Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation
Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation
复制标题
DOI：
10.1182/blood.v99.10.3792
复制
发表时间：
2002-05-15
期刊：
影响因子：
20.3
通讯作者：
Bhatia, R
中科院分区：
文献类型：
--
作者：
Holtz, MS;Slovak, ML;Bhatia, R
甲磺酸伊马替尼（STI 571）是治疗慢性粒细胞白血病（CML）的一种新的有前途的药物。尚未评价甲磺酸伊马替尼对CML中原始恶性祖细胞的影响，并且尚不清楚祖细胞生长的抑制是否代表增殖增加的抑制、凋亡的诱导或两者兼而有之。我们在此证明，体外暴露于患者通常达到的浓度（1-2 μ M）的甲磺酸伊马替尼96小时，可抑制BCR/ABL阳性原始祖细胞（6周长期培养起始细胞[LTCIC]）以及定向祖细胞（集落形成细胞[CFC]）。未观察到对正常LTCIC的抑制，对正常CFC的抑制明显较少。较高浓度的甲磺酸伊马替尼（5 μ M）没有显著增加对CML或正常LTCIC的抑制，但增加了对CIVIL CFC的抑制，并在较小程度上增加了对正常CFC的抑制。使用荧光染料羧基荧光素二乙酸琥珀酰亚胺酯分析细胞分裂表明，甲磺酸伊马替尼（1-2 μ M）抑制CML原始（CD 34（+）CD 38（-））和定型（CD 34（+）CD 38（+））祖细胞的循环的程度比正常细胞大得多。相反，用1至2 μ M伊马替尼甲磺酸盐处理没有显著增加经历凋亡的细胞的百分比。尽管较高浓度的甲磺酸伊马替尼（5 μ M）导致CIVIL细胞凋亡增加，但正常样品中的凋亡也增加。总之，在临床相关浓度下，甲磺酸伊马替尼通过逆转异常增加的增殖选择性抑制CIVIL原始祖细胞，但不显著增加细胞凋亡。这些结果表明，抑制Bcr-Abl酪氨酸激酶的甲磺酸伊马替尼恢复正常的造血，通过消除CML祖细胞的增殖优势，但消除所有CIVIL祖细胞可能不会发生。(C)2002年，美国血液学会。
Imatinib mesylate (STI571) is a promising new treatment for chronic myelogenous leukemia (CML). The effect of imatinib mesylate on primitive malignant progenitors in CML has not been evaluated, and it Is not clear whether suppression of progenitor growth represents inhibition of Increased proliferation, induction of apoptosis, or both. We demonstrated here that in vitro exposure to concentrations of imatinib mesylate usually achieved in patients (1-2 muM) for 96 hours inhibited BCR/ABL-positive primitive progenitors (6-week long-term culture-initiating cells [LTCICs]) as well as committed progenitors (colony-forming cells [CFCs]). No suppression of normal LTCICs and significantly less suppression of normal CFCs were observed. A higher concentration of imatinib mesylate (5 muM) did not significantly increase suppression of CML or normal LTCICs but did increase suppression of CIVIL CFCs, and to a lesser extent, normal CFCs. Analysis of cell division using the fluorescent dye carboxyfluorescein diacetate succinimidyl ester indicated that imatinib mesylate (1-2 muM) inhibits cycling of CML primitive (CD34(+)CD38(-)) and committed (CD34(+)CD38(+)) progenitors to a much greater extent than normal cells, Conversely, treatment with 1 to 2 muM imatinib mesylate did not significantly increase the percentage of cells undergoing apoptosis. Although a higher concentration of imatinib mesylate (5 muM) led to an increase in apoptosis of CIVIL cells, apoptosis also increased in normal samples. In summary, at clinically relevant concentrations, imatinib mesylate selectively suppresses CIVIL primitive progenitors by reversing abnormally increased proliferation but does not significantly increase apoptosis. These results suggest that inhibition of Bcr-Abl tyrosine kinase by imatinib mesylate restores normal hematopolesis by removing the proliferative advantage of CML progenitors but that elimination of all CIVIL progenitors may not occur. (C) 2002 by The American Society of Hematology.