Synergistic activity of linifanib and irinotecan increases the survival of mice bearing orthotopically implanted human anaplastic thyroid cancer.
Synergistic activity of linifanib and irinotecan increases the survival of mice bearing orthotopically implanted human anaplastic thyroid cancer.
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发表时间：
2020-07
影响因子：
5.3
通讯作者：
Marta Banchi;P. Orlandi;D. Gentile;G. Alí;Elisabetta Fini;G. Fontanini;G. Francia;G. Bocci
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文献类型：
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作者：
Marta Banchi;P. Orlandi;D. Gentile;G. Alí;Elisabetta Fini;G. Fontanini;G. Francia;G. Bocci
甲状腺未分化癌（ATC）是最具侵袭性的甲状腺癌，迫切需要新的联合疗法来延长患者的生存期。目前尚无有关 CSF-1R 抑制剂利尼替尼 (linifanib) 与伊立替康 (irinotecan) 组合在 ATC 中的临床前活性的数据。该研究的目的是评估利尼法尼加伊立替康的体外和体内活性。对暴露于 SN-38（伊立替康、利尼替尼单独用药及其联合用药的活性代谢物）的 8305C 和 8505C 人 ATC 细胞系进行增殖和凋亡测定。采用组合指数法评价协同作用。通过 ELISA 对 pospho-CSF-1R 水平进行定量。使用单一药物或其组合治疗体内 ATC 原位异种移植物，以评估它们对生存的影响。对 ATC 组织样本进行组织学和免疫组织化学分析。 SN-38 和 linifanib 均以浓度依赖性方式在体外抑制 8305C 和 8505C 细胞的增殖，而它们的联合治疗显示出对 ATC 细胞的强烈协同作用。在单独使用利尼法尼和与 SN-38 联合治疗的两种 ATC 细胞系中都发现了显着的促凋亡活性。此外，在 8505C 和 8305C 细胞中，24 小时和 72 小时后，linifanib 显着降低了磷酸化 CSF-1R 的水平，并且在同时施用 SN-38 的情况下也观察到了这一点。在体内，利尼替尼和伊立替康的组合比任一单一疗法产生了更好的生存结果，并导致显着更高的中位生存期。经组织学证实，在一些小鼠中，该组合产生了完全反应，疾病宏观消失。总之，利尼替尼/伊立替康组合的协同 ATC 抗肿瘤活性显着增加了 ATC 受影响小鼠的存活率并诱导了一些完全反应，表明该方案在 ATC 患者治疗中的潜在作用。
Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancer, and novel combined therapies are urgently needed to prolong patient survival. No data are currently available on the preclinical activity of the combination of linifanib, a CSF-1R inhibitor, and irinotecan in ATC. The aim of the study was to evaluate the in vitro and in vivo activity of linifanib plus irinotecan. Proliferation and apoptosis assays were performed on 8305C and 8505C human ATC cell lines exposed to SN-38, the active metabolite of irinotecan, linifanib alone, and their concomitant combination. Synergism was evaluated by the combination index method. Quantification of pospho-CSF-1R levels was performed by ELISA. In vivo ATC orthotopic xenografts were treated with the single drugs, or their combination, to evaluate their impact on survival. Histology and immunohistochemistry were performed on ATC tissue samples. Both SN-38 and linifanib inhibited in vitro the proliferation of 8305C and 8505C cells in a concentration-dependent manner, whereas their concomitant treatment revealed a strong synergism in the ATC cells. A significant pro-apoptotic activity was found in both ATC cell lines treated with linifanib alone and in combination with SN-38. Moreover, linifanib significantly decreased the levels of phospho-CSF-1R after 24 h and 72 h in both 8505C and 8305C cells, and this was also observed with the concomitant administration of SN-38. In vivo, the combination of linifanib and irinotecan produced a greater survival result than either monotherapy, and resulted in a significant higher median survival. In some of the mice the combination produced a complete response with a macroscopic disappearance of the disease, as confirmed by histology. In conclusion, the synergistic ATC antitumor activity of linifanib/irinotecan combination significantly increased the survival of ATC affected mice and induced some complete responses, suggesting a potential role of this schedule in ATC patient's treatment.