9-CIS RETINOIC ACID INDUCES COMPLETE REMISSION BUT DOES NOT REVERSE CLINICALLY ACQUIRED RETINOID RESISTANCE IN ACUTE PROMYELOCYTIC LEUKEMIA

Citation
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
Citations number
41
Categorie Soggetti
Hematology
Journal title
BloodACNP
ISSN journal
00064971
Volume
85
Issue
11
Year of publication
1995
Pages
3021 - 3027
Database
ISI
SICI code
0006-4971(1995)85:11<3021:9RAICR>2.0.ZU;2-O
Abstract
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.