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Articles by A. J. Gescher
Total Records ( 2 ) for A. J. Gescher
  S Thomasset , D. P Berry , H Cai , K West , T. H Marczylo , D Marsden , K Brown , A Dennison , G Garcea , A Miller , D Hemingway , W. P Steward and A. J. Gescher
 

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 ApcMin 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.

  H Cai , S Sale , R Schmid , R. G Britton , K Brown , W. P Steward and A. J. Gescher
 

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 ApcMin mice, a model of human gastrointestinal malignancies; (b) growth of APC10.1 mouse adenoma cells in vitro; and (c) prostaglandin E-2 generation in HCA-7 human-derived colorectal cancer cells in vitro. Life-long consumption of PMF with the diet at 0.2% reduced ApcMin mouse adenoma number and burden by 43% and 61%, respectively, whereas apigenin was inactive. Tricin has previously shown activity in this model. IC50 values for murine adenoma cell growth inhibition by PMF, tricin, and apigenin were 6, 13, and 18 µmol/L, respectively. In ApcMin mice that received flavones (0.2%) for 4 weeks, adenoma cell proliferation as reflected by Ki-67 staining was reduced by PMF and tricin, but not by apigenin. On incubation with HCA-7 cells for 6 hours, PMF reduced prostaglandin E-2 generation with an IC50 of 0.8 µmol/L, a fraction of the respective values reported for tricin or apigenin. In silico PMF docked into the cyclooxygenase active site with greater affinity than tricin or apigenin. The results suggest that the rank order of cancer chemopreventive efficacy in ApcMin mice is PMF > tricin > apigenin, supporting the notion that the presence of O-methyl in the flavone molecular scaffold promotes gastrointestinal cancer chemopreventive efficacy.

 
 
 
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