Combination therapy with lenvatinib and radiation significantly inhibits thyroid cancer growth by uptake of tyrosine kinase inhibitor
Combination therapy with lenvatinib and radiation significantly inhibits thyroid cancer growth by uptake of tyrosine kinase inhibitor
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DOI：
10.1016/j.yexcr.2020.112390
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发表时间：
2021-01-01
影响因子：
3.7
通讯作者：
Kanda, Akira
中科院分区：
文献类型：
--
作者：
Suzuki, Kensuke;Iwai, Hiroshi;Kanda, Akira
虽然外科治疗治愈了90%的分化型甲状腺癌(DTC)患者，但其余的患者，包括晚期DTC患者，临床结果很差。这些患有不可手术疾病的患者只有两种选择，即放射性碘治疗和酪氨酸激酶抑制剂(如lenvatinib)，这两种药物与治疗相关的不良事件发生率高，只能延长大约5-15个月的无进展生存期。在本研究中，我们研究了lenvatinib和放射(CTLR)联合治疗DTC的抗肿瘤作用。CTLR在体外协同抑制细胞复制和集落形成，抑制裸鼠肿瘤生长，无明显毒副作用，并抑制增殖标记物Ki-67的表达。CTLR还可诱导细胞凋亡和G2/M期细胞周期停滞。此外，用高效液相色谱和质谱仪对细胞内药物摄取的定量分析表明，照射后48h，细胞内对药物的摄取显著增加。这些数据表明，辐射引起的细胞膜通透性增加增加了左旋替尼的细胞内浓度，有助于协同作用。这种基于机制的联合治疗潜力表明，联合治疗是治疗晚期甲状腺癌的一种有效的新策略，副作用较少，可能是开发临床应用方案的里程碑。
Although surgical treatment cures >90% of differentiated thyroid cancer (DTC) patients, the remaining patients, including advanced DTC cases, have poor clinical outcomes. These patients with inoperable disease have only two choices of radioactive iodine therapy and tyrosine kinase inhibitors such as lenvatinib, which have a high incidence of treatment-related adverse events and can only prolong progression free survival by approximately 5-15 months.In this study, we investigated the antitumor effects of combination therapy with lenvatinib and radiation (CTLR) for DTC. CTLR synergistically inhibited cell replication and colony formation in vitro and tumor growth in nude mice without apparent toxicities and suppressed the expression of proliferation marker (Ki-67). CTLR also induced apoptosis and G2/M phase cell cycle arrest. Moreover, quantitative analysis of the intracellular uptake of lenvatinib using liquid chromatography and mass spectrometry demonstrated that intracellular uptake of lenvatinib was significantly increased 48 h following irradiation. These data suggest that increased membrane permeability caused by irradiation increases the intracellular concentration of levatinib, contributing to the synergistic effect.This mechanism-based potential of combination therapy suggests a powerful new therapeutic strategy for advanced thyroid cancer with fewer side effects and might be a milestone for developing a regimen in clinical practice.