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AM580, a stable benzoic derivative of retinoic acid, has powerful and
selective cyto-differentiating effects on acute promyelocytic leukemia
cells
M Gianni, M Li Calzi, M Terao, G Guiso, S Caccia, T Barbui, A Rambaldi and E Garattini
Molecular Biology Unit, Centro Catullo e Daniela Borgomainerio, Istituto di
Ricerche Farmacologiche, Mario Negri, Milano, Italy.
All-trans retinoic acid (ATRA) is successfully used in the cyto-
differentiating treatment of acute promyelocytic leukemia (APL).
Paradoxically, APL cells express PML-RAR, an aberrant form of the retinoic
acid receptor type alpha (RAR alpha) derived from the leukemia- specific
t(15;17) chromosomal translocation. We show here that AM580, a stable
retinobenzoic derivative originally synthesized as a RAR alpha agonist, is
a powerful inducer of granulocytic maturation in NB4, an APL-derived cell
line, and in freshly isolated APL blasts. After treatment of APL cells with
AM580 either alone or in combination with granulocyte colony-stimulating
factor (G-CSF), the compound induces granulocytic maturation, as assessed
by determination of the levels of leukocyte alkaline phosphatase, CD11b,
CD33, and G-CSF receptor mRNA, at concentrations that are 10- to 100-fold
lower than those of ATRA necessary to produce similar effects. By contrast,
AM580 is not effective as ATRA in modulating the expression of these
differentiation markers in the HL-60 cell line and in freshly isolated
granulocytes obtained from the peripheral blood of chronic myelogenous
leukemia patients during the stable phase of the disease. In NB4 cells, two
other synthetic nonselective RAR ligands are capable of inducing LAP as
much as AM580, whereas RAR beta- or RAR gamma-specific ligands are totally
ineffective. These results show that AM580 is more powerful than ATRA in
modulating the expression of differentiation antigens only in cells in
which PML-RAR is present. Binding experiments, using COS-7 cells
transiently transfected with PML-RAR and the normal RAR alpha, show that
AM580 has a lower affinity than ATRA for both receptors. However, in the
presence of PML-RAR, the synthetic retinoid is a much better transactivator
of retinoic acid-responsive element-containing promoters than the natural
retinoid, whereas, in the presence of RAR alpha, AM580 and ATRA have
similar activity. This may explain the strong cyto-differentiating
potential of AM580 in PML-RAR-containing leukemic cells.
Volume 87,
Issue 4,
pp. 1520-1531,
02/15/1996
Copyright © 1996 by The American Society of Hematology
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