Wh. Miller et al., 9-CIS RETINOIC ACID INDUCES COMPLETE REMISSION BUT DOES NOT REVERSE CLINICALLY ACQUIRED RETINOID RESISTANCE IN ACUTE PROMYELOCYTIC LEUKEMIA, Blood, 85(11), 1995, pp. 3021-3027
9-cis retinoic acid (RA) is a high-affinity ligand for both retinoic a
cid receptors (RARs) and retinoid ''X'' receptors (RXRs), Although all
-trans RA does not bind to RXRs, RAR/RXR heterodimers or RXR/RXR homod
imers bind to specific DNA response elements and modulate proliferatio
n and differentiation of normal and malignant cells, Because the devel
opment of clinical resistance to all-trans RA has been associated with
a progressive decrease in plasma drug concentrations, we evaluated th
e ability of g-cis RA to induce in vitro cytodifferentiation in subclo
nes of a retinoid-sensitive and resistant APL cell line (NB4) and in s
hort-term cultures of fresh leukemic cells aspirated from patients. We
also evaluated the clinical activity and pharmacokinetics of B-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 relativel
y equivalent degrees of sensitivity to both g-cis RA and all-trans RA
at concentrations ranging from 10(-6) to 10(-8) mol/L; however, no sub
stantial cytodifferentiation was observed using either drug alone or i
n combination (10(-6) mol/L of each) in retinoid-resistant NB4 cells.
Seven patients with APL who had previously relapsed from a remission i
nduced by all-trans RA were treated with 9-cis RA at daily oral doses
ranging from 30 to 230 mg/m(2). Pharmacokinetic studies showed that th
e 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 dos
e 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 wer
e effective against retinoid-sensitive cells in vitro. Despite these f
avorable pharmacokinetic results, only one of the seven patients achie
ved 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 g-cis
RA may not induce its own catabolism to the same degree as all-trans R
A, this feature does not appear to overcome clinically acquired resist
ance to all-trans RA in APL, Nonetheless, the drug can induce complete
remissions in patients with APL and may be useful for extended therap
y in other diseases. Future studies should address the use of lower do
ses in patients who have not previously received retinoid therapy. (C)
1995 by The American Society of Hematology.