AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells
AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells
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DOI：
10.1182/blood.v87.4.1520.bloodjournal8741520
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发表时间：
1996-02-15
期刊：
影响因子：
20.3
通讯作者：
Garattini, E
中科院分区：
文献类型：
--
作者：
Gianni, M;Calzi, ML;Garattini, E
全反式维甲酸（ATRA）成功用于急性早幼粒细胞白血病（APL）的细胞分化治疗。矛盾的是，APL细胞表达PML-RAR，这是一种源自白血病特异性t染色体易位的视黄酸受体α (RAR α)的异常形式。我们在此表明，AM580是一种稳定的维甲酸衍生物，最初是作为RAR α激动剂合成的，在APL衍生细胞系NB4和新分离的APL母细胞中是一种强大的粒细胞成熟诱诱剂。在用AM580单独或与粒细胞集落刺激因子（G-CSF）联合治疗APL细胞后，该化合物诱导粒细胞成熟，通过测定白细胞碱性磷酸酶，CD11b, CD33，和G-CSF受体mRNA，其浓度比产生类似效果所需的ATRA低10至100倍。相比之下，AM580在调节HL-60细胞系和从慢性髓性白血病患者外周血中获得的新分离的粒细胞在疾病稳定期中这些分化标志物的表达方面不如ATRA有效。在NB4细胞中，另外两种合成的非选择性RAR配体与AM580一样能够诱导LAP，而RAR β或RAR γ特异性配体则完全无效。这些结果表明，AM580仅在PML-RAR存在的细胞中比ATRA更有效地调节分化抗原的表达。利用瞬时转染PML-RAR和正常RAR α的COS-7细胞进行的结合实验表明，AM580对这两种受体的亲和力低于ATRA。然而，在PML-RAR存在的情况下，合成类维甲酸是一个比天然类维甲酸更好的反激活剂，而在RAR α存在的情况下，AM580和ATRA具有相似的活性。这可能解释了AM580在含pml - rar的白血病细胞中具有很强的细胞分化潜能。(C) 1996年由美国血液病学会出版。
All-trans retinoic acid (ATRA) is successfully used in the cyto-differentiating treatment of acute promyelocytic leukemia (APL). Paradoxically, APL cells express PML-RAR, an aberrant form of the retinoic acid receptor type alpha (RAR alpha) derived from the leukemia-specific t(15;17) chromosomal translocation. We show here that AM580, a stable retinobenzoic derivative originally synthesized as a RAR alpha agonist, is a powerful inducer of granulocytic maturation in NB4, an APL-derived cell line, and in freshly isolated APL blasts, After treatment of APL cells with AM580 either alone or in combination with granulocyte colony-stimulating factor (G-CSF), the compound induces granulocytic maturation, as assessed by determination of the levels of leukocyte alkaline phosphatase, CD11b, CD33, and G-CSF receptor mRNA, at concentrations that are 10- to 100-fold lower than those of ATRA necessary to produce similar effects. By contrast, AM580 is not so effective as ATRA in modulating the expression of these differentiation markers in the HL-60 cell line and in freshly isolated granulocytes obtained from the peripheral blood of chronic myelogenous leukemia patients during the stable phase of the disease. In NB4 cells, two other synthetic nonselective RAR ligands are capable of inducing LAP as much as AM580, whereas RAR beta- or RAR gamma-specific ligands are totally ineffective. These results show that AM580 is more powerful than ATRA in modulating the expression of differentiation antigens only in cells in which PML-RAR is present. Binding experiments, using COS-7 cells transiently transfected with PML-RAR and the normal RAR alpha, show that AM580 has a lower affinity than ATRA for both receptors. However, in the presence of PML-RAR, the synthetic retinoid is a much better transactivator of retinoic acid-responsive element-containing promoters than the natural retinoid, whereas, in the presence of RAR alpha, AM580 and ATRA have similar activity. This may explain the strong cyto-differentiating potential of AM580 in PML-RAR-containing leukemic cells. (C) 1996 by The American Society of Hematology.