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首页> 外文期刊>Cancer chemotherapy and pharmacology. >A novel multi-targeted tyrosine kinase inhibitor, linifanib (ABT-869), produces functional and structural changes in tumor vasculature in an orthotopic rat glioma model
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A novel multi-targeted tyrosine kinase inhibitor, linifanib (ABT-869), produces functional and structural changes in tumor vasculature in an orthotopic rat glioma model

机译：在原位大鼠神经胶质瘤模型中，新型的多靶点酪氨酸激酶抑制剂linifanib（ABT-869）在肿瘤血管中产生功能和结构变化

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Tyrosine kinase inhibitors represent a class of targeted therapy that has proven to be successful for cancer treatment. Linifanib is a novel, orally active multi-targeted receptor tyrosine kinase (RTK) inhibitor that exhibits potent antitumor and antiangiogenic activities against a broad spectrum of experimental tumors and malignancies in patients. The compound is currently being evaluated in phase 2 and 3 clinical trials. To investigate the effectiveness of linifinib against gliomas and the mechanism of drug action, we characterized treatment-induced antitumor and antiangiogenic responses to linifanib in an orthotopic rat glioma model. The effect of linifanib treatment on tumor growth was determined by tumor volume assessment using anatomical magnetic resonance imaging (MRI). Changes in tumor microvessel function were evaluated with dynamic contrast-enhanced MRI (DCE-MRI). Immunohistochemistry (IHC) was applied to excised tumor samples to examine underlying changes in vascular structures and target receptor expression. Linifanib (10 mg/kg) given twice daily inhibited tumor growth following treatment for 7 days with tumor volumes being 149 ± 30 and 66 ± 7 mm 3 for vehicle-and linifanib-treated groups, respectively. A significant reduction of 37 ± 13% in tumor perfusion and microvessel permeability (measured by K trans) was observed as early as 2 h after administration compared with vehicle treatment. Continuous linifanib administration further reduced K trans at later time points until the end of the study (7 days post-treatment). At day 7, K trans was reduced by 75 ± 32% for linifanib treatment compared with vehicle treatment. Significant reduction in total blood vessel density and improved vessel wall integrity were observed, and staining for target receptor expression confirmed inhibition of phospho VEGFR-2 and PDGFR-β by linifanib treatment. These results demonstrate significant antitumor and antiangiogenic activity against gliomas by linifanib, a property that may result from the inhibition of VEGFR-2 and PDGFR-β-mediated vascular changes. DCE-MRI measured K trans changes at early treatment stages may be a useful pharmacodynamic marker for linifanib activity in clinical trials, and basal K trans may provide predictive value for tumor progression.
机译：酪氨酸激酶抑制剂代表了一类靶向疗法，已被证明对于癌症治疗是成功的。 Linifanib是一种新型的口服活性多靶点受体酪氨酸激酶（RTK）抑制剂，对多种实验性肿瘤和恶性肿瘤均表现出强大的抗肿瘤和抗血管生成活性。该化合物目前正在2期和3期临床试验中进行评估。为了研究linifinib对抗神经胶质瘤的有效性和药物作用机制，我们在原位大鼠神经胶质瘤模型中表征了治疗诱导的对linifanib的抗肿瘤和抗血管生成反应。通过使用解剖磁共振成像（MRI）的肿瘤体积评估来确定利尼法尼治疗对肿瘤生长的影响。用动态对比增强MRI（DCE-MRI）评估肿瘤微血管功能的变化。免疫组织化学（IHC）被应用于切除的肿瘤样本，以检查血管结构和靶受体表达的潜在变化。每天两次给予Linifanib（10 mg / kg）治疗7天后，抑制了肿瘤生长，媒介物和Linifanib治疗组的肿瘤体积分别为149±30和66±7 mm 3。与赋形剂治疗相比，最早在给药后2小时观察到肿瘤灌注和微血管通透性显着降低37±13％（通过K trans测定）。在以后的时间点，直到研究结束（治疗后7天），连续服用linifanib进一步降低了钾的反式。与媒介物治疗相比，利尼法尼治疗的第7天，K trans降低了75±32％。观察到总血管密度的显着降低和改善的血管壁完整性，并且针对靶受体表达的染色证实了利福尼单抗对磷酸化VEGFR-2和PDGFR-β的抑制。这些结果表明，利尼法尼布对神经胶质瘤具有显着的抗肿瘤和抗血管生成活性，这种特性可能是由于抑制了VEGFR-2和PDGFR-β介导的血管变化而产生的。 DCE-MRI在早期治疗阶段测得的K反式变化可能是临床试验中利尼法尼活性的有用药效学标志物，基础K反式可为肿瘤进展提供预测价值。

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