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).
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.
Bradley
D P
DP
Department of Enabling Capabilities and Sciences, AstraZeneca, Macclesfield, Cheshire, UK. Daniel.Bradley@astrazeneca.com
Tessier
J L
JL
Checkley
D
D
Kuribayashi
H
H
Waterton
J C
JC
Kendrew
J
J
Wedge
S R
SR
D000818:Animals; D002138:Calibration; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D003287:Contrast Media; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D007211:Indoles
D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D010880:Piperidines; D011799:Quinazolines; C435266:contrast agent P792; C500926:cediranib; D007211:Indoles; C452423:vandetanib