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9-cis retinoic acid induces complete remission but does not reverse
clinically acquired retinoid resistance in acute promyelocytic leukemia
WH Miller , A Jakubowski, WP Tong, VA Miller, JR Rigas, F Benedetti, GM Gill, JA Truglia, E Ulm and M Shirley
Department of Medicine, Memorial Sloan Kettering Cancer Center, Cornell
University Medical College, New York, NY 10021, USA.
9-cis retinoic acid (RA) is a high-affinity ligand for both retinoic acid
receptors (RARs) and retinoid "X" receptors (RXRs). Although all- trans RA
does not bind to RXRs, RAR/RXR heterodimers or RXR/RXR homodimers bind to
specific DNA response elements and modulate proliferation and
differentiation of normal and malignant cells. Because the development of
clinical resistance to all-trans RA has been associated with a progressive
decrease in plasma drug concentrations, we evaluated the ability of 9-cis
RA to induce in vitro cytodifferentiation in subclones of a
retinoid-sensitive and resistant APL cell line (NB4) and in short-term
cultures of fresh leukemic cells aspirated from patients. We also evaluated
the clinical activity and pharmacokinetics of 9-cis RA (LGD 1057) in
patients with APL who were previously treated with all-trans RA. In vitro
tests of both retinoid- sensitive NB4 cells, as well as samples of fresh
cells from 11 patients with APL, showed relatively equivalent degrees of
sensitivity to both 9- cis RA and all-trans RA at concentrations ranging
from 10(-6) to 10(-8) mol/L; however, no substantial cytodifferentiation
was observed using either drug alone or in combination (10(-6) mol/L of
each) in retinoid- resistant NB4 cells. Seven patients with APL who had
previously relapsed from a remission induced by all-trans RA were treated
with 9- cis RA at daily oral doses ranging from 30 to 230 mg/m2.
Pharmacokinetic studies showed that the mean terminal plasma half-life of
9-cis RA (1.3 hours) changed very little after several weeks of dosing,
although the mean change per dose level in area under the plasma
concentration x time curves and peak plasma concentrations showed a
decrease by 49% and 45%, respectively. Peak plasma concentrations equaled
or exceeded concentrations that were effective against retinoid-sensitive
cells in vitro. Despite these favorable pharmacokinetic results, only one
of the seven patients achieved complete remission, corroborating in vitro
studies of blasts from three of the nonresponders that showed a relatively
equivalent degree of resistance to both retinoids. Our results suggest that
while 9-cis RA may not induce its own catabolism to the same degree as
all-trans RA, this feature does not appear to overcome clinically acquired
resistance to all-trans RA in APL. Nonetheless, the drug can induce
complete remissions in patients with APL and may be useful for extended
therapy in other diseases. Future studies should address the use of lower
doses in patients who have not previously received retinoid
therapy.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 85,
Issue 11,
pp. 3021-3027,
06/01/1995
Copyright © 1995 by The American Society of Hematology
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