Vitamin D5 in Prevention of Mammary Carcinogenesis

说明(申请人提供)：维生素D5系列化合物不同于D3系列化合物。在维生素D5中，C-24位有一个乙基。早些时候，我们发现维生素D5的类似物，1α-羟基维生素D5(1α(OH)D5)，与其他维生素D类似物相比，是相对无毒和无钙化的。在过去两年的资助期内，我们已经证明1α(OH)D5在抑制MNU和DMBA诱导的大鼠乳腺癌的发病率和多发性方面都是有效的。我们还发现，在致癌促进期，1α(OH)D5的作用更为显著。在这里，我们将评估1α(OH)D5在临床相关实验方案中的疗效，无论是单独使用还是与他莫昔芬联合使用。最近，正常和转化的人乳腺上皮细胞的基因芯片图谱表明，在差异表达的基因中，细胞周期调控基因Prohibitin在转化的细胞中上调。此外，转化细胞经1α(OH)D5处理后，抑制素表达下调。这为理解D5介导的转化细胞的细胞周期调控提供了线索。我们推测，除了维生素D受体外，禁止素可能是1α(OH)D5在化学预防中作用的一个重要靶点。关于D2、D4和D5系列维生素D类似物的代谢和药代动力学的报道很少。最近，Jones和他的同事报道，C24甲基或乙基可能是维生素D4和D5类似物的代谢决定因素(2)。格伦维尔·琼斯博士将在这个项目上与我们合作，评估正常和肿瘤乳腺细胞和组织中1pha(OH)D5的新陈代谢。了解1α(OH)D5的作用机制和代谢对于开发这种临床应用的类似物是至关重要的。为确定以下具体目标提出了建议： 1.在手术切除第一个可触及的肿瘤后，1α(OH)D5是否可以防止肿瘤的发展？1α(OH)D5和他莫昔芬的组合是否比单独使用任何一种药物提供更强的保护？ 2.禁止素是否在这些细胞的细胞转化和化学预防效果中起作用？ 3.1α(OH)D5在正常和肿瘤乳腺上皮细胞和组织中是如何代谢的？

DESCRIPTION (provided by applicant): The vitamin D5 series of compounds are different from the D3 series. In vitamin D5, there is an ethyl group at the C-24 position. Earlier, we showed that an analog of vitamin D5, 1alpha-Hydroxyvitamin D5 (1alpha(OH)D5), is relatively nontoxic and non-calcemic compared to other vitamin D analogs (1). During the past 2 years of the funding period, we have shown that 1alpha(OH)D5 was effective in inhibiting both the tumor incidence and multiplicity of MNU- and DMBA-induced mammary carcinogenesis in rats. We also showed that the effect of 1alpha(OH)D5 was more prominent during the promotion phase of carcinogenesis. Here we will evaluate efficacy of 1alpha(OH)D5 in clinically relevant experimental protocol either singly or in combination with tamoxifen. More recently, the gene array profile of normal and transformed human mammary epithelial cells suggested that, among the differentially expressed genes, prohibitin, a cell cycle regulatory gene was upregulated in transformed cells. Moreover, prohibitin was down-regulated when transformed cells were treated with 1alpha(OH)D5. This provides a clue for understanding D5-mediated cell cycle regulation in transformed cells. We hypothesize that, in addition to vitamin D receptor, prohibitin may be an essential target for the action of 1alpha(OH)D5 in chemoprevention. Very little has been reported regarding the metabolism and pharmacokinetics of the D2, D4, and D5 series of vitamin D analogs. Recently, Jones and colleagues reported that C24 methyl or ethyl might be a metabolic determinant for vitamin D4 and D5 analogs (2). Dr. Glenville Jones will collaborate with us on this project to evaluate metabolism of 1alpha(OH)D5 in normal and neoplastic breast cells and tissues. Understanding of both the mechanism of action and metabolism of 1alpha(OH)D5 is crucial in developing this analog for clinical application. The following specific aims are proposed to determine: 1. Whether 1alpha (OH)D5 prevents development of tumors subsequent to surgical excision of the first palpable tumor? Whether the combination of 1alpha(OH)D5 and tamoxifen provide enhanced protection compared to either agent alone? 2. Whether prohibitin plays a role in cell transformation and chemopreventive efficacy in these cells? 3. How is 1alpha(OH)D5 metabolized in normal and neoplastic mammary epithelial cells and tissues?