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DEVELOPMENT OF VITAMIN D ANALOGS POSSESSING STRUCTURAL SELECTIVE REGULATORY ACTIVITY TOWARDS CANCER CELL DIFFERENTIATION AND APOPTOSIS

对癌细胞分化和凋亡具有结构选择性调节活性的维生素 D 类似物的开发

基本信息

批准号：
12672139
负责人：
OKANO Toshio
金额：
$ 1.98万
依托单位：
KOBE PHARMACEUTICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

It has been well documented in vitro and in vivo that 1a, 25-dihydroxyvitamin D3 (1a, 25(OH)2D3), an active form of vitamin D3, exhibits a variety of anti-tumor activities including inhibition of proliferation, induction of cell differentiation and apoptosis towards breast, prostate, lung and colon cancer cell lines. These effects are extremely strong when compared to those of other natural compounds and theft clinical applications are anticipated. However, there are still lots of issues regarding the efficacy and safety of these analogs. To address these issues, we performed this project from 2000 to 2001 and our results were as follows.(1) The insertion of a methyl group into the C-2 position of the A-ring of the active form of vitamin D extremely enhanced its biological activity.(2) The epimerization of the hydroxy group at the C-1 and C-3 positions of the A-ring induced the selective activity of cell differentiation and apoptosis.(3) The hybrid analogs with the above two characteristics were found to be a promising candidate for the treatment of cancer.In 2002, we tried to clarify the structure motifs related to the efficacy and safety of vitamin D analogs, especially a non-calcemic analog OCT at the gene, cell, and human levels. The results were as follows.1) OCT is metabolized via two major pathways, dehydration and epimerization.2) The enzymes responsible for the above two metabolic pathways are thought to be different from the known enzymes involved in the hydroxylation of vitamin D.3) The regulatory mechanism to control the above two pathways seems to exist.4) We confirmed that the CYP24 and CYP27A1 expression vector systems using E-Coli are powerful tools for screening general biological activity of vitamin D analogs.

在体外和体内都有充分的证据表明，维生素D3的活性形式1a， 25-二羟基维生素D3 （1a, 25(OH)2D3）对乳腺癌、前列腺癌、肺癌和结肠癌细胞系具有多种抗肿瘤活性，包括抑制增殖、诱导细胞分化和凋亡。与其他天然化合物相比，这些效果非常强，预计会有临床应用。然而，关于这些类似物的有效性和安全性仍然存在许多问题。为了解决这些问题，我们从2000年到2001年进行了这个项目，我们的结果如下。(1)在维生素D活性形式的a环的C-2位置插入一个甲基，极大地增强了其生物活性。(2) a环C-1和C-3位羟基的外显异构化诱导了细胞分化和凋亡的选择性活性。(3)具有上述两种特征的杂交类似物被认为是治疗癌症的有希望的候选物。2002年，我们试图阐明与维生素D类似物的有效性和安全性相关的结构基元，特别是在基因、细胞和人体水平上的非钙化类似物OCT。结果如下：1) OCT的代谢途径主要有两种：脱水和外聚化。2)负责上述两种代谢途径的酶被认为与已知参与维生素d羟基化的酶不同。3)控制上述两种途径的调节机制似乎存在。4)我们证实了使用大肠杆菌的CYP24和CYP27A1表达载体系统是筛选维生素D类似物一般生物活性的有力工具。