A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on markers of their metabolism in normal mucosa of colorectal adenoma patients.
A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on markers of their metabolism in normal mucosa of colorectal adenoma patients.
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DOI：
10.1158/0008-5472.can-10-1560
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发表时间：
2011-01-15
期刊：
影响因子：
11.2
通讯作者：
Bostick RM
中科院分区：
文献类型：
--
作者：
Ahearn TU;McCullough ML;Flanders WD;Long Q;Sidelnikov E;Fedirko V;Daniel CR;Rutherford RE;Shaukat A;Bostick RM
在癌细胞系和啮齿动物模型中，钙和维生素 D 有利地调节结肠上皮细胞的增殖、分化和凋亡。这些作用可能通过钙受体 (CaR)、维生素 D 受体 (VDR) 和 P450 细胞色素 CYP27B1 和 CYP24A1 的局部表达进行调节，但尚未在人体中进行研究。为了解决这一差距，我们进行了一项随机、双盲、安慰剂对照的 2×2 析因临床试验。至少患有一处经病理证实的结直肠腺瘤的患者接受 2 g/天的元素钙和/或 800 IU/天的维生素 D3 治疗，与安慰剂相比，治疗时间超过 6 个月（N=92；23 人/组）。通过标准化自动免疫组织化学检测正常直肠粘膜活检中 CaR、VDR、CYP27B1 和 CYP24A1 的表达和分布，并通过图像分析进行定量。在补钙组中，CaR 表达增加了 27% (p=0.03)，CYP24A1 表达减少了 21% (p=0.79)。在补充维生素 D3 的组中，CaR 表达增加了 39% (p=0.01)，CYP27B1 表达增加了 159% (p=0.06)。在同时补充钙和维生素 D3 的患者中，VDR 表达增加了 19% (p=0.13)，CaR 表达增加了 24% (p=0.05)。这些结果为进一步研究钙和维生素 D3 作为结直肠肿瘤的化学预防剂，以及 CaR、VDR、CYP27B1 和 CYP24A1 作为结直肠肿瘤的可修改的肿瘤前风险生物标志物提供了机制支持。
In cancer cell lines and rodent models calcium and vitamin D favorably modulate cell proliferation, differentiation, and apoptosis in colonic epithelia. These effects may be modulated by local expression of the calcium receptor (CaR), the vitamin D receptor (VDR), and the P450 cytochromes CYP27B1 and CYP24A1, however, they have yet to be investigated in humans. To address this gap, we conducted a randomized, double-blinded, placebo-controlled 2×2 factorial clinical trial. Patients with at least one pathology-confirmed colorectal adenoma were treated with 2 g/day elemental calcium and/or 800 IU/day vitamin D3 versus placebo over 6 months (N=92; 23/group). CaR, VDR, CYP27B1, and CYP24A1 expression and distribution in biopsies of normal-appearing rectal mucosa were detected by standardized automated immunohistochemistry and quantified by image analysis. In the calcium-supplemented group CaR expression increased 27% (p=0.03) and CYP24A1 expression decreased 21% (p=0.79). In the vitamin D3-supplemented group CaR expression increased 39% (p=0.01) and CYP27B1 expression increased 159% (p=0.06). In patients supplemented with both calcium and vitamin D3 VDR expression increased 19% (p=0.13) and CaR expression increased 24% (p=0.05). These results provide mechanistic support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms, and CaR, VDR, CYP27B1, and CYP24A1 as modifiable, pre-neoplastic risk biomarkers for colorectal neoplasms.