Banchi Marta, Orlandi Paola, Gentile Daniela, Alì Greta, Fini Elisabetta, Fontanini Gabriella, Francia Giulio, Bocci Guido
Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa Pisa, Italy.
Dipartimento di Patologia Chirurgica, Medica, Molecolare e Dell'Area Critica, Università di Pisa Pisa, Italy.
Am J Cancer Res. 2020 Jul 1;10(7):2120-2127. eCollection 2020.
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.
间变性甲状腺癌（ATC）是甲状腺癌中侵袭性最强的一种，迫切需要新的联合疗法来延长患者生存期。目前尚无关于CSF-1R抑制剂林尼法尼与伊立替康联合用于ATC的临床前活性的数据。本研究的目的是评估林尼法尼联合伊立替康的体外和体内活性。对暴露于伊立替康的活性代谢产物SN-38、单独的林尼法尼及其联合用药的8305C和8505C人ATC细胞系进行增殖和凋亡检测。采用联合指数法评估协同作用。通过酶联免疫吸附测定法对磷酸化CSF-1R水平进行定量。用单一药物或其联合用药处理体内ATC原位异种移植瘤，以评估它们对生存期的影响。对ATC组织样本进行组织学和免疫组织化学检测。SN-38和林尼法尼均以浓度依赖性方式在体外抑制8305C和8505C细胞的增殖，而它们的联合处理在ATC细胞中显示出强烈的协同作用。在单独用林尼法尼处理以及与SN-38联合处理的两种ATC细胞系中均发现显著的促凋亡活性。此外，林尼法尼在8505C和8305C细胞中24小时和72小时后均显著降低磷酸化CSF-1R水平，在与SN-38联合给药时也观察到这一现象。在体内，林尼法尼和伊立替康的联合用药比单一疗法产生了更好的生存结果，并导致显著更高的中位生存期。在一些小鼠中，联合用药产生了完全缓解，疾病在宏观上消失，组织学证实了这一点。总之，林尼法尼/伊立替康联合用药的协同性ATC抗肿瘤活性显著提高了受ATC影响小鼠的生存期，并诱导了一些完全缓解，表明该方案在ATC患者治疗中具有潜在作用。
