Use of dynamic contrast-enhanced MRI to evaluate acute treatment with ZD6474, a VEGF signalling inhibitor, in PC-3 prostate tumours

Br J Cancer. 2003 Nov 17;89(10):1889-95. doi: 10.1038/sj.bjc.6601386.

Abstract

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.

MeSH terms

  • Adenocarcinoma / blood supply
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / pathology*
  • Animals
  • Capillary Permeability
  • Contrast Media / administration & dosage*
  • Dose-Response Relationship, Drug
  • Gadolinium DTPA / administration & dosage*
  • Humans
  • Magnetic Resonance Imaging / methods*
  • Male
  • Mice
  • Neoplasms, Experimental
  • Piperidines / administration & dosage
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Prostatic Neoplasms / blood supply
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology*
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use*
  • Reproducibility of Results
  • Signal Transduction
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors

Substances

  • Contrast Media
  • Piperidines
  • Quinazolines
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Gadolinium DTPA
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine