Zhou J Y, Norman A W, Akashi M, Chen D L, Uskokovic M R, Aurrecoechea J M, Dauben W G, Okamura W H, Koeffler H P
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
Blood. 1991 Jul 1;78(1):75-82.
We describe several novel analogs of the seco-steroid 1,25(OH)2-vitamin D3[1,25(OH)2D3] and their effects on differentiation and proliferation of HL-60 human myeloid leukemic cells in vitro as well as their effects on calcium metabolism in vivo. The 1 alpha-25(OH)2-16ene-23yne-26,27F6-vitamin D3 is the most potent analog reported to date, having about 80-fold more activity than the reference 1,25(OH)2D3 for inhibition of proliferation and induction of differentiation of HL-60 cells. Also, this analog decreased RNA expression of MYC oncogene in HL-60 by 90% at 5 x 10(-10) mol/L. Intriguingly, intestinal calcium absorption and bone calcium mobilization mediated in vivo by 1 alpha-25(OH)2-16ene-23yne-26,27F6-D3 was found to be markedly (15-fold) less than that of 1,25(OH)2D3. In addition, 1 alpha-25(OH)2D3 bound to 1,25(OH)2D3 receptors of both HL-60 and intestine more avidly than did 1 alpha-25(OH)2-16ene-23yne-26,27F6-D3. This novel analog may open up new therapeutic strategies for several hematopoietic, skin, and bone abnormalities and may provide a new tool to understand how vitamin D3 seco-steroids induce cellular differentiation.
我们描述了几种新型的开环甾体1,25(OH)2-维生素D3[1,25(OH)2D3]类似物，以及它们对HL-60人髓系白血病细胞体外分化和增殖的影响，以及它们对体内钙代谢的影响。1α-25(OH)2-16烯-23炔-26,27F6-维生素D3是迄今为止报道的最有效的类似物，在抑制HL-60细胞增殖和诱导分化方面的活性比参考的1,25(OH)2D3高约80倍。此外，该类似物在5×10(-10)mol/L时可使HL-60中MYC癌基因的RNA表达降低90%。有趣的是，发现1α-25(OH)2-16烯-23炔-26,27F6-D3在体内介导的肠道钙吸收和骨钙动员明显（15倍）低于1,25(OH)2D3。此外，1α-25(OH)2D3比1α-25(OH)2-16烯-23炔-26,27F6-D3更紧密地结合HL-60和肠道的1,25(OH)2D3受体。这种新型类似物可能为几种造血、皮肤和骨骼异常开辟新的治疗策略，并可能提供一种新工具来理解维生素D3开环甾体如何诱导细胞分化。
