Delva L, Cornic M, Balitrand N, Guidez F, Micléa J M, Delmer A, Teillet F, Fenaux P, Castaigne S, Degos L
Laboratoire de Biologie Cellulaire Hématopoïétique, Université Paris VII, Centre Hayem, France.
Blood. 1993 Oct 1;82(7):2175-81.
All-trans retinoic acid (ATRA) induces leukemic cell differentiation and complete remission (CR) in a high proportion of patients with acute promyelocytic leukemia (AML3 subtype). However, relapses occur when ATRA is prescribed as maintenance therapy, and resistance to a second ATRA-induction therapy is frequently observed. An induced hypercatabolism of ATRA has been suggested as a possible mechanism leading to reduced ATRA sensitivity and resistance. CRABPII, an RA cytoplasmic binding protein linked to RA's metabolization pathway, is induced by ATRA in different cell systems. To investigate whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed, we studied the CRABP levels and in vitro sensitivity to ATRA of AML3 cells before and at relapse from ATRA. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with "virgin"-AML3 cells (n = 31; P < .05). Dose-response studies were performed in 2 cases at relapse and showed decreased sensitivity to low ATRA concentrations. CRABPII levels and in vitro differentiation characteristics of AML3 cells before and at relapse from ATRA therapy were studied concomittantly in 4 patients. High levels of CRABPII (median, 20 fmol/mg of protein) were detected in the cells of the 4 patients at relapse but were not detected before ATRA therapy. Three of these patients showed a decrease in differentiation induction of their leukemic cells, and a failure to achieve CR with a second induction therapy of ATRA 45 mg/m2/day was noted in all patients treated (n = 3). Results from this study provide evidence to support the hypothesis of induced-ATRA metabolism as one of the major mechanisms responsible for ATRA resistance. Monitoring CRABPII levels after ATRA withdrawal may help to determine when to administer ATRA in the maintenance or relapse therapy of AML3 patients.
全反式维甲酸（ATRA）可诱导急性早幼粒细胞白血病（AML3亚型）的大部分患者白血病细胞分化并实现完全缓解（CR）。然而，当将ATRA用作维持治疗时会出现复发，并且经常观察到对第二次ATRA诱导治疗产生耐药性。有人提出ATRA诱导的分解代谢增强是导致ATRA敏感性降低和耐药的一种可能机制。CRABPII是一种与视黄酸代谢途径相关的视黄酸细胞质结合蛋白，在不同细胞系统中可被ATRA诱导产生。为了研究AML3细胞复发时的特定特征是否可以解释所观察到的体内耐药性，我们研究了ATRA治疗前和复发时AML3细胞的CRABP水平以及对ATRA的体外敏感性。与“原始”AML3细胞（n = 31；P <.05）相比，复发的AML3细胞（n = 12）显示出分化诱导能力降低。对2例复发患者进行了剂量反应研究，结果显示对低浓度ATRA的敏感性降低。在4例患者中同时研究了ATRA治疗前和复发时AML3细胞的CRABPII水平和体外分化特征。在4例复发患者的细胞中检测到高水平的CRABPII（中位数为20 fmol/mg蛋白质），但在ATRA治疗前未检测到。其中3例患者的白血病细胞分化诱导能力下降，并且在所有接受治疗的患者（n = 3）中均未观察到采用45 mg/m2/天的第二次ATRA诱导治疗实现CR。本研究结果提供了证据支持ATRA诱导代谢是导致ATRA耐药的主要机制之一这一假说。在停用ATRA后监测CRABPII水平可能有助于确定在AML3患者的维持或复发治疗中何时给予ATRA。
