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Effects of AZD2171 and vandetanib (ZD6474, Zactima) on haemodynamic variables in an SW620 human colon tumour model: an investigation using dynamic contrast-enhanced MRI and the rapid clearance blood pool contrast agent, P792 (gadomelitol)

Lookup NU author(s): Professor Steve Wedge

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Abstract

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 (PSρ, 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, T₁-weighted, spoiled gradient-echo technique. Both compounds reduced gadomelitol uptake into the tumour. AZD2171 and vandetanib, respectively, (a) greatly reduced PSρ 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 PSρ 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.

Publication metadata

Author(s): Bradley DP, Tessier JL, Checkley D, Kuribayashi H, Waterton JC, Kendrew J, Wedge SR

Publication type: Article

Publication status: Published

Journal: NMR in Biomedicine

Year: 2008

Volume: 21

Issue: 1

Pages: 42-52

ISSN (print): 0952-3480

ISSN (electronic): 1099-1492

Publisher: John Wiley & Sons Ltd.

URL: http://dx.doi.org/10.1002/nbm.1161

DOI: 10.1002/nbm.1161

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