Emerging Flt3 kinase inhibitors in the treatment of leukaemia.
Emerging Flt3 kinase inhibitors in the treatment of leukaemia.
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DOI：
10.1517/14728214.11.1.153
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发表时间：
2006-03-01
影响因子：
3.4
通讯作者：
Serve, Hubert
中科院分区：
文献类型：
--
作者：
Tickenbrock, Lara;Muller-Tidow, Carsten;Serve, Hubert
急性髓系白血病（AML）的特点是骨髓中高度增殖的白血病细胞浸润，这些细胞在髓系发育的不同阶段停止分化并具有生存优势。传统上，对于符合条件的患者，AML 采用积极的细胞毒疗法进行治疗，然后进行同种异体骨髓移植。然而，尽管采取了这种积极的治疗，许多患者还是复发并最终死于该疾病。在约 30% 的 AML 患者的白血病原始细胞中发现了受体酪氨酸激酶 Flt3 编码序列的激活突变。据描述，这些突变会严重改变该受体的信号传导特性，并在细胞系模型和原代小鼠骨髓中具有转化活性。携带最常见 Flt3 突变的患者的预后往往比没有突变的同类患者更差。因此，Flt3 似乎是一个有希望的治疗干预靶点。临床试验中正在评估几种抑制 Flt3 激酶活性的小分子用于治疗 AML。本文综述了Flt3的信号转导和生物学功能及其在正常和恶性造血过程中的突变以及针对Flt3激酶抑制的药物开发的最新进展。
Acute myeloid leukaemia (AML) is characterised by the infiltration of the bone marrow with highly proliferative leukaemic cells that stop to differentiate at different stages of myeloid development and carry survival advantages. Conventionally, AML is treated with aggressive cytotoxic therapy, in eligible patients followed by allogeneic bone marrow transplantation. However, despite this aggressive treatment, many patients relapse and eventually die from the disease. Activating mutations in the coding sequence of the receptor tyrosine kinase Flt3 are found in leukaemic blasts from approximately 30% of AML patients. The mutations have been described to severely alter the signalling properties of this receptor and to have transforming activity in cell-line models and in primary mouse bone marrow. The prognosis of patients harbouring the most common Flt3 mutations tends to be worse than that of comparable patients without the mutations. Thus, Flt3 seems a promising target for therapeutic intervention. Several small molecules that inhibit Flt3 kinase activity are being evaluated for the treatment of AML in clinical trials. This review article discusses the signal transduction and biological function of Flt3 and its mutations in normal and malignant haematopoiesis and recent progress in drug development aiming at the inhibition of Flt3 kinases.