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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2441-2449
19-nor Vitamin-D Analogs: A New Class of Potent Inhibitors of
Proliferation and Inducers of Differentiation of Human Myeloid
Leukemia Cell Lines
Hiroya Asou,
Michiaki Koike,
Elena Elstner,
Moray Cambell,
Jennifer Le,
Milan R. Uskokovic,
Nanao Kamada, and
H. Phillip Koeffler
From the Division of Hematology/Oncology, Cedars-Sinai Medical
Center, UCLA School of Medicine, Los Angeles, CA; Hoffmann-La Roche
Inc, Nutley, NJ; and the Department of Cancer Cytogenetics, Research
Institute for Radiation Biology & Medicine, Hiroshima University,
Hiroshima, Japan.
We have studied the in vitro biological activities and mechanisms of
action of 1,25-dihydroxyvitamin D3 (1,25D3) and
nine potent 1,25D3 analogs on proliferation and
differentiation of myeloid leukemia cell lines (HL-60, retinoic
acid-resistant HL-60 [RA-res HL-60], NB4 and Kasumi-1). The common
novel structural motiff for almost all the analogs included removal of
C-19 (19-nor); each also had unsaturation of the side chain. All the
compounds were potent; for example, the concentration of analogs
producing a 50% clonal inhibition (ED50) ranged between 1 × 10 9 to 4 × 1011 mol/L when using
the HL-60 cell line. The most active compound [1,25(OH)2-16,23E-diene-26-trifluoro-19-nor-cholecalciferol
(Ro 25-9716)] had an ED50 of 4 × 1011
mol/L; in contrast, the 1,25D3 produced an ED50
of 109 mol/L with the HL-60 target cells. Ro 25-9716 (109 mol/L, 3 days) was a strong inducer of myeloid
differentiation because it caused 92% of the HL-60 cells to express
CD11b and 75% of these cells to reduce nitroblue tetrazolium (NBT).
This compound (108 mol/L, 4 days) also caused HL-60
cells to arrest in the G1 phase of the cell cycle (88%
cells in G1 v 48% of the untreated control cells).
The p27kip-1, a cyclin-dependent kinase inhibitor which is
important in blocking the cell cycle, was induced more quickly and
potently by Ro 25-9716 (107 mol/L, 0 to 5 days) than by
1,25D3, suggesting a possible mechanism by which these
analogs inhibit proliferation of leukemic growth. The NB4 promyelocytic
leukemia cells cultured with the Ro 25-9716 were also inhibited in
their clonal proliferation (ED50, 5 × 1011
mol/L) and their expression of CD11b was enhanced (80% positive [109 mol/L, 4 days] v 27% untreated NB4
cells). Moreover, the combination of Ro 25-9716 (109
mol/L) and all-trans retinoic acid (ATRA, 107 mol/L)
induced 92% of the NB4 cells to reduce NBT, whereas only 26% of the
cells became NBT positive after a similar exposure to the combination
of 1,25D3 and ATRA. Surprisingly, Ro 25-9716 also inhibited
the clonal growth of poorly differentiated leukemia cell lines (RA-res
HL-60 [ED50, 4 × 109 mol/L] and Kasumi-1
[ED50, 5 × 1010 mol/L]). For HL-60
cells, Ro 25-9716 markedly decreased the percent of the cells in S
phase of the cell cycle and increased the expression of the
cyclin-dependent kinase inhibitor, p27kip-1. In summary,
19-nor vitamin D3 compounds strongly induced
differentiation and inhibited clonal proliferation of various myeloid
leukemia cell lines, suggesting a therapeutic niche for their use in
myeloid leukemia.
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