Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial
Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial
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DOI：
10.1158/1940-6207.capr-10-0186
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发表时间：
2010-09-01
影响因子：
3.3
通讯作者：
Nakajima, Atsushi
中科院分区：
文献类型：
--
作者：
Hosono, Kunihiro;Endo, Hiroki;Nakajima, Atsushi
二甲双胍被广泛用于治疗糖尿病。我们先前在两种大肠癌变的啮齿动物模型中显示了二甲双胍的化学预防作用。然而，除了流行病学研究外，人们对二甲双胍在人类结直肠癌发生中的作用知之甚少。这项初步研究的目的是评价二甲双胍对直肠异常隐窝病灶(ACF)的化学预防作用，ACF是结直肠癌的内窥镜替代标记物。我们前瞻性地随机将26名患有ACF的非糖尿病患者随机分为二甲双胍(250 mg/d，n=12)和不治疗(对照组，n=14)；23名患者可进行终点分析(9名二甲双胍和14名对照)；两组在ACF数量和其他基线临床特征方面相似。放大结肠镜检查在基线和1个月后盲法测定每个患者的直肠ACF数量(所有实验室终点分析都是如此)。我们还检测了结肠上皮细胞的增殖活性(通过增殖细胞核抗原标记指数)和凋亡活性(通过末端脱氧核苷酸转移酶dUTP缺口末端标记)。治疗1个月时，二甲双胍组平均每例患者ACF数显著减少(治疗前8.78±-6.45vs5.11+/-4.99，P=0.007)，而对照组患者平均ACF数无明显变化(7.23+/-6.65vs7.56+/-6.75，P=0.609)。二甲双胍患者正常直肠上皮细胞增殖细胞核抗原指数明显降低，而凋亡细胞指数无明显变化。这项首次报道的二甲双胍抑制人类结直肠癌发生的试验提供了初步证据，表明二甲双胍抑制人类结肠上皮细胞增殖和直肠ACF的形成，这表明它有望用于结直肠癌的化学预防。癌症前传；3(9)；1077-83。(C)2010年AACR。
The biguanide metformin is widely used for treating diabetes mellitus. We previously showed the chemopreventive effect of metformin in two rodent models of colorectal carcinogenesis. However, besides epidemiologic studies, little is known about the effects of metformin on human colorectal carcinogenesis. The objective of this pilot study was to evaluate the chemopreventive effect of metformin on rectal aberrant crypt foci (ACF), which are an endoscopic surrogate marker of colorectal cancer. We prospectively randomized 26 nondiabetic patients with ACF to treatment with metformin (250 mg/d, n = 12) or no treatment (control, n = 14); 23 patients were evaluable for end point analyses (9 metformin and 14 control); the two groups were similar in ACF number and other baseline clinical characteristics. Magnifying colonoscopy determined the number of rectal ACF in each patient at baseline and after 1 month in a blinded fashion (as were all laboratory end point analyses). We also examined proliferative activity in colonic epithelium (via proliferating cell nuclear antigen labeling index) and apoptotic activity (via terminal deoxynucleotidyl transferase dUTP nick-end labeling). At 1 month, the metformin group had a significant decrease in the mean number of ACF per patient (8.78 +/- 6.45 before treatment versus 5.11 +/- 4.99 at 1 month, P = 0.007), whereas the mean ACF number did not change significantly in the control group (7.23 +/- 6.65 versus 7.56 +/- 6.75, P = 0.609). The proliferating cell nuclear antigen index was significantly decreased and the apoptotic cell index remained unaltered in normal rectal epithelium in metformin patients. This first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation in humans, suggesting its promise for the chemoprevention of colorectal cancer. Cancer Prev Res; 3(9); 1077-83. (C) 2010 AACR.