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首页> 外文期刊>Molecular cancer therapeutics >Effective Concentration of a Multikinase Inhibitor within Bone Marrow Correlates with In Vitro Cell Killing in Therapy-Resistant Chronic Myeloid Leukemia
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Effective Concentration of a Multikinase Inhibitor within Bone Marrow Correlates with In Vitro Cell Killing in Therapy-Resistant Chronic Myeloid Leukemia

机译：骨髓内多激酶抑制剂的有效浓度与抗药性慢性粒细胞白血病的体外细胞杀伤有关

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Leukemia cells escape BCR-ABL-targeted therapy by developing mutations, such as T315I, in the p210(BCR-ABL) fusion protein in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Although most effort has been focused on development of new tyrosine kinase inhibitors, enrichment of these small-molecule inhibitors in the tumor tissue can also have a profound impact on treatment outcomes. Here, we report that a 2-hour exposure of the T315I-mutant CML cells to 10 mu mol/L of the multikinase inhibitor TG101209 suppressed BCR-ABL-independent signaling and caused cell-cycle arrest at G(2)-M. Further increase in drug concentration to 17.5 mmol/L blocked phosphorylation of the mutant BCR-ABL kinase and its downstream JAK2 and STAT5. The effective dosage to overcome therapy resistance identified in an in vitro setting serves as a guidance to develop the proper drug formulation for in vivo efficacy. A targeted formulation was developed to achieve sustained bone marrow TG101209 concentration at or above 17.5 mu mol/L for effective killing of CML cells in vivo. Potent inhibition of leukemia cell growth and extended survival were observed in two murine models of CML treated with 40 mg/kg intravenously administered targeted TG101209, but not with the untargeted drug at the same dosage. Our finding provides a unique approach to develop treatments for therapy-resistant CML. (C) 2016 AACR.
机译：白血病细胞通过在费城染色体阳性慢性粒细胞白血病（CML）的p210（BCR-ABL）融合蛋白中产生突变（例如T315I）来逃脱BCR-ABL靶向治疗。尽管大多数努力都集中在开发新的酪氨酸激酶抑制剂上，但是肿瘤组织中这些小分子抑制剂的富集也会对治疗结果产生深远影响。在这里，我们报告说T315I突变的CML细胞2小时暴露于10μmol / L的多激酶抑制剂TG101209抑制了BCR-ABL独立的信号传导并导致细胞周期停滞在G（2）-M。药物浓度进一步提高到17.5 mmol / L可以阻止突变BCR-ABL激酶及其下游JAK2和STAT5的磷酸化。在体外环境中确定的克服治疗抗性的有效剂量可作为指导，以开发出具有体内功效的合适药物制剂。开发了靶向制剂，以达到在体内有效杀死CML细胞达到或高于17.5μmol/ L的持续骨髓TG101209浓度。在用40 mg / kg静脉内靶向TG101209静脉注射治疗的CML的两个鼠模型中，观察到了对白血病细胞生长的有效抑制和延长的存活期，但未用相同剂量的未靶向药物治疗。我们的发现为开发抗治疗性CML的治疗方法提供了独特的方法。 （C）2016 AACR。

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