Permeability to macromolecular contrast media quantified by dynamic MRI correlates with tumor tissue assays of vascular endothelial growth factor (VEGF)

Abstract

Purpose To correlate dynamic MRI assays of macromolecular endothelial permeability with microscopic area-density measurements of vascular endothelial growth factor (VEGF) in tumors. Methods and Material This study compared tumor xenografts from two different human cancer cell lines, MDA-MB-231 tumors (n=5), and MDA-MB-435 (n=8), reported to express respectively higher and lower levels of VEGF. Dynamic MRI was enhanced by a prototype macromolecular contrast medium (MMCM), albumin-(Gd-DTPA)35. Quantitative estimates of tumor microvascular permeability (KPS; μl/min·100cm3), obtained using a two-compartment kinetic model, were correlated with immunohistochemical measurements of VEGF in each tumor. Results Mean KPS was 2.4 times greater in MDA-MB-231 tumors (KPS=58±30.9μl/min·100cm3) than in MDA-MB-435 tumors (KPS=24±8.4μl/min·100cm) (p<0.05). Correspondingly, the area-density of VEGF in MDA-MB-231 tumors was 2.6 times greater (27.3±2.2%, p<0.05) than in MDA-MB-435 cancers (10.5±0.5%, p<0.05). Considering all tumors without regard to cell type, a significant positive correlation (r=0.67, p<0.05) was observed between MRI-estimated endothelial permeability and VEGF immunoreactivity. Conclusion Correlation of MRI assays of endothelial permeability to a MMCM and VEGF immunoreactivity of tumors support the hypothesis that VEGF is a major contributor to increased macromolecular permeability in cancers. When applied clinically, the MMCM-enhanced MRI approach could help to optimize the appropriate application of VEGF-inhibiting therapy on an individual patient basis.

Vasculature-specific MRI reveals differential anti-angiogenic effects of a biomimetic peptide in an orthotopic breast cancer model

“…Fourteen days were chosen as a suitable early growth stage time point based on the tumor volume (~70 mm 3 ). Typical imaging studies using xenografts derived from the MDA-MB-231 cell line employ tumors in the 100–1,000 mm 3 volume range [27, 28]. In this study, we used early-stage tumors to avoid confounding effects from necrosis and possible anti-angiogenic resistance.…”

Evaluation of a Novel Macromolecular Cascade-Polymer Contrast Medium for Dynamic Contrast-Enhanced MRI Monitoring of Antiangiogenic Bevacizumab Therapy in a Human Melanoma Model

“…Additionally, a lack in standardization of acquisition and postprocessing protocols (30) may be in part responsible that some investigators had difficulties to duplicate each others' results (31). Alternatively, macromolecular contrast media (molecular weight >60 kDa) have been proposed for monitoring antiangiogenic treatment because they follow a primarily intravascular distribution profile with a pronounced extravasation through the hyperpermeable endothelium of angiogenically active tissues under VEGF stimulation, allowing for a sensitive assessment of angiogenic activity in tumors (29,32). …”

“…The degree of the vascular response varied for both investigated MMCM with the specific tumor with pre- versus post-K PS differences ranging from zero (no change) to 100% declines in response to bevacizumab treatment. This demonstration of a variable but gradable response can be anticipated based on the recognized variability in cancer biology and in drug responsiveness for individual tumors: even cancers with similar histopathology can differ widely in behavior and VEGF expression (32). The specific biology that underlies the application of macromolecular probes to assess the angiogenesis process is that permeability to macromolecular solutes is a direct indication of the activity of VEGF.…”

Präklinische Bildgebung im Tiermodell bei Strahlentherapie

“…Therapieresponse zum Monitoring antiangiogener Therapien angewendet werden können[5,11,66,67,68]. Darüber hinaus korrelieren die erhobenen Parameter der Mikrozirkulation signifikant mit der Sauerstoffversorgung des Gewebes in Zervixkarzinomen sowie mit Tumorzellhypoxie in Kopf-und Halstumoren.…”