20-EPI-VITAMIN-D3 ANALOGS - A NOVEL CLASS OF POTENT REGULATORS OF CELL-GROWTH AND IMMUNE-RESPONSES
20-EPI-VITAMIN-D3 ANALOGS - A NOVEL CLASS OF POTENT REGULATORS OF CELL-GROWTH AND IMMUNE-RESPONSES
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DOI：
10.1016/0006-2952(91)90426-6
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发表时间：
1991-09-27
影响因子：
5.8
通讯作者：
HANSEN, K
中科院分区：
文献类型：
--
作者：
BINDERUP, L;LATINI, S;HANSEN, K
20-表维生素 D3 类似物是一类新型维生素 D3 衍生物，在结构上与 1-α,25-二羟基胆钙化醇 (1-α,25(OH)2D3) 相关。它们的特点是侧链碳 20 处的立体化学发生了改变。在体外，这些新的类似物被发现作为人组织细胞淋巴瘤细胞系 U 937 的生长和分化调节剂比 1-α,25(OH)2D3 更有效，尽管体内的钙活性几乎没有变化。最有效的类似物 KH 1060 在 10(-12) M 时可抑制细胞增殖 50%（活性比 1-α,25(OH)2D3 强 14,000 倍）。同时，KH 1060 在浓度低至 10(-14) M 时即可诱导细胞分化。此外，20-表维生素 D3 类似物被发现是白细胞介素 1 或同种抗原诱导的 T 淋巴细胞增殖的非常有效的抑制剂。在这方面，它们比强效免疫抑制剂环孢菌素 A (CyA) 的活性高几个数量级。 KH 1060 是最有效的类似物，在 3 x 10(-16) M 时可抑制白细胞介素-1 诱导的小鼠胸腺细胞增殖 50%，在 5 x 10(-15) M 时可抑制小鼠脾淋巴细胞的同种异体刺激。这些作用被认为是通过抑制活化的 T 淋巴细胞释放白细胞介素 2 来介导的。这些新的类似物在预防移植排斥以及治疗牛皮癣、癌症和自身免疫性疾病方面具有潜在的意义。
The 20-epi-vitamin D3 analogues are a novel class of vitamin D3 derivatives, structurally related to 1-alpha,25-dihydroxycholecalciferol (1-alpha,25(OH)2D3). They are characterized by an altered stereochemistry at carbon 20 in the side-chain. In vitro, these new analogues were found to be considerably more potent as regulators of growth and differentiation in the human histiocytic lymphoma cell line U 937 than 1-alpha,25(OH)2D3, despite a practically unchanged calcemic activity in vivo. The most potent analogue, KH 1060, inhibited cell proliferation by 50% at 10(-12) M (14,000 times more active than 1-alpha,25(OH)2D3). At the same time, KH 1060 induced cell differentiation at concentrations as low as 10(-14) M. In addition, the 20-epi-vitamin D3 analogues were found to be very potent inhibitors of T-lymphocyte proliferation induced by interleukin-1 or alloantigen. In this respect, they were several orders of magnitude more active than the potent immunosuppressive agent cyclosporin A (CyA). KH 1060, the most potent analogue, inhibited interleukin-l-induced mouse thymocyte proliferation by 50% at 3 x 10(-16) M and allogeneic stimulation of mouse spleen lymphocytes at 5 x 10(-15) M. These effects were considered to be mediated by inhibition of interleukin-2 release from activated T-lymphocytes. The new analogues are of potential interest in the prevention of graft rejection and in the treatment of psoriasis, cancer and auto-immune diseases.