Song J, Medline A, Mason J B, Gallinger S, Kim Y I
Department of Medicine, University of Toronto, Ontario, Canada.
Cancer Res. 2000 Oct 1;60(19):5434-40.
Dietary folate appears to be inversely related to colorectal cancer risk. This study investigated the effects of dietary intervention with folate or the development of intestinal polyps in Min (Apc +/-) mice. Weanling Mil mice were fed diets containing 0, 2 (basal requirement), 8, or 20 mg folate/kg diet. At 3 and 6 months of dietary intervention, 50% of the mice from each group were sacrificed, and the small intestine and colon were analyzed for polyps and aberrant crypt foci (ACF). Serum folate concentrations accurately reflected dietary folate levels (P < 0.001). At 3 months no significant difference in the average number of total small intestinal polyps was observed among the four groups. However, increasing dietary folate levels significantly reduced the number of ileal, but not duodenal or jejunal, polyps in a dose-dependent manner (P-trend = 0.001); folate supplementation at 20 mg/kg diet was associated with a 68-78% reduction in the number of ileal polyps compared with the other three diets (P < 0.007). The number of ileal polyps was inversely correlated with serum folate concentrations (P = 0.03). At 3 months, increasing dietary folate levels significantly decreased the number of colonic ACF in a dose-dependent manner (P = 0.05); the control and two folate supplemented diets significantly reduced the number of colonic ACF by 75 100% compared with the folate-deficient diet (P < 0.04). The number of colonic ACF was inversely correlated with serum folate concentration (P = 0.05). No significant difference in the number of colonic adenoma was observed among the four groups at 3 months. At 6 months, no significant differences in the average number of total small intestinal, duodenal, and jejunal polyps, colonic adenomas, and colonic ACF wer observed among the four groups. However, the folate-deficient diet had 62-76% lower number of ileal polyps compared with the control and two folate-supplemented diets (P < 0.003). Serum folate concentrations, but not dietary folate levels, were directly correlated with the number of ilea polyps (P = 0.006). These data suggest that dietary folate supplementation suppresses the development of ileal polyps and colonic ACF in this model However, at later time points, folate supplementation appears to have an opposite effect on ileal polyps. These data generally support the role of folate in intestinal tumorigenesis suggested in epidemiological studies and chemical carcinogen animal models. Notwithstanding the limitations associated with this model, these data suggest that the optimal timing and dose of folate intervention need to be determined for safe and effective folate chemoprevention.
膳食叶酸似乎与结直肠癌风险呈负相关。本研究调查了叶酸饮食干预对Min（Apc+/-）小鼠肠道息肉发生的影响。将断乳的Min小鼠喂食含0、2（基础需求量）、8或20mg叶酸/kg饮食的日粮。在饮食干预3个月和6个月时，每组处死50%的小鼠，分析小肠和结肠中的息肉及异常隐窝病灶（ACF）。血清叶酸浓度准确反映了膳食叶酸水平（P<0.001）。3个月时，四组之间小肠息肉总数的平均数无显著差异。然而，增加膳食叶酸水平以剂量依赖方式显著减少了回肠息肉数量，但十二指肠和空肠息肉数量未减少（P趋势=0.001）；与其他三种日粮相比，20mg/kg饮食的叶酸补充使回肠息肉数量减少了68 - 78%（P<0.007）。回肠息肉数量与血清叶酸浓度呈负相关（P = 0.03）。3个月时，增加膳食叶酸水平以剂量依赖方式显著减少了结肠ACF数量（P = 0.05）；与叶酸缺乏日粮相比，对照组和两种叶酸补充日粮使结肠ACF数量显著减少了75 - 100%（P<0.04）。结肠ACF数量与血清叶酸浓度呈负相关（P = 0.05）。3个月时，四组之间结肠腺瘤数量无显著差异。6个月时，四组之间小肠、十二指肠、空肠息肉总数的平均数、结肠腺瘤和结肠ACF数量均无显著差异。然而，与对照组和两种叶酸补充日粮相比，叶酸缺乏日粮的回肠息肉数量低62 - 76%（P<0.003）。血清叶酸浓度而非膳食叶酸水平与回肠息肉数量直接相关（P = 0.006）。这些数据表明，在该模型中膳食补充叶酸可抑制回肠息肉和结肠ACF的发生。然而，在更晚的时间点，叶酸补充对回肠息肉似乎有相反的作用。这些数据总体上支持了流行病学研究和化学致癌物动物模型中所提示的叶酸在肠道肿瘤发生中的作用。尽管该模型存在局限性，但这些数据表明，为了安全有效地进行叶酸化学预防，需要确定叶酸干预的最佳时机和剂量。
