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

维生素D3的活性形式1 α，25-二羟基维生素D3（1a，25（OH）2D 3）具有多种抗肿瘤活性，包括抑制乳腺癌、前列腺癌、肺癌和结肠癌细胞系的增殖、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，预期可用于临床应用。然而，关于这些类似物的有效性和安全性仍然存在很多问题。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)在活性形式维生素D的A环的C-2位插入甲基极大地增强了其生物活性。(2)A环C-1和C-3位羟基的差向异构化诱导细胞分化和凋亡的选择性活性。(3)2002年，我们试图从基因、细胞和人体水平阐明与维生素D类似物，特别是非钙调素类似物OCT的有效性和安全性相关的结构基序。结果表明：1）OCT的代谢主要有两条途径，2）负责上述两种代谢途径的酶被认为与已知的参与维生素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E-大肠杆菌是筛选维生素D类似物一般生物活性的有力工具。

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.