3801

Background: Blocking the signalling pathway mediated by the vascular endothelial growth factor (VEGF) receptors and their ligands inhibits angiogenesis and results in anti-tumour effects in vivo. DC101 (ImClone Systems), a monoclonal anti-VEGFR2 antibody, has previously been shown to reduce the growth rates of tumour xenografts after chronic treatments. The objective of our work was to investigate the potential of new microimaging tools to elucidate this important aspect of therapeutic response. Methods: Using ultrasound biomicroscopy (UBM) and micro Computed Tomography (microCT), we have examined the early effects of DC101 on tumour vasculature and its growth inhibitory effects after a chronic therapy. UBM is a non-invasive imaging modality which allows longitudinal study of disease progression in small animals. Operating at 40 MHz, UBM yields high resolution (40-60 μm) images of intradermal xenografts of human melanoma cancer cells (MeWo) in nude mice. Image-based caliper measurements of tumours were acquired and volumes were calculated using an ellipsoidal formula. Novel processing of real-time (30 fps) UBM image speckle is used to identify regions of active flow. This allows the differentiation of functional flow movements from stationary tissue, which are subsequently used to estimate vascular densities in tumours. Contrast-enhanced microCT studies provide images with resolution of ∼ 20 microns, and has previously revealed significant distortions in the vascular architecture of MeWo xenografts. 800 μg of DC101 was injected (i.p.) into nude mice with MeWo xenografts every third day for three weeks (n=5). UBM imaging and microCT were performed on day 6, 13, 20 and 27 post xenografting. To examine early vascular changes, imaging and microCT were performed 24 and 48 hours after administration of a single dosage of DC101 on day 19 post xenografting. Results: DC101 significantly inhibited the growth of MeWo xenografts after a three-week therapy (68.3% reduction vs control, p<0.05). An acute decrease in vascular density was detected 48 hrs after administration of a single dose of DC101 (66.3% reduction vs control, p<0.05), as determined by speckle flow processing of six UBM cineloop acquisitions per tumour per timepoint (0, 24, 48 hr) (24 measurements per group). Analysis performed using contrast-enhanced microCT included measurements of vascular densities and vessel diameters. Tortuosity in the micro-circulation of DC101-treated tumours is also assessed. Conclusions: Significant changes in blood volume were demonstrated as early as 24 hours after DC101 adminstration. Our findings are also in agreement with the published cytostatic effect of DC101 on tumour growth and alterations of tumour vasculature, and suggests a role for DC101 in vascular-targeting in addition to inhibiting neovascularization.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]