Assessment of the in vivo antitumor effects of ENMD-2076, a novel multitargeted kinase inhibitor, against primary and cell line-derived human colorectal cancer xenograft models.
Assessment of the in vivo antitumor effects of ENMD-2076, a novel multitargeted kinase inhibitor, against primary and cell line-derived human colorectal cancer xenograft models.
复制标题
DOI：
10.1158/1078-0432.ccr-10-0325
复制
发表时间：
2010-06-01
期刊：
影响因子：
--
通讯作者：
Eckhardt SG
中科院分区：
文献类型：
--
作者：
Tentler JJ;Bradshaw-Pierce EL;Serkova NJ;Hasebroock KM;Pitts TM;Diamond JR;Fletcher GC;Bray MR;Eckhardt SG
本体内研究旨在研究ENMD-2076（一种小分子激酶抑制剂，对Aurora激酶A和B以及其他几种与癌症相关的酪氨酸激酶（包括血管内皮生长因子受体2、cKit和成纤维细胞生长因子受体1）具有活性）对人结直肠癌（CRC）鼠异种移植模型的疗效。HT-29 CRC细胞系异种移植物用媒介物或ENMD-2076（100或200 mg/kg）每日口服处理28天。肿瘤生长抑制，动态对比增强磁共振成像和18 FDG-正电子发射断层扫描进行评估的抗增殖，抗血管生成，抗代谢反应，分别。还通过免疫组织化学方法分析了对增殖的影响。另外，用ENMD-2076（100 mg/kg）处理来自原发性和转移性部位的三个患者来源的异种移植物，并评估肿瘤生长抑制。在HT-29异种移植模型中，ENMD-2076诱导初始肿瘤生长抑制，随后消退。通过动态对比增强磁共振成像测量，治疗与显著的肿瘤变白相关，表明血管分布丧失，肿瘤血管通透性和灌注显著降低。正电子发射断层扫描显示治疗第3天和第21天18FDG摄取显著减少，这与Ki-67评估的增殖显著减少相关。如通过肿瘤生长抑制所测量的，所有三种测试的患者来源的异种移植物对ENMD 2076治疗敏感。ENMD-2076对CRC的细胞系和患者来源的异种移植模型显示出稳健的抗肿瘤活性，其可通过功能成像检测，支持该药剂在CRC中的临床研究。
This in vivo study was designed to investigate the efficacy of ENMD-2076, a small-molecule kinase inhibitor with activity against the Aurora kinases A and B, and several other tyrosine kinases linked to cancer, including vascular endothelial growth factor receptor 2, cKit, and fibroblast growth factor receptor 1, against murine xenograft models of human colorectal cancer (CRC). HT-29 CRC cell line xenografts were treated with either vehicle or ENMD-2076 (100 or 200 mg/kg) orally daily for 28 days. Tumor growth inhibition, dynamic contrast-enhanced magnetic resonance imaging, and 18FDG-positron emission tomography were conducted to assess the anti-proliferative, antiangiogenic, and antimetabolic responses, respectively. Effects on proliferation were also analyzed by immunohistochemical methods. Additionally, three patient-derived xenografts from primary and metastatic sites were treated with ENMD-2076 (100 mg/kg) and assessed for tumor growth inhibition. In the HT-29 xenograft model, ENMD-2076 induced initial tumor growth inhibition followed by regression. Treatment was associated with significant tumor blanching, indicating a loss of vascularity and substantial reductions in tumor vascular permeability and perfusion as measured by dynamic contrast-enhanced magnetic resonance imaging. Positron emission tomography scanning showed significant decreases in 18FDG uptake at days 3 and 21 of treatment, which was associated with a marked reduction in proliferation as assessed by Ki-67. All three of the patient-derived xenografts tested were sensitive to treatment with ENMD 2076 as measured by tumor growth inhibition. ENMD-2076 showed robust antitumor activity against cell line and patient-derived xenograft models of CRC that is detectable by functional imaging, supporting clinical investigation of this agent in CRC.