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1 alpha,25-Dihydroxy-20-epi-vitamin D3: an extraordinarily potent inhibitor
of leukemic cell growth in vitro
E Elstner, YY Lee, M Hashiya, S Pakkala, L Binderup, AW Norman, WH Okamura and HP Koeffler
Department of Medicine, UCLA School of Medicine, Cedars-Sinai Medical
Center.
We have evaluated seven recently synthesized vitamin D3 analogs for their
abilities to inhibit clonal growth of leukemic cells, to induce leukemic
cell differentiation, to stimulate clonal growth of normal myeloid
committed stem cells, and to transactivate a reporter gene having a
1,25(OH)2D3 response element (VDRE). The 1,25(OH)2-20-epi-D3 showed
extraordinary activity; at 10(-11) mol/L it inhibited clonal growth of 87%
of HL-60 myeloblast cells, 60% of S-LB1 cells (human T- cell lymphotropic
virus type 1 [HTLV-1]-immortalized human T-lymphocyte cell line) and 50% of
leukemic clonogenic cells (colony-forming unit- leukemia) obtained from
patients with acute myelogenous leukemia. No effect of either 1,25(OH)2D3
or 1,25(OH)2-20-epi-D3 was observed on the clonal proliferation of an
HTLV-1-immortalized human T-lymphocyte cell line (Ab-VDR) having
nonfunctional 1,25 (OH)2D3 cellular receptors (VDR). The abilities of
1,25(OH)2-20-epi-D3 to induce differentiation of HL-60 cells, as measured
by generation of superoxide and nonspecific esterase production, was less
than its antiproliferative activities. This analog stimulated
colony-forming unit-granulocyte-macrophage growth from normal human bone
marrow. To gain insights into the remarkable antileukemic activities of
1,25(OH)2-20-epi-D3, we examined its ability to enter HL-60 cells, bind to
the VDR, and interact with a transfected VDRE attached upstream of a TK
promoter-driven reporter gene (chloramphenicol acetyl transferase [CAT]).
The 1,25(OH)2-20-epi- D3 potently increased CAT activity (> 16-fold, as
compared with cells transfected with control receptor having no VDRE);
paradoxically, 1,25(OH)2-20-epi-D3 was of equal potency to 1,25(OH)2D3 in
transactivating the VDRE-containing reporter gene, even though the analog
had a 1,000-fold greater antileukemic effect as compared with 1,25(OH)2D3.
In summary, we have identified an extremely potent 1,25(OH)2D3 analog with
antiproliferative and differentiating effects on leukemic cells and that
may be clinically useful. This analog appears to generate biologic
responses via the classical VDR pathway, but further studies are required
to elucidate the mechanism by which this analog produces its prominent
activities.
Volume 84,
Issue 6,
pp. 1960-1967,
09/15/1994
Copyright © 1994 by The American Society of Hematology
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