Wali R K, Bissonnette M, Khare S, Hart J, Sitrin M D, Brasitus T A
Department of Medicine, University of Chicago Hospitals and Clinics, Pritzker School of Medicine, Illinois 60637, USA.
Cancer Res. 1995 Jul 15;55(14):3050-4.
Vitamin D3 and its metabolites, particularly 1 alpha,25-dihydroxyvitamin D3 (1 alpha, 25(OH)2D3), have received increasing attention as potential anticarcinogens in the prevention of cancers in a number of organs, including the colon. These agents, however, have the potential to induce hypercalcemia, thus limiting their practical use for these purposes. In the present studies it was, therefore, of interest to determine whether dietary supplementation with 1 alpha,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalcifero l (RO24-5531), a recently synthesized apparently noncalcemic analogue of 1 alpha,25(OH)2D3, inhibited colon cancer induced by azoxymethane (AOM). Rats were placed on a standard diet or fed this diet with supplemental RO24-5531 (2.5 nmol/kg feed) before and during (initiation arm), or after AOM or vehicle administration (postinitiation arm). After 34 weeks of study, animals in each group were sacrificed, and their colons were removed and examined macroscopically and microscopically for the presence of tumors. At the time of sacrifice, the animals' serum calcium, phosphorus, 25-hydroxyvitamin D3 and 1 alpha,25(OH)2D3 levels were also analyzed. The results of these studies demonstrated that dietary RO24-5531 supplementation during the initiation arm of these experiments significantly reduced (by 70%) the incidence of AOM-induced colonic tumors compared to rats on the standard diet without RO24-5531. Moreover, this dietary regimen abolished the development of adenocarcinomas in this model. Although there was also a trend for dietary RO24-5531 supplementation during the postinitiation arm of this study to reduce the incidence of colon tumors, this did not reach statistical significance (P > 0.05). In addition, neither dietary RO24-5531 supplementation regimen significantly influenced the animals' rates of growth or their serum levels of calcium, phosphorus, or 25-hydroxyvitamin D3. These studies, therefore, demonstrate for the first time that supplemental dietary RO24-5531 is a chemopreventive agent in the AOM model of experimental colonic carcinogenesis. They also suggest that this agent may ultimately prove useful in clinical colon cancer chemopreventive trials.
维生素D3及其代谢产物，尤其是1α,25 - 二羟基维生素D3（1α,25(OH)2D3），作为潜在的抗癌物质在预防包括结肠在内的多个器官的癌症方面受到了越来越多的关注。然而，这些药物有可能引发高钙血症，从而限制了它们在此类用途上的实际应用。因此，在本研究中，确定在饮食中补充1α,25 - 二羟基 - 16 - 烯 - 23 - 炔 - 26,27 - 六氟胆钙化醇（RO24 - 5531）（一种最近合成的明显无血钙升高作用的1α,25(OH)2D3类似物）是否能抑制由氧化偶氮甲烷（AOM）诱导的结肠癌具有重要意义。将大鼠置于标准饮食中，或者在AOM或赋形剂给药之前及期间（起始组），或之后（起始后组），给其喂食添加了RO24 - 5531（2.5 nmol/kg饲料）的这种饮食。经过34周的研究后，处死每组动物，取出它们的结肠，进行大体和显微镜检查以确定是否存在肿瘤。在处死时，还分析了动物的血清钙、磷、25 - 羟基维生素D3和1α,25(OH)2D3水平。这些研究结果表明，在这些实验的起始组中，饮食补充RO24 - 5531与未添加RO24 - 5531的标准饮食大鼠相比，显著降低了（70%）AOM诱导的结肠肿瘤发生率。此外，这种饮食方案消除了该模型中腺癌的发生。尽管在本研究的起始后组中饮食补充RO24 - 5531也有降低结肠肿瘤发生率的趋势，但未达到统计学意义（P > 0.05）。另外，两种饮食补充RO24 - 5531方案均未显著影响动物的生长速率或其血清钙、磷或25 - 羟基维生素D3水平。因此，这些研究首次证明饮食补充RO24 - 5531在实验性结肠致癌的AOM模型中是一种化学预防剂。它们还表明这种药物最终可能在临床结肠癌化学预防试验中有用。
