Evaluation of vitamin D analogs as therapeutic agents for prostate cancer.
Evaluation of vitamin D analogs as therapeutic agents for prostate cancer.
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维生素 D 类似物作为前列腺癌治疗剂的评估。
DOI：
10.1007/978-3-642-55580-0_20
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发表时间：
2003
期刊：
影响因子：
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通讯作者：
Schwartz,GaryG
中科院分区：
文献类型：
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作者：
Chen,TaiC;Holick,MichaelF;Lokeshwar,BalL;Burnstein,KerryL;Schwartz,GaryG
前列腺癌细胞含有1α，25-二羟维生素D（1α，（OH）2D 3）的特异性受体（VDR），已知其抑制这些细胞的增殖和侵袭。这些结果支持1α，（OH）2D 3用于前列腺癌治疗。然而，由于1α，（OH）2D 3可引起高钙血症，因此钙离子较少但表现出有效抗增殖活性的1α，（OH）2D 3类似物作为治疗剂将是有吸引力的。我们研究了四种维生素D化合物：25-羟基维生素D3 [25（OH）D3]，其在前列腺细胞中转化为1α，（OH）2D 33，以及1α，（OH）2D 33的三种类似物：EB 1089，19-去甲-1 α，（OH）2D 32和六氟-1 α，（OH）2D 33（F6-1α，（OH）2D 33）。在临床试验中，19-去甲-1 α，（OH）2D 32的钙含量低于1α，（OH）2D 33。F6-1α，（OH）2D 33在体外抑制角质形成细胞增殖的活性比1α，（OH）2D 33高100倍，并且持续时间更长。在植入Leydig细胞瘤的大鼠中，EB 1089的钙离子含量低于1α，（OH）2D 33。用~ 3 H-TdR掺入法研究了25（OH）D_3，19-去甲-1 α，（OH）_2D_32和F_6 -1α，（OH）_2D_33对细胞增殖的影响，并与1α，（OH）_2D_33进行了比较。此外，我们研究了在25（OH）D3和19-nor-1α，（OH）2D 32存在下，前列腺细胞中VDR的反式激活。对于EB 1089，我们在大鼠Dunning MAT LyLu前列腺癌模型中比较了其对前列腺癌转移的抑制作用与1α，（OH）2D 33体内诱导的抑制作用。我们发现1α，（OH）2D 33和19-nor-1α，（OH）2D 32对前列腺细胞中3 H-胸苷掺入DNA产生了类似的剂量依赖性抑制作用，并且在PC-3/VDR细胞中CAT报告基因反式激活试验中表现相似。
Prostate cancer cells contain specific receptors (VDR) for 1α,25-dihydroxyvitamin D (1α,(OH)2D3), which is known to inhibit the proliferation and invasiveness of these cells. These findings support the use of 1α,(OH)2D3for prostate cancer therapy. However, because 1α,(OH)2D3can cause hypercalcemia, analogs of 1α,(OH)2D3that are less calcemic but which exhibit potent antiproliferative activity would be attractive as therapeutic agents. We studied four vitamin D compounds: 25-hydroxyvitaminD3 [25(OH)D3], which is converted to 1α,(OH)2D33 in prostate cells, and three analogs of 1α,(OH)2D33: EB1089, 19- nor-1α,(OH)2D32 and hexafluoro-1α,(OH)2D33 (F6-1α,(OH)2D33). 19-nor- 1α,(OH)2D32 has been shown to be less calcemic than 1α,(OH)2D33 in clinical trials. F6-1α,(OH)2D33 has been shown to be 100-fold more active than 1α,(OH)2D33 and to be longer-lasting in inhibiting keratinocyte proliferation in vitro. EB1089 has been shown to be less calcemic than 1α,(OH)2D33 in rats implanted with Leydig cell tumors. For 25(OH)D3, 19-nor-1α,(OH)2D32 and F6-1α,(OH)2D33, we studied the in vitro effects and compared their activity to 1α,(OH)2D33 on cellular proliferation by 3H-thymidine incorporation assay. In addition, we studied transactivation of the VDR in the presence of 25(OH)D3 and 19-nor-1α,(OH)2D32 in prostate cells. For EB1089, we compared its inhibition of prostate cancer metastasis to that induced by 1α,(OH)2D33 in vivo in the rat Dunning MAT LyLu prostate cancer model. We found that 1α,(OH)2D33 and 19-nor-1α,(OH)2D32 caused similar dose-dependent inhibition in 3H-thymidine incorporation into DNA in prostate cells and behaved similarly in the CAT reporter gene transactivation assay in PC-3/VDR cells.