Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down Syndrome cells: A contributing factor to the superior event free survival of Down Syndrome children with acute myeloid leukemia
Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down Syndrome cells: A contributing factor to the superior event free survival of Down Syndrome children with acute myeloid leukemia
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DOI：
10.1182/blood.v87.8.3395.bloodjournal8783395
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发表时间：
1996-04-15
期刊：
影响因子：
20.3
通讯作者：
Ravindranath, Y
中科院分区：
文献类型：
--
作者：
Taub, JW;Matherly, LH;Ravindranath, Y
与非唐氏综合征儿童相比，患有急性髓细胞白血病（AML）的唐氏综合征（DS）儿童在接受含有1-β-D-阿拉伯呋喃糖基胞嘧啶（ara-C）的方案治疗时，无事件生存率（EFS）显著更高。阿糖胞苷的敏感性和代谢进行了检查，从DS和非DS患者AML，DS婴儿与短暂性骨髓增生性疾病，EB病毒（EBV）转化的淋巴母细胞样细胞系与三体21。暴露于阿糖胞苷72小时后，与非DS成髓细胞相比，DS成髓细胞对阿糖胞苷的敏感性约高10倍（通过3-[4，5-二甲基-噻唑-2-基]-2，5-二苯基溴化四唑（MTT）比色敏感性试验测量）。与5 μ mol/L ara-C孵育后，DS成髓细胞中1-β-D-阿拉伯呋喃糖基胞嘧啶5 '-三磷酸（ara-CTP）的平均水平显著高于非DS成髓细胞（621.4 vs228.4 pmol/mg蛋白）。与二倍体染色体数目的细胞系相比，DS细胞系也产生了更高水平的ara-CTP（在1和5 μ mol/L ara-C时，分别为66.5 v13.6 pmol/mg蛋白和137.6 v41.7 pmol/mg蛋白）。DS细胞中ara-CTP水平升高伴随着内源性脱氧胞苷三磷酸（dCTP）池水平略低，ara-C掺入DNA的程度略大，双链DNA链断裂的相对数量增加。DS和非DS细胞的细胞周期分布无显著差异。这些体外研究支持我们的假设，即DS细胞中阿糖胞苷代谢增强可能是AML DS儿童上级生存率的一个促成因素，并且可能基于定位于21号染色体的基因（包括胱硫醚-β-合酶）的基因剂量效应。进一步研究所涉及的机制（dCTP池和DNA甲基化的改变）可能会改善所有AML患者的治疗。(C)1996年，美国血液学会。
Down syndrome (DS) children with acute myeloid leukemia (AML) have significantly higher event-free survival (EFS) rates compared with non-DS children when treated with protocols containing 1-beta-D-arabinofuranosylcytosine (ara-C). Sensitivity and metabolism of ara-C was examined in myeloblasts from DS and non-DS patients with AML, DS infants with the transient myeloproliferative disorder, and Epstein-Barr Virus (EBV) transformed lymphoblastoid cell lines with and without trisomy 21. DS myeloblasts were approximately 10-fold more sensitive to ara-C (measured by the 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) colorimetric sensitivity assay), compared with non-DS myeloblasts, following exposure to ara-C for 72 hours. Mean levels of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) were significantly higher in DS myeloblasts compared with non-DS myeloblasts after incubation with 5 mu mol/L ara-C (621.4 v 228.4 pmol/mg protein). DS cell lines also generated higher levels of ara-CTP compared with cell lines with diploid chromosome numbers (66.5 v 13.6 pmol/mg protein and 137.6 v 41.7 pmol/mg protein at 1 and 5 mu mol/L ara-C, respectively). Elevated ara-CTP levels in the DS cells were accompanied by slightly lower levels of endogenous deoxycytidine triphosphate (dCTP) pools, slightly greater extent of ara-C incorporation into DNA, and increased relative numbers of double strand DNA strand breaks. There were no significant differences in the cell cycle distributions of DS and non-DS cells. These in vitro studies support our hypothesis that enhanced metabolism of ara-C in DS cells may be a contributing factor to the superior survival rate of DS children with AML and is possibly based on a gene dosage effect of genes localized to chromosome 21 including cystathionine-beta-synthase. Further study of the mechanisms tie, alterations in dCTP pools and DNA methylation) involved may lead to improvements in the treatment of all AML patients. (C) 1996 by The American Society of Hematology.