title: Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia.
abstract: Although all-trans retinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), all groups have described clinical relapses despite continued RA treatment. This finding suggests that resistance to the cytodifferentiating effects of the retinoid had been acquired. To investigate potential mechanisms of clinical resistance to RA, we serially evaluated the clinical pharmacology of the drug in APL patients treated with this agent. Leukemic cells from patients relapsing from RA treatment were cultured in the presence of RA and examined for evidence of morphologic maturation. We also studied messenger RNA expression of the newly described gene product of the (15;17) translocation in APL, PML/RA receptor-alpha (PML/RAR-alpha). Serial pharmacokinetic studies showed that continuous daily RA treatment was associated with a marked decrease in plasma drug concentrations at the time of relapse compared with the initial day of therapy. Doubling the RA dose in six patients failed to reinduce response at the time of relapse and also failed to significantly augment plasma RA concentrations. However, leukemic cells obtained at the time of relapse from four patients retained in vitro sensitivity to the differentiating activity of RA (10(-6) mol/L). No change was observed in the pattern of PML/RAR-alpha expression assessed by Northern blot analysis at the time of relapse compared with pretreatment in two patients who were tested. These results indicate that clinical relapse and "resistance" to continuous treatment with all-trans RA in APL is associated with progressive reduction of plasma concentrations, potentially to levels below those that sustain differentiation of leukemic cells in vivo. Long-term success of this treatment will require the development of strategies that circumvent this pharmacologic phenomenon.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021.
authors.forename: J
authors.initials: J
authors.lastname: Muindi
authors.forename: S R
authors.initials: SR
authors.lastname: Frankel
authors.forename: W H
authors.initials: WH
authors.lastname: Miller
authors.forename: A
authors.initials: A
authors.lastname: Jakubowski
authors.forename: D A
authors.initials: DA
authors.lastname: Scheinberg
authors.forename: C W
authors.initials: CW
authors.lastname: Young
authors.forename: E
authors.initials: E
authors.lastname: Dmitrovsky
authors.forename: R P
authors.initials: RP
authors.lastname: Warrell
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009364:Neoplasm Recurrence, Local; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid; D012074:Remission Induction; D014178:Translocation, Genetic; D014212:Tretinoin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014212:Tretinoin