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.
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.
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DOI：
10.1182/blood.v79.2.299.bloodjournal792299
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发表时间：
1992-01
期刊：
影响因子：
20.3
通讯作者：
J. Muindi;S. Frankel;W. Miller;A. Jakubowski;D. Scheinberg;C. Young;E. Dmitrovsky;R. Warrell
中科院分区：
文献类型：
--
作者：
J. Muindi;S. Frankel;W. Miller;A. Jakubowski;D. Scheinberg;C. Young;E. Dmitrovsky;R. Warrell
尽管全反式维甲酸（RA）诱导高比例的急性早幼粒细胞白血病（APL）患者完全缓解，但所有组均描述了临床复发，尽管继续RA治疗。这一发现表明，对类维生素A的细胞分化作用的抗性已经获得。为了研究RA临床耐药的潜在机制，我们在接受该药物治疗的APL患者中连续评价了该药物的临床药理学。在RA存在下培养RA治疗复发患者的白血病细胞，并检查形态成熟的证据。我们还研究了新描述的APL（15;17）易位基因产物PML/RA受体-α（PML/RAR-α）的信使RNA表达。系列药代动力学研究表明，连续每日RA治疗与复发时的血浆药物浓度相比治疗的第一天显著降低相关。在6例患者中，RA剂量加倍未能在复发时恢复应答，也未能显著增加血浆RA浓度。然而，从4名患者复发时获得的白血病细胞在体外对RA（10（-6）mol/L）的分化活性保持敏感性。在两名接受检测的患者中，复发时与治疗前相比，通过北方印迹分析评估的PML/RAR-α表达模式未观察到变化。这些结果表明，APL患者的临床复发和对全反式RA持续治疗的“抵抗”与血浆浓度的逐渐降低相关，可能降低至低于维持体内白血病细胞分化的水平。这种治疗的长期成功将需要开发规避这种药理学现象的策略。
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.