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Myeloma cell growth arrest, apoptosis, and interleukin-6 receptor
modulation induced by EB1089, a vitamin D3 derivative, alone or in
association with dexamethasone
D Puthier, R Bataille, S Barille, MP Mellerin, JL Harousseau, A Ponzio, N Robillard, J Wijdenes and M Amiot
Oncogenese Immunohematologique Inserm U211, Institut de Biologie, Nantes,
France.
We have previously shown that malignant plasma cells expressed the specific
receptor for 1,25-dihydroxyvitamin D3 and that this derivative could
significantly inhibit the proliferation of such malignant cells. More
recently, new vitamin D3 derivatives have been generated with
extraordinarily potent inhibitory effects on leukemic cell growth in vitro.
These new data prompted us to (re)investigate the capacity of such new
vitamin D3 derivatives to inhibit myeloma cell growth in comparison with
that of dexamethasone, a potent antitumoral agent in multiple myeloma. In
the current study, we show that EB1089, a new vitamin D3 derivative, (1)
induces G1 growth arrest of human myeloma cells, which is only partially
reversed by interleukin-6 (IL-6); (2) induces apoptosis in synergy with
dexamethasone, IL-6, leukemia- inhibitory factor, and Oncostatin M, with an
agonistic anti-gp130 monoclonal antibody being unable to prevent this
apoptosis; (3) downregulates both the gp80 (ie, the alpha chain of the IL-6
receptor [IL-6Ralpha]) expression on malignant plasma cells and the
production of soluble IL-6Ralpha, and finally (4) inhibits the deleterious
upregulation of gp80 expression induced by dexamethasone while limiting the
dexamethasone-induced upregulation of gp130 expression. Considering that
these in vitro effects of EB1089 have been observed at doses obtainable in
vivo (without hypercalcemic effects), our present data strongly suggest
that EB1089 could have a true interest in the treatment of multiple
myeloma, especially in association with dexamethasone.
Volume 88,
Issue 12,
pp. 4659-4666,
12/15/1996
Copyright © 1996 by The American Society of Hematology
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