Thomasset Sarah, Berry David P, Cai Hong, West Kevin, Marczylo Tim H, Marsden Debbie, Brown Karen, Dennison Ashley, Garcea Giuseppe, Miller Andrew, Hemingway David, Steward William P, Gescher Andreas J
Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE2 7LX, United Kingdom.
Cancer Prev Res (Phila). 2009 Jul;2(7):625-33. doi: 10.1158/1940-6207.CAPR-08-0201.
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 approximately 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.
天然存在的花青素在啮齿动物模型中具有预防结直肠癌的特性。我们研究了富含花青素的标准化越橘提取物米托花青素是否会引起与化学预防功效一致的药效学变化，并在血液、尿液和靶组织中产生可测量水平的花青素。25名计划接受原发性肿瘤或肝转移瘤切除的结直肠癌患者在手术前7天每天服用1.4克、2.8克或5.6克米托花青素（含0.5 - 2.0克花青素）。通过高效液相色谱（HPLC）结合可见或质谱检测分析越橘花青素。通过对结直肠癌组织中Ki-67进行免疫组织化学测定增殖情况。测定血浆中胰岛素样生长因子（IGF）-I的浓度。在血浆、结直肠组织和尿液中鉴定出米托花青素的花青素以及甲基和葡萄糖醛酸代谢物，但在肝脏中未鉴定出。血浆和尿液中的花青素浓度大致呈剂量依赖性，最高剂量时肿瘤组织中达到约179纳克/克。在所有服用米托花青素的患者的肿瘤组织中，与干预前值相比，增殖减少了7%。低剂量导致循环IGF-I浓度有小幅但不显著的降低。总之，重复给予越橘花青素具有药效学作用，并在人体中产生的花青素浓度类似于Apc(Min)小鼠（一种对花青素化学预防特性敏感的家族性腺瘤性息肉病腺瘤模型）中的浓度。有必要对含<0.5克越橘花青素的剂量进行研究，以判断它们是否适合开发为结直肠癌化学预防剂。
