Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit
Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit
复制标题
DOI：
10.1016/s0301-472x(03)00112-7
复制
发表时间：
2003-08-01
影响因子：
2.6
通讯作者：
Metcalfe, DD
中科院分区：
文献类型：
--
作者：
Akin, C;Brockow, K;Metcalfe, DD
Objective. STI 571是一种酪氨酸激酶抑制剂，可抑制干细胞因子（SCF）受体kit的激酶活性。由于影响密码子816的c-kit激活突变与人肥大细胞肿瘤相关，我们确定STI 571是否对肿瘤和正常人肥大细胞产生类似的细胞毒性作用。我们研究了将STI 571以增加的浓度（0.01至10微摩尔）加入到两种HMC-1人肥大细胞白血病细胞系中的作用，这两种细胞系在密码子816或560处携带两种不同的激活c-kit突变，以及药物对从携带突变密码子816或野生型c-kit的患者获得的短期骨髓培养物的作用。STI 571不能抑制携带密码子816突变的HMC-1（560，816）细胞的生长，但有效地抑制携带野生型密码子816的c-kit的HMC-1560的增殖。STI 571在携带密码子816 c-kit突变的患者的短期培养物中不诱导肿瘤性骨髓肥大细胞的优先杀伤。与此相反，STI 571可显著降低无c-kit基因816密码子突变的患者的肥大细胞数量。这些结果表明，STI 571，虽然有效地杀死肥大细胞与野生型c-kit，没有显示出优先的细胞毒性肿瘤的人肥大细胞，因此可能不是有效的治疗与密码子816 c-kit突变相关的人系统性肥大细胞增多症。(C)2003年国际实验血液学学会。爱思唯尔公司出版
Objective. STI571 is a tyrosine kinase inhibitor which inhibits the kinase activity of kit, the receptor for stem cell factor (SCF). Because activating mutations of c-kit affecting codon 816 are associated with human mast cell neoplasms, we determined whether STI571 exerted a similar cytotoxic effect on neoplastic and normal human mast cells.Methods. We investigated the effect of addition of STI571 in increasing concentrations (0.01 to 10 micromolar) to two HMC-1 human mast cell leukemia cell lines carrying two different activating c-kit mutations in codons 816 or 560, as well as the effect of the drug on short-term bone marrow cultures obtained from patients who carry a mutated codon 816 or wild-type c-kit.Results. STI571 failed to inhibit the growth of HMC-1(560,816) cells bearing a codon 816 mutation but effectively suppressed the proliferation of HMC-1560 carrying c-kit with the wild-type codon 816. STI571 did not induce preferential killing of neoplastic bone marrow mast cells in short-term cultures from patients bearing a codon 816 c-kit mutation. In contrast, STI571 caused a dramatic reduction in mast cells in patients without codon 816 c-kit mutations.Conclusion. These results suggest that STI571, while effectively killing mast cells with wildtype c-kit, did not show preferential cytotoxicity to neoplastic human mast cells and thus may not be effective in the treatment of human systemic mastocytosis associated with codon 816 c-kit mutations. (C) 2003 International Society for Experimental Hematology. Published by Elsevier Inc.