A PROTECTIVE ROLE OF 1,25-DIHYDROXYVITAMIN D3 IN CHEMICALLY-INDUCED RAT COLON CARCINOGENESIS
A PROTECTIVE ROLE OF 1,25-DIHYDROXYVITAMIN D3 IN CHEMICALLY-INDUCED RAT COLON CARCINOGENESIS
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DOI：
10.1093/carcin/13.12.2293
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发表时间：
1992-12-01
期刊：
影响因子：
4.7
通讯作者：
LAMPRECHT, SA
中科院分区：
文献类型：
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作者：
BELLELI, A;LEVY, J;LAMPRECHT, SA
一个有趣的观察发现，1，25-二羟基维生素D3[1，25(OH)2D3]受体存在于不参与钙稳态的组织中，并且1，25(OH)2D3在包括大肠细胞在内的各种癌细胞系中发挥抗增殖和促进分化的作用。因此，研究1，25(OH)2D3在小鼠结肠癌发生模型中的表达和生物活性是很有意义的。用1，2-二甲基肼二盐酸盐(DMH)连续给药诱导雄性大鼠结肠癌。在对照组和DMH处理的大鼠结肠粘膜高速上清液中检测1，25(OH)2D3受体的水平和结合特性。在同时进行的研究中，在DMH攻击前、同时和之后分别皮下注射1，25(OH)2D3(400 ng/只)，测定结肠胞浆中与生长相关的DMH诱导酶鸟氨酸脱羧酶(ODC)的活性。同时测定血清钙离子水平。接受相同治疗方案的大鼠在停止DMH给药10周后处死，打开整个结肠并检查肿瘤。结果表明：(I)大鼠结肠粘膜只有一类高亲和力的1，25(OH)2D3受体；(Ii)DMH可使1，25(OH)2D3结合位点显著减少(50%)，而不影响K(D)值；(Iii)DMH与1，25(OH)2D3合用可抑制维生素D诱导的高钙血症，并使血清钙浓度恢复到基础水平；(Iv)DMH激发前给予的1，25(OH)2D3可消除DMH诱导的早期结肠腺ODC活性峰值，并显著减少结肠腺癌数量(50%)。目前的发现表明，一种结肠特异的强致癌物干扰了1，25(OH)2D3的生物表达，并且在致癌伤害之前给予维生素D能够显著降低结肠肿瘤的发生率，可能是作为一种抗增殖或促进分化的药物。
The intriguing observation has been made that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] receptors are present in tissues not involved in calcium homeostasis and that 1,25(OH)2D3 exerts an antiproliferative, differentiation-promoting action in a variety of cancer cell lines, including cells of the large intestine. It was therefore deemed of interest to study 1,25(OH)2D3 expression and biological activity in a murine model of colon carcinogenesis. Colon carcinogenesis was induced in male rats by the sequential administration of 1,2-dimethylhydrazine dihydrochloride (DMH). Levels and binding characteristics of 1,25(OH)2D3 receptors were assessed in control and DMH-treated rat colonic mucosal high-speed supernatants. In concurrent studies, 1,25(OH)2D3 was administered (s.c., 400 ng/rat) prior to, together with and after DMH challenge and the activity of ornithine decarboxylase (ODC), a growth-related DMH-induced enzyme, was determined in colonic cytosols. Serum Ca2+ levels were measured concurrently. Rats submitted to identical treatment schedules were killed 10 weeks after termination of DMH administration and the whole colon was opened and examined for tumors. The results show that (i) rat colonic mucosa possesses a single class of high-affinity 1,25(OH)2D3 receptors; (ii) DMH administration provokes a marked reduction (50%) in 1,25(OH)2D3 binding sites without affecting K(d) values; (iii) DMH administered concurrently with 1,25(OH)2D3 suppressed the vitamin D-induced hypercalcemia and restored serum Ca2+ concentrations to basal levels; and (iv) 1,25(OH)2D3 delivered prior to DMH challenge obliterated the typical DMH-induced early colonic ODC activity peak and markedly reduced (50%) the number of colon adenocarcinomas. The present findings indicate that a colon-specific potent carcinogen interferes with the biological expression of 1,25(OH)2D3 and that vitamin D administered prior to a carcinogenic insult is able to reduce significantly the incidence of colon tumors, presumably acting as an antiproliferative or differentiation-promoting agent.