Bradley D P, Tessier J L, Checkley D, Kuribayashi H, Waterton J C, Kendrew J, Wedge S R
Department of Enabling Capabilities and Sciences, AstraZeneca, Macclesfield, Cheshire, UK.
NMR Biomed. 2008 Jan;21(1):42-52. doi: 10.1002/nbm.1161.
The effect of two novel therapeutic agents on tumour haemodynamics was investigated using a fast dynamic contrast-enhanced (DCE)-MRI protocol (0.5 s/image) sensitive to signal changes in both the vascular input function and tumour during the administration of the macromolecular rapid clearance blood pool agent (MM-RCBPA), gadomelitol (P792, Vistarem). This enabled simultaneous measurement of the tumour blood flow per unit volume of tissue (F/V(T), mL/s/mL), the fractional plasma volume (V(p), %), and the permeability surface area product per unit volume of tissue (PSrho, s(-1)) in subcutaneous SW620 human colorectal tumour xenografts grown in nude rats before and after (at 0 and 22 h; imaging at 24 h) acute treatment with AZD2171 (3 mg/kg) and vandetanib (ZD6474, Zactima; 50 mg/kg), which have inhibitory activity against vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase. MRI was performed at 4.7 T using a single-slice, modified, T(1)-weighted, spoiled gradient-echo technique. Both compounds reduced gadomelitol uptake into the tumour. AZD2171 and vandetanib, respectively, (a) greatly reduced PSrho to 19.7 +/- 9.5% and 28.9 +/- 14.1% of baseline (P = 0.007 and P = 0.02), (b) markedly reduced V(p) to 31.2 +/- 19.1% and 54.8 +/- 21.2% of baseline (P = 0.015 and P = 0.09), and (c) had no significant effect on F/V(T). There was no significant difference between groups treated with AZD2171 and vandetanib when each variable was compared. The reductions in PSrho and V(p) are consistent with inhibition of VEGF signalling. AZD2171 (3 mg/kg) and vandetanib (50 mg/kg) were also found to produce a comparable chronic inhibition of SW620 tumour growth (89% for both). This study shows that DCE-MRI using an MM-RCPBA can be used to distinguish tumour vascular flow, volume, and permeability surface area product in a tumour model, and enables the acute effects of VEGF signalling inhibition to be examined in detail.
使用一种快速动态对比增强（DCE）-MRI方案（0.5秒/图像），在给予大分子快速清除血池剂（MM-RCBPA）钆喷酸葡胺（P792，Vistarem）期间，研究了两种新型治疗药物对肿瘤血流动力学的影响，该方案对血管输入功能和肿瘤中的信号变化均敏感。这使得能够同时测量在裸鼠体内生长的皮下SW620人结肠直肠癌异种移植瘤在急性给予AZD2171（3毫克/千克）和凡德他尼（ZD6474，Zactima；50毫克/千克）前后（0小时和22小时；24小时成像）每单位组织体积的肿瘤血流量（F/V(T)，毫升/秒/毫升）、血浆分数体积（V(p)，%）以及每单位组织体积的通透表面积乘积（PSrho，秒⁻¹），AZD2171和凡德他尼对血管内皮生长因子受体-2（VEGFR-2）酪氨酸激酶具有抑制活性。在4.7 T下使用单层面、改良的T(1)加权、扰相梯度回波技术进行MRI检查。两种化合物均减少了钆喷酸葡胺在肿瘤中的摄取。AZD2171和凡德他尼分别（a）将PSrho大幅降低至基线的19.7±9.5%和28.9±14.1%（P = 0.007和P = 0.02），（b）将V(p)显著降低至基线的31.2±19.1%和54.8±21.2%（P = 0.015和P = 0.09），并且（c）对F/V(T)无显著影响。当比较每个变量时，接受AZD2171和凡德他尼治疗的组之间无显著差异。PSrho和V(p)的降低与VEGF信号传导的抑制一致。还发现AZD2171（3毫克/千克）和凡德他尼（50毫克/千克）对SW620肿瘤生长产生相当的慢性抑制作用（两者均为89%）。本研究表明，使用MM-RCPBA的DCE-MRI可用于区分肿瘤模型中的肿瘤血管流量、体积和通透表面积乘积，并能够详细检查VEGF信号传导抑制的急性效应。
