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Articles by K Brown
Total Records ( 4 ) for K Brown
  D Correa , L Schwartz , W. R Jarnagin , S Tuorto , R DeMatteo , M D'Angelica , P Allen , K Brown and Y. Fong
 

Objective  To determine the time course of liver hypertrophy after portal vein embolization (PVE).

Design  In a cohort study, computed tomography volumetrics were calculated for livers during a 1-year period after PVE.

Setting  Tertiary liver cancer treatment center.

Patients  Ten patients who were subjected to PVE and were found subsequently to not be candidates for liver resection.

Intervention  Right PVE.

Main Outcome Measures  Left and right liver volumes.

Results  The left liver continued growing for the entire first year after PVE, while the right liver continued to atrophy. The total volume remained remarkably constant.

Conclusion  Early PVE during administration of a course of neoadjuvant therapy would be beneficial for enhanced growth of the liver before liver resection.

  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.

  L. M Howells , R. G Britton , M Mazzoletti , P Greaves , M Broggini , K Brown , W. P Steward , A. J Gescher and S. Sale
 

Some naturally occurring flavonols, exemplified by quercetin, seem to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3',4',5'-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, ApcMin mice and human-derived HCT116 adenocarcinoma–bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of ApcMin or from either day 7 before ("TMFol early") or day 7 after ("TMFol late") tumor inoculation in HCT116 mice. The ability of TMFol to affect tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved caspase-3, respectively, was studied in HCT116 tumors. TMFol tumor levels were measured by high-performance liquid chromatography. Consumption of TMFol reduced small intestinal adenoma burden in ApcMin mice by 47%, compared with control mice (P < 0.002). The TMFol early regimen approximately halved HCT116 tumor size (P < 0.05), decreased tumor proliferation, and increased apoptosis, whereas the TMFol late regimen had no significant effect when compared with controls. In tumor tissues from mice, in which TMFol reduced tumor development, p53 expression was increased 3-fold in ApcMin and 1.5-fold in HCT116 tumor–bearing mice (P = 0.02). TMFol increased p53 also in cells derived from these tumors. TMFol was detected in HCT116 tumors, but levels did not correlate with tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the flavonol structure may generate safe and efficacious cancer chemopreventive agents. Cancer Prev Res; 3(8); 929–39. ©2010 AACR.

 
 
 
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