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Development of a novel 1,25(OH)2-vitamin D3 analog with potent ability to
induce HL-60 cell differentiation without modulating calcium metabolism
JY Zhou, AW Norman, M Akashi, DL Chen, MR Uskokovic, JM Aurrecoechea, WG Dauben, WH Okamura and HP Koeffler
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
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.
Volume 78,
Issue 1,
pp. 75-82,
07/01/1991
Copyright © 1991 by The American Society of Hematology
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