Role of α1 acid glycoprotein in the in vivo resistance of human BCR-ABL+ leukemic cells to the Abl inhibitor STI571
Role of α1 acid glycoprotein in the in vivo resistance of human BCR-ABL+ leukemic cells to the Abl inhibitor STI571
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DOI：
10.1093/jnci/92.20.1641
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发表时间：
2000-10-18
影响因子：
10.3
通讯作者：
D'Incalci, M
中科院分区：
文献类型：
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作者：
Gambacorti-Passerini, C;Barni, R;D'Incalci, M
背景：慢性粒细胞白血病是由染色体易位引起的，染色体易位导致致癌融合蛋白 Bcr-Abl，Bcr-Abl 是一种酪氨酸激酶，其活性被抗肿瘤药物 STI571 抑制。这种药物可以治愈注射人类白血病细胞的小鼠，但在开始治疗时，对于患有大肿瘤的动物来说，治疗最终会失败。我们建立了小鼠模型来探索体内耐药机制。方法：裸鼠注射KU812 Ber-Abl(+)人白血病细胞。 1 天（无明显肿瘤）、8 天或 15 天（肿瘤 >1 g）后，用 STI571（每 8 小时 160 mg/kg）治疗小鼠。从复发动物身上回收的细胞用于体外实验。统计检验是双面的。结果：所有接受 STI571 治疗的小鼠的肿瘤最初都消退了，但所有接受肿瘤细胞注射 15 天后的小鼠最终都复发了。复发的动物对进一步的 STI571 治疗没有反应，尽管 STI571 的血浆浓度很高，但它们体内的 Bcr-Abl 激酶活性没有被 STI571 抑制。然而，来自耐药动物的肿瘤细胞在体外对 STI571 敏感，这表明复发动物血浆中的一种分子可能会使该药物失活。血浆蛋白油酸性糖蛋白（AGP）在体外以生理浓度结合STI571，并以剂量依赖性方式阻断STI571抑制Bcr-Abl激酶活性的能力。血浆 AGP 浓度与肿瘤负荷密切相关。红霉素与 STI571 竞争 AGP 结合。当携带大肿瘤的动物单独使用 STI571 或 STI571 与红霉素联合治疗时，联合治疗后观察到更大的肿瘤缩小和更好的长期无瘤生存（第 180 天时，12 只动物中的 10 只与 13 只中的 1 只；P < .001）。结论：复发动物血浆中的 AGP 与 STI571 结合，阻止该化合物抑制 Bcr/Abl 酪氨酸激酶。红霉素等分子与 STI571 竞争与 AGP 的结合，可能会增强该药物的治疗潜力。
Background: Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl, Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571. This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated. We created a mouse model to explore the mechanism of resistance in vivo, Methods: Nude mice were injected with KU812 Ber-Abl(+) human leukemic cells. After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours). Cells recovered from relapsing animals were used for in vitro experiments. Statistical tests were two-sided. Results: Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug. However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma protein oil acid glycoprotein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner. Plasma AGP concentrations were strongly associated with tumor load. Erythromycin competed with STI571 for AGP binding. When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P < .001) were observed after the combination treatment. Conclusion: AGP in the plasma of relapsed animals binds to STI571, preventing this compound from inhibiting the Bcr/Abl tyrosine kinase. Molecules such as erythromycin that compete with STI571 for binding to AGP may enhance the therapeutic potential of this drug.