Marchetti M, Falanga A, Giovanelli S, Oldani E, Barbui T
Haematology Department, Osepadali Riuniti, Bergamo, Italy.
Br J Haematol. 1996 May;93(2):360-6. doi: 10.1046/j.1365-2141.1996.4911029.x.
Pulmonary distress symptoms and thrombotic complications are side-effects of all-trans-retinoic acid (ATRA) therapy for remission induction in acute promyelocytic leukaemia (APL). The ATRA-induced increase of leukaemic cell adhesive molecules may be responsible. To explore this we used a functional assay to study the effect of ATRA treatment on the adhesion of blast cells to cultured human endothelial cells (EC), endothelial cell matrix (ECM), and interleukin 1beta-activated EC (IL1 + EC). NB4 cells, a maturation-inducible human promyelocytic leukaemia cell line, were treated with 1 microM ATRA or the vehicle (control), labelled with 51Cr and tested in the adhesion assay. ATRA increased NB4 adhesion to EC (P<0.01), ECM (P<0.001) and IL1 + EC (P=n.s.). An inhibition study with anti-EC adhesion receptors MoAbs indicated that anti-E-selectin, anti-VCAM-1 and anti-ICAM-1 effectively inhibited cell adhesion to IL1 + EC (18+/-7%, 45 +/-6.9% and 29+/-6% inhibition, respectively) and to unstimulated EC. Preincubation of ATRA-treated NB4 cells with MoAbs anti-VLA4 and anti-LFA1, the VCAM-1 and ICAM-1 counter-receptors respectively, resulted in a significant inhibition of adhesion. Cytofluorimetric analysis of the NB4 cell membrane molecules confirmed the increase under ATRA of VLA4, LFA1, MAC1 and ICAM-1. Therefore ATRA increases NB4 cell adhesion to the endothelium and the subendothelial matrix. These findings parallel the increment of NB4 surface adhesive molecules, among which VLA4 and LFA1 appear to play an important part. These mechanisms may contribute to the complications of ATRA therapy in APL.
肺部窘迫症状和血栓形成并发症是全反式维甲酸（ATRA）治疗急性早幼粒细胞白血病（APL）诱导缓解过程中的副作用。ATRA诱导白血病细胞黏附分子增加可能是其原因。为探究这一点，我们采用功能测定法研究ATRA处理对原始细胞黏附于培养的人内皮细胞（EC）、内皮细胞基质（ECM）和白细胞介素1β激活的EC（IL1 + EC）的影响。用1 microM ATRA或溶剂（对照）处理可诱导成熟的人早幼粒细胞白血病细胞系NB4细胞，用51Cr标记并在黏附测定中进行检测。ATRA增加了NB4对EC（P<0.01）、ECM（P<0.001）和IL1 + EC（P无显著差异）的黏附。用抗EC黏附受体单克隆抗体进行的抑制研究表明，抗E-选择素、抗血管细胞黏附分子-1（VCAM-1）和抗细胞间黏附分子-1（ICAM-1）分别有效抑制细胞对IL1 + EC（分别为18±7%、45±6.9%和29±6%抑制）和未刺激EC的黏附。分别用抗VLA4和抗LFA1单克隆抗体对经ATRA处理的NB4细胞进行预孵育，VLA4和LFA1分别是VCAM-1和ICAM-1的反受体，结果导致黏附显著抑制。对NB4细胞膜分子的细胞荧光分析证实，在ATRA作用下VLA4、LFA1、MAC1和ICAM-1增加。因此，ATRA增加了NB4细胞对内皮和内皮下基质的黏附。这些发现与NB4表面黏附分子的增加平行，其中VLA4和LFA1似乎起重要作用。这些机制可能导致ATRA治疗APL时出现并发症。
