Use of dynamic contrast-enhanced MRI to evaluate acute treatment with ZD6474, a VEGF signalling inhibitor, in PC-3 prostate tumours.
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 x kg(-1) 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% (P<0.001) was evident with 50 and 100 mg x kg(-1) ZD6474, a reduction of 12.5% (P<0.05) at 25 mg x kg(-1), and a reduction that did not reach statistical significance at 12.5 mg kg(-1). 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.
Checkley
D
D
Department of Enabling Science and Technology, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Tessier
J J
JJ
Kendrew
J
J
Waterton
J C
JC
Wedge
S R
SR
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D000818:Animals; D002199:Capillary Permeability; D003287:Contrast Media / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D019786:Gadolinium DTPA / Q000008:administration & dosage*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015203:Reproducibility of Results; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D003287:Contrast Media; D010880:Piperidines; D011799:Quinazolines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019786:Gadolinium DTPA; C452423:vandetanib