Kim Seungwon, Schiff Bradley A, Yigitbasi Orhan G, Doan Dao, Jasser Samar A, Bekele B Nebiyou, Mandal Mahitosh, Myers Jeffrey N
Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Unit 441, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, USA.
Mol Cancer Ther. 2005 Apr;4(4):632-40. doi: 10.1158/1535-7163.MCT-04-0293.
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies with a mean survival of only 6 months. The poor prognosis of patients with ATC reflects the current lack of curative therapeutic options and the need for development of novel therapeutic strategies. In this study, we report the results of a preclinical study of AEE788, a dual inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, against ATC. AEE788 was able to inhibit the proliferation and induce apoptosis of ATC cell lines in vitro. Administration of AEE788, alone and in combination with paclitaxel, to athymic nude mice bearing s.c. ATC xenografts inhibited the growth of ATC xenografts by 44% and 69%, respectively, compared with the control group. Furthermore, tumors from mice treated with AEE788, alone and in combination with paclitaxel, showed increase in apoptosis of tumor cells by approximately 6- and 8-fold, respectively, compared with the control group. The microvessel density within the ATC xenografts was decreased by >80% in the mice treated with AEE788 alone and in combination with paclitaxel compared with the control group. Lastly, immunofluorescence microscopy showed the inhibition of EGFR autophosphorylation on the tumor cells as well as the inhibition of VEGFR-2 autophosphorylation on tumor endothelium. Considering the fact that curative options seldom exist for patients with ATC, concurrent inhibition of EGFR and VEGFR tyrosine kinases seems to be a valid and promising anticancer strategy for these patients.
间变性甲状腺癌（ATC）是最具侵袭性的人类恶性肿瘤之一，平均生存期仅为6个月。ATC患者预后较差，这反映出目前缺乏有效的治疗选择，需要开发新的治疗策略。在本研究中，我们报告了表皮生长因子受体（EGFR）和血管内皮生长因子受体（VEGFR）酪氨酸激酶双重抑制剂AEE788针对ATC的临床前研究结果。AEE788在体外能够抑制ATC细胞系的增殖并诱导其凋亡。将AEE788单独及与紫杉醇联合应用于皮下接种ATC异种移植物的无胸腺裸鼠，与对照组相比，分别使ATC异种移植物的生长抑制了44%和69%。此外，与对照组相比，单独使用AEE788及与紫杉醇联合使用的小鼠肿瘤中，肿瘤细胞凋亡分别增加了约6倍和8倍。与对照组相比，单独使用AEE788及与紫杉醇联合使用的小鼠体内，ATC异种移植物中的微血管密度降低了80%以上。最后，免疫荧光显微镜检查显示肿瘤细胞上的EGFR自磷酸化受到抑制，肿瘤内皮细胞上的VEGFR-2自磷酸化也受到抑制。鉴于ATC患者很少有治愈的选择，同时抑制EGFR和VEGFR酪氨酸激酶似乎是这些患者一种有效的、有前景的抗癌策略。
