FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo
FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo
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DOI：
10.1182/blood-2010-01-266742
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发表时间：
2011-03-24
期刊：
影响因子：
20.3
通讯作者：
Levis, Mark
中科院分区：
文献类型：
--
作者：
Sato, Takashi;Yang, Xiaochuan;Levis, Mark
我们研究了在急性髓性白血病患者中的体内FLT 3抑制作用，这些患者接受化疗，然后使用FLT 3抑制剂来替尼，并将新诊断的急性髓性白血病患者与复发患者进行比较。因为我们注意到，与新诊断的患者相比，复发患者体内通过来鲁替尼抑制FLT 3的效果较差，所以我们研究了血浆FLT 3配体（FL）水平是否会影响这些患者中FLT 3抑制的疗效。在强化化疗后，新诊断患者的FL水平在诱导治疗的第15天上升到平均488 pg/mL，而复发患者的FL水平上升到平均1148 pg/mL。FL水平随着化疗的连续疗程而升高，在第四个疗程后平均为3251 pg/mL。在体外，浓度与患者中观察到的浓度相似的外源性FL减轻了5种不同FLT 3抑制剂（来洛替尼、米多替林、索拉非尼、KW-2449和AC 220）的FLT 3抑制和细胞毒性。化疗后FL水平的急剧增加代表了在这种临床环境中抑制FLT 3的可能障碍。这些发现可能对FLT 3抑制剂试验的设计和结果产生重要影响，并进一步表明将FL作为治疗策略的基本原理。（血。2011;117（12）：3286-3293）
We examined in vivo FLT3 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly diagnosed acute myeloid leukemia patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. After intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients, whereas they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated FLT3 inhibition and cytotoxicity for each of 5 different FLT3 inhibitors (lestaurtinib, midostaurin, sorafenib, KW-2449, and AC220). The dramatic increase in FL level after chemotherapy represents a possible obstacle to inhibiting FLT3 in this clinical setting. These findings could have important implications regarding the design and outcome of trials of FLT3 inhibitors and furthermore suggest a rationale for targeting FL as a therapeutic strategy. (Blood. 2011;117(12):3286-3293)