Use of dynamic contrast-enhanced MRI to evaluate acute treatment with ZD6474, a VEGF signalling inhibitor, in PC-3 prostate tumours

Abstract

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), using gadopentetate dimeglumine, was used to monitor acute effects on tumour vascular permeability following inhibition of vascular endothelial growth factor-A (VEGF-A) signal transduction. Mice bearing PC-3 human prostate adenocarcinoma xenografts were treated with ZD6474, a VEGF receptor-2 (KDR) tyrosine kinase inhibitor. The pharmacokinetic parameter K trans was obtained, which reflects vascular permeability and perfusion. Mice were imaged immediately before, and following, acute treatment with ZD6474 (12.5 -100 mg kg À1 orally). Whole tumours were analysed to obtain mean K trans values, and a histogram approach was used to examine intratumour heterogeneity. Reproducibility of K trans measurements gave inter-and intra-animal coefficients of variation of 40 and 18%, respectively. Dose-related reductions in K trans were evident following acute ZD6474 treatment. A K trans reduction of approximately 30% (Po0.001) was evident with 50 and 100 mg kg À1 ZD6474, a reduction of 12.5% (Po0.05) at 25 mg kg À1 , and a reduction that did not reach statistical significance at 12.5 mg kg À1 . A correlation between this dose response and the growth inhibitory effect of ZD6474 following chronic treatment was also observed. The histogram analysis of the data indicated that ZD6474-induced a K trans reduction in both the most enhancing rim and the core of PC-3 tumours. Dynamic contrast-enhanced magnetic resonance imaging may have a role in assessing the acute effects of VEGF signalling inhibition, in clinical dose-ranging studies.

ZD6474, a Potent Inhibitor of Vascular Endothelial Growth Factor Signaling, Combined With Radiotherapy

“…These observations are consistent with previous reports of reduced tumor vascular permeability/perfusion after acute ZD6474 treatment (assessed by dynamic contrast-enhanced magnetic resonance imaging; ref. 26) and reduced CD31 staining in Calu-6 xenografts after chronic long-term (24-day) exposure to ZD6474 (16).…”

Cluster analysis of quantitative parametric maps from DCE-MRI: application in evaluating heterogeneity of tumor response to antiangiogenic treatment

“…mean or median values on the whole tumor region) or by pre-defined rigid boundaries between rim and core regions [29]. Histogram analysis is considered to be more sensitive in detecting changes in tumor heterogeneity after treatment, than conventional summary statistics, looking to changes in histogram shape (kurtosis) and asymmetry (skewness), although it does so at the expense of including spatial information [28,30]. Alternative techniques are those based on texture-analysis, providing quantitative estimates of tumor heterogeneity, also considering their spatial distribution [31].…”

“…So far, there is no consensus on which is the optimal method for tumor heterogeneity assessment. ROIs can be drawn to encompass the entire tumor region, or to split the tumor into regions which are spatially defined (poorly enhanced inner regions or core and strongly enhanced periphery regions or rim) [28]. Consequently, the spatial heterogeneity information is discarded by current quantitative analysis methods employing simple summary statistics (e.g.…”

Heterogeneity in the angiogenic response of a BT474 human breast cancer to a novel vascular endothelial growth factor‐receptor tyrosine kinase inhibitor: Assessment by voxel analysis of dynamic contrast‐enhanced MRI

“…An alternative approach to ROI analysis is the use of voxel-by-voxel analysis over the whole tumor volume to obtain information throughout the entire tumor. Histograms of selected pharmacokinetic parameters have already been used to depict heterogeneity within tumors (6,7,(21)(22)(23). However, the problem of quantitatively assessing histogram changes as response parameters for characterizing tumor response to treatment remains to be investigated.…”