Marzola Pasquina, Degrassi Anna, Calderan Laura, Farace Paolo, Crescimanno Caterina, Nicolato Elena, Giusti Anna, Pesenti Enrico, Terron Andrea, Sbarbati Andrea, Abrams Tinya, Murray Lesley, Osculati Francesco
Dipartimento di Scienze Morfologico-Biomediche, Sezione di Anatomia ed Istologia, Università di Verona, Verona, Italy.
Clin Cancer Res. 2004 Jan 15;10(2):739-50. doi: 10.1158/1078-0432.ccr-0828-03.
The purpose of this research was to assess in vivo by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) the antiangiogenic effect of SU6668, an oral, small molecule inhibitor of the angiogenic receptor tyrosine kinases vascular endothelial growth factor receptor 2 (Flk-1/KDR), platelet-derived growth factor receptor, and fibroblast growth factor receptor 1.
A s.c. tumor model of HT29 human colon carcinoma in athymic mice was used. DCE-MRI with a macromolecular contrast agent was used to measure transendothelial permeability and fractional plasma volume, accepted surrogate markers of tumor angiogenesis. CD31 immunohistochemical staining was used for assessing microvessels density and vessels area. Experiments were performed after 24 h, and 3, 7, and 14 days of treatment.
DCE-MRI clearly detected the early effect (after 24 h of treatment) of SU6668 on tumor vasculature as a 51% and 26% decrease in the average vessel permeability measured in the tumor rim and core (respectively). A substantial decrease was also observed in average fractional plasma volume in the rim (59%) and core (35%) of the tumor. Histological results confirmed magnetic resonance imaging findings. After 3, 7, and 14 days of treatment, postcontrast magnetic resonant images presented a thin strip of strongly enhanced tissue at the tumor periphery; histology examination showed that this hyperenhanced ring corresponded to strongly vascularized tissue adjacent but external to the tumor. Histology also revealed a strong decrease in the thickness of peripheral viable tissue, with a greatly reduced vessel count. SU6668 greatly inhibited tumor growth, with 60% inhibition at 14 days of treatment.
DCE-MRI detected in vivo the antiangiogenic efficacy of SU6668.
本研究旨在通过动态对比增强磁共振成像（DCE-MRI）在体内评估SU6668的抗血管生成作用。SU6668是一种口服的小分子血管生成受体酪氨酸激酶抑制剂，可抑制血管内皮生长因子受体2（Flk-1/KDR）、血小板衍生生长因子受体和成纤维细胞生长因子受体1。
采用无胸腺小鼠的HT29人结肠癌皮下肿瘤模型。使用含大分子造影剂的DCE-MRI测量跨内皮通透性和血浆分数容积，这是公认的肿瘤血管生成替代标志物。采用CD31免疫组化染色评估微血管密度和血管面积。在治疗24小时、3天、7天和14天后进行实验。
DCE-MRI清楚地检测到SU6668对肿瘤脉管系统的早期作用（治疗24小时后），表现为肿瘤边缘和核心处测得的平均血管通透性分别降低51%和26%。肿瘤边缘（59%）和核心（35%）的平均血浆分数容积也显著降低。组织学结果证实了磁共振成像结果。治疗3天、7天和14天后，对比增强磁共振图像显示肿瘤周边有一条强烈增强的薄组织带；组织学检查表明，这条高增强环对应于肿瘤相邻但外部的高度血管化组织。组织学还显示外周存活组织厚度显著降低，血管数量大大减少。SU6668极大地抑制了肿瘤生长，治疗14天时抑制率为60%。
DCE-MRI在体内检测到了SU6668的抗血管生成功效。
