Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia.
Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia.
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DOI：
10.1182/blood.v97.5.1404
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发表时间：
2001-03
期刊：
影响因子：
20.3
通讯作者：
D. Peters;R. Hoover;M. Gerlach;E. Koh;H. Zhang;K. Choe;P. Kirschmeier;W. Bishop;G. Daley
中科院分区：
文献类型：
--
作者：
D. Peters;R. Hoover;M. Gerlach;E. Koh;H. Zhang;K. Choe;P. Kirschmeier;W. Bishop;G. Daley
BCR/ABL是导致慢性粒细胞白血病（CML）的癌蛋白，通过Ras依赖性和Ras非依赖性机制转化造血细胞。法尼基蛋白转移酶抑制剂（FTIs）被设计为阻断突变型Ras信号传导，但它们也抑制野生型Ras转化细胞的生长，这意味着其他法尼基化靶点有助于FTI作用。在本研究中，对临床候选药物FTI SCH 66336抑制BCR/ABL转化的能力进行了表征。当针对BCR/ABL-BaF 3细胞（一种小鼠白血病细胞系）进行测试时，SCH 66336可有效抑制软琼脂集落形成，减缓增殖，并使细胞对凋亡刺激物敏感。活化的鸟苷三磷酸（GTP）结合Ras蛋白和电泳迁移率变动分析AP-1 DNA结合的定量表明，Ras效应途径被SCH 66336抑制。然而，SCH 66336在软琼脂集落形成和细胞增殖测定中比显性阴性Ras更具抑制性，表明对Ras以外的靶点具有活性。用SCH 66336处理的BCR/ABL-BaF 3细胞的细胞周期分析揭示了G2/M阻断，这与最近的报道一致，即调节G2/M检查点的着丝粒蛋白是FTI作用的关键法尼基化靶点。静脉注射BCR/ABL-BaF 3细胞的小鼠发生急性白血病，并在4周内死亡，伴有大量脾肿大、白色血细胞计数升高和贫血。相比之下，几乎所有接受SCH 66336治疗的小鼠都存活下来，并且在一年多的时间里保持无病状态。此外，SCH 66336选择性地抑制原代人CML细胞的造血集落形成。FTI SCH 66336作为一种口服无毒化合物，其作用机制与ABL酪氨酸激酶抑制不同，有望用于治疗BCR/ABL诱导的白血病。
BCR/ABL, the oncoprotein responsible for chronic myeloid leukemia (CML), transforms hematopoietic cells through both Ras-dependent and -independent mechanisms. Farnesyl protein transferase inhibitors (FTIs) were designed to block mutant Ras signaling, but they also inhibit the growth of transformed cells with wild-type Ras, implying that other farnesylated targets contribute to FTI action. In the current study, the clinical candidate FTI SCH66336 was characterized for its ability to inhibit BCR/ABL transformation. When tested against BCR/ABL-BaF3 cells, a murine cell line that is leukemogenic in mice, SCH66336 potently inhibited soft agar colony formation, slowed proliferation, and sensitized cells to apoptotic stimuli. Quantification of activated guanosine triphosphate (GTP)-bound Ras protein and electrophoretic mobility shift assays for AP-1 DNA binding showed that Ras effector pathways are inhibited by SCH66336. However, SCH66336 was more inhibitory than dominant-negative Ras in assays of soft agar colony formation and cell proliferation, suggesting activity against targets other than Ras. Cell cycle analysis of BCR/ABL-BaF3 cells treated with SCH66336 revealed G2/M blockade, consistent with recent reports that centromeric proteins that regulate the G2/M checkpoint are critical farnesylated targets of FTI action. Mice injected intravenously with BCR/ABL-BaF3 cells developed acute leukemia and died within 4 weeks with massive splenomegaly, elevated white blood cell counts, and anemia. In contrast, nearly all mice treated with SCH66336 survived and have remained disease-free for more than a year. Furthermore, SCH66336 selectively inhibited the hematopoietic colony formation of primary human CML cells. As an oral, nontoxic compound with a mechanism of action distinct from that of ABL tyrosine kinase inhibition, FTI SCH66336 shows promise for the treatment of BCR/ABL-induced leukemia.