Department of Hematology and Oncology, Charité-University Medicine, Berlin, Germany
Department of Hematology and Oncology, Charité-University Medicine, Berlin, Germany.
Anticancer Res. 2014 Sep;34(9):4909-14.
BACKGROUND/AIM: BCR-ABL-positive (BCR-ABL(+)) leukemia is very difficult to treat although much improvement has been achieved due to the clinical application of imatinib and the second-generation tyrosine kinase inhibitors (TKIs). This study aimed to evaluate for the first time the treatment value of the multiple tyrosine kinase inhibitor TKI258 in BCR-ABL(+) leukemia.
Proliferation of different BCR-ABL(+) leukemic cells was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; cell apoptosis with Annexin V/propidium iodide (PI) and flow cytometry. Gene expression at the protein level was determined by western blotting.
This drug showed treatment efficacy in naïve and imatinib-resistant BCR-ABL(+) leukemia cells, particularly in cells harboring T315I-mutated BCR-ABL, for which no effective inhibitor is available to date. By combination with the mTOR inhibitor RAD001, a synergistic effect on cell proliferation was observed in these cell lines.
TKI258 may become a potent therapeutic agent, either alone or in combination with RAD001, for treatment of BCR-ABL(+) leukemia.
背景/目的：尽管由于伊马替尼和第二代酪氨酸激酶抑制剂（TKI）的临床应用，BCR-ABL 阳性（BCR-ABL(+））白血病的治疗取得了很大进展，但这种疾病仍然难以治疗。本研究首次旨在评估多靶点酪氨酸激酶抑制剂 TKI258 在 BCR-ABL(+)白血病中的治疗价值。
用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法测量不同 BCR-ABL(+)白血病细胞的增殖；用 Annexin V/碘化丙啶（PI）和流式细胞术测量细胞凋亡。通过蛋白质印迹测定基因表达水平。
该药物对初治和伊马替尼耐药的 BCR-ABL(+)白血病细胞均显示出治疗效果，特别是对目前尚无有效抑制剂的 T315I 突变 BCR-ABL 细胞。与 mTOR 抑制剂 RAD001 联合使用时，在这些细胞系中观察到对细胞增殖的协同作用。
TKI258 可能成为一种有效的治疗剂，无论是单独使用还是与 RAD001 联合使用，都可用于治疗 BCR-ABL(+)白血病。
