthocyanins from a standardized bilberry extract (mirtoselect). Analysis of mirtoselect by HPLC with UV detection produced spectra with 15 peaks compatible with anthocyanin components found in mirtoselect within a total run time of 15 min. Chromatographic analysis of human urine obtained after an oral dose of mirtoselect yielded 19 anthocyanin peaks. Mass spectrometric analysis employing multiple reaction monitoring suggests the presence of unchanged anthocyanins and anthocyanidin glucuronide metabolites.

Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance.

Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E(2) (PGE(2)) production, or suppression of oxidative DNA adduct (M(1)G) formation. We designed a dose-escalation study to explore the pharmacology of curcumin in humans. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies consumed capsules compatible with curcumin doses between 0.45 and 3.6 g daily for up to 4 months. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed by high-pressure liquid chromatography and mass spectrometry. Three biomarkers of the potential activity of curcumin were translated from preclinical models and measured in patient blood leukocytes: glutathione S-transferase activity, levels of M(1)G, and PGE(2) production induced ex vivo. Dose-limiting toxicity was not observed. Curcumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g curcumin engendered 62% and 57% decreases in inducible PGE(2) production in blood samples taken 1 hour after dose on days 1 and 29, respectively, of treatment compared with levels observed immediately predose (P < 0.05). A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. PGE(2) production in blood and target tissue may indicate biological activity. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.