9-cis retinoic acid induces complete remission but does not reverse clinically acquired retinoid resistance in acute promyelocytic leukemia.
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)
Miller
W H
WH
Department of Medicine, Memorial Sloan Kettering Cancer Center, Cornell University Medical College, New York, NY 10021, USA.
Jakubowski
A
A
Tong
W P
WP
Miller
V A
VA
Rigas
J R
JR
Benedetti
F
F
Gill
G M
GM
Truglia
J A
JA
Ulm
E
E
Shirley
M
M
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006207:Half-Life; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D015473:Leukemia, Promyelocytic, Acute / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D015514:Oncogene Proteins, Fusion / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000032:analysis; D012074:Remission Induction; D012176:Retinoids / Q000494:pharmacology; D016879:Salvage Therapy; D016896:Treatment Outcome; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D014408:Biomarkers, Tumor; D007155:Immunologic Factors; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; D012176:Retinoids; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin