Non-invasivein vivoimaging of vessel calibre in orthotopic prostate tumour xenografts

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Susceptibility contrast magnetic resonance imaging (MRI), utilising ultrasmall superparamagnetic iron oxide (USPIO) particles, was evaluated for the quantitation of vessel size index (Rv, μm), a weighted average measure of tumour blood vessel calibre, and fractional tumour blood volume (fBV, %), in orthotopically propagated murine PC3 prostate tumour xenografts. Tumour vascular architecture was assessedin vivoby MRI prior to and 24 hr after treatment with 200 mg/kg of the vascular disrupting agent ZD6126. A Bayesian hierarchical model (BHM) was used to reduce the uncertainty associated with quantitation ofRv and fBV. Quantitative histological analyses of the uptake of Hoechst 33342 for perfused vasculature, and haematoxylin and eosin staining for necrosis, were also performed to qualify the MRI data. A relatively large medianRv of 40.3 μm (90% confidence interval (CI90) = 37.4, 44.0 μm) and a high fBV of 5.4% (CI90 = 5.3, 5.5%) were determined in control tumours, which agreed with histologically determined vessel size index. Treatment with ZD6126 significantly (p< 0.01) reduced tumourRv (34.2μm, CI90 = 31.2, 38.0 μm) and fBV (3.9%, CI90 = 3.8, 4.1%), which were validated against histologically determined significant reductions in perfusion and vessel size, and increased necrosis. Together these data (i) highlight the use of a BHM to optimise the inferential power available from susceptibility contrast MRI data, (ii) provide strong evaluation and qualification ofRv and fBV as non-invasive imaging biomarkers of tumour vascular morphology, (iii) reveal the presence of a different vascular phenotype and (iv) demonstrate that ZD6126 exhibits good anti-vascular activity against orthotopic prostate tumours.

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