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9-cis-retinoic acid: effects on normal and leukemic hematopoiesis in vitro
A Sakashita, M Kizaki, S Pakkala, G Schiller, N Tsuruoka, R Tomosaki, JF Cameron, MI Dawson and HP Koeffler
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
Retinoic acid exhibits effects on the proliferation and differentiation of
many hematopoietic cells. Cellular responsiveness to retinoic acid (RA) is
conferred through two distinct classes of nuclear receptors, the RA
receptors (RARs) and the retinoid X receptors (RXRs). The RARs bind to both
9-cis- and all-trans-RAs, but 9-cis-RA alone directly binds and activates
RXR. This suggested that 9-cis-RA could have expanded hematopoietic
activities as compared with all-trans-RA. We compared the abilities of
9-cis- and all-trans-RAs to induce differentiation and inhibit
proliferation of three acute myelogenous leukemia (AML) cell lines and
fresh leukemic cells from 28 patients and found that: (1) 9-cis-RA in
general was more potent than all-trans-RA in suppressing the clonal growth
of two AML cell lines and 17 AML samples from patients, including four from
individuals with acute promyelocytic leukemia (APL). Eleven leukemic
samples, including three from patients with chronic myelogenous or chronic
myelomonocytic leukemia, were relatively refractory to both retinoids. (2)
The range of activities of both retinoids was similar except that the
clonal growth of samples from three AML patients were inhibited by
9-cis-RA, but not by all-trans-RA. (3) Both retinoids inhibited the clonal
proliferation of leukemia cells without necessarily inducing their
differentiation; in fact, the only fresh AML cells that were able to
undergo differentiation were from patients with APL and one individual with
M2 AML. (4) Both retinoids enhanced myeloid and erythroid clonal growth
from normal individuals, and 9-cis-RA showed slightly more stimulation of
the myeloid clonal growth than did the all-trans-RA. Our study suggests
that 9-cis-RA is worthy of further study for the treatment of selected
individuals with AML.
Volume 81,
Issue 4,
pp. 1009-1016,
02/15/1993
Copyright © 1993 by The American Society of Hematology
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