Dynamic contrast-enhanced MRI of vascular changes induced by the VEGF-signalling inhibitor ZD4190 in human tumour xenografts

Dynamic contrast-enhanced magnetic resonance imaging (DCEMRI) was used to examine the acute effects of treatment with an inhibitor of vascular endothelial growth factor (VEGF) signaling. ZD4190 is an orally bioavailable inhibitor of VEGF receptor-2 (KDR) tyrosine kinase activity, which elicits broad...

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Published in:Magnetic resonance imaging 2003-06, Vol.21 (5), p.475-482
Main Authors: Checkley, David, Tessier, Jean J.L., Wedge, Stephen R., Dukes, Michael, Kendrew, Jane, Curry, Brenda, Middleton, Brian, Waterton, John C.
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Biological and medical sciences
Contrast Media
Dynamic MRI
Female
Gadolinium DTPA
Humans
K trans
Magnetic Resonance Imaging - methods
Male
Medical sciences
Mice
Mice, Nude
Neoplasm Transplantation
Neoplasms, Experimental - blood supply
Neoplasms, Experimental - pathology
Quinazolines - pharmacology
Transplantation, Heterologous
Triazoles - pharmacology
Vascular Endothelial Growth Factor A - antagonists & inhibitors
VEGF signaling
ZD4190
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Summary:Dynamic contrast-enhanced magnetic resonance imaging (DCEMRI) was used to examine the acute effects of treatment with an inhibitor of vascular endothelial growth factor (VEGF) signaling. ZD4190 is an orally bioavailable inhibitor of VEGF receptor-2 (KDR) tyrosine kinase activity, which elicits broad-spectrum antitumour activity in preclinical models following chronic once-daily dosing. Nude mice, bearing established (0.5-1.0 mL volume) human prostate (PC-3), lung (Calu-6) and breast (MDA-MB-231) tumor xenografts, were dosed with ZD4190 (p.o.) using a 1 day (0 and 22 h) or 7 day (0, 24, 48, 72, 96,120,144, and 166 h) treatment regimen. DCEMRI was employed 2 h after the last dose of ZD4190, using the contrast agent gadopentetate dimeglumine. Dynamic data were fit to a compartmental model to obtain voxelwise K trans , the transfer constant for gadopentetate into the tumor. K trans was averaged over the entire tumor, and a multi-threshold histogram analysis was also employed to account for tumor heterogeneity. Reductions in K trans reflect reductions in flow, in endothelial surface area, and/or in vascular permeability. A vascular input function was obtained for each mouse simultaneously with the tumor DCEMRI data. ZD4190 treatment produced a dose-dependent (12.5-100 mg.kg −1 per dose) reduction in K trans in PC-3 prostate tumors. At 100 mg.kg −1, the largest concentration examined, ZD4190 reduced K trans in PC-3 tumors by 31% following 2 doses (1 day treatment regimen; p < 0.001) and by 53% following 8 doses (7 day regimen; p < 0.001). Comparative studies in the three models using a showed similar reductions in K trans for the lung and breast tumors using the histogram analysis, although the statistical significance was lost when K trans was averaged over the entire tumor. Collectively these studies suggest that DCEMRI using gadopentetate may have potential clinically, for monitoring inhibition of VEGF signaling in solid tumors.
ISSN:0730-725X
1873-5894
DOI:10.1016/S0730-725X(02)00644-6