Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells
Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells
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DOI：
10.1182/blood-2003-10-3381
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发表时间：
2004-12-15
期刊：
影响因子：
20.3
通讯作者：
Heinrich, MC
中科院分区：
文献类型：
--
作者：
Yee, KWH;Schittenhelm, M;Heinrich, MC
胎儿肝脏酪氨酸激酶3内部串联重复（FLT 3 ITD）突变是与成人急性髓性白血病（AML）相关的最常见的分子异常。为了利用这一分子靶点，已经开发了许多有效和特异性的FLT 3激酶抑制剂，目前正在难治性AML患者的早期临床试验中进行测试。为了探索FLT 3抑制剂与标准AML化疗药物组合的功效，我们测试了FLT 3抑制剂SU 11248与阿糖胞苷或柔红霉素组合对表达突变体（FLT 3 ITD或FLT 3 D835 V）或野生型（WT）FLT 3的细胞系的增殖和存活的影响。当与阿糖胞苷或柔红霉素联合使用时，SU 11248对FLT 3依赖性白血病细胞增殖具有相加-协同抑制作用。SU 11248与传统抗白血病药物的协同作用在诱导细胞凋亡方面更为明显。SU 11248抑制表达突变型FLT 3 ITD但不表达WT FLT 3蛋白的原代AML成髓细胞的增殖。SU 11248和阿糖胞苷联合使用可协同抑制表达FLT 3 ITD但不表达WT FLT 3蛋白的原代AML成髓细胞的增殖。这些数据表明，在AML化疗方案中添加强效FLT 3抑制剂（如SU 11248）可改善治疗结果。(C)2004年，美国血液学会。
Fetal liver tyrosine kinase 3 internal tandem duplication (FLT3 ITD) mutations are the most common molecular abnormality associated with adult acute myeloid leukemia (AML). To exploit this molecular target, a number of potent and specific FLT3 kinase inhibitors have been developed and are currently being tested in early phase clinical trials of patients with refractory AML. To explore the efficacy of combining a FLT3 inhibitor with standard AML chemotherapy drugs, we tested the effect of combining the FLT3 inhibitor SU11248 with cytarabine or daunorubicin on the proliferation and survival of cell lines expressing either mutant (FLT3 ITD or FLT3 D835V) or wild-type (WT) FLT3. SU11248 had additive-to-synergistic inhibitory effects on FLT3-dependent leukemic cell proliferation when combined with cytarabine or daunorubicin. The synergistic interaction of SU11248 and the traditional antileukemic agents was more pronounced for induction of apoptosis. SU11248 inhibited the proliferation of primary AML myeloblasts expressing mutant FLT3 ITD but not WT FLT3 protein. Combining SU11248 and cytarabine synergistically inhibited the proliferation of primary AML myeloblasts expressing FLT3 ITD but not WT FLT3 protein. These data suggest that the addition of potent FLT3 inhibitors such as SU11248 to AML chemotherapy regimens could result in improved treatment results. (C) 2004 by The American Society of Hematology.