Imaging of VEGF Receptor Kinase Inhibitor-Induced Antiangiogenic Effects in Drug-Resistant Human Adenocarcinoma Model

Abstract

Small molecule vascular endothelial growth factor (VEGF) receptor tyrosinase kinase inhibitors (VEGFRTKIs) show great promise in inducing antiangiogenic responses in tumors. We investigated whether antiangiogenic tumor responses induced by an experimental VEGFR-TKI (AG013925; Pfizer Global Research, Development) could be reported by magnetic resonance imaging (MRI) during the initial phase of treatment. We used MRI, superparamagnetic nanoparticles for measuring relative vascular volume fraction (rVVF) in a drug-resistant colon carcinoma model. Athymic mice harboring MV522 xenografts were treated with VEGFR-TKI (25 mg/kg, p.o., with a 12-hour interval in between treatments), were imaged after three consecutive treatments. Relative tumor blood volume fractions were calculated using ΔR2* maps that were scaled by the known VVF value of an in-plane skeletal muscle (1.9%). There was a pronounced, statistically significant (P < .001) decrease of tumor rVVF in treated animals (0.95 ± 0.24%; mean ± SEM, n= 66 slices, eight mice) compared to mice that received a placebo (2.91 ± 0.24%; mean SEM, n = 66 slices, nine mice). Tumor histology confirmed a three-fold decrease of vascular density, a concomitant increase of apoptotic cell index. Hence, we demonstrated that: 1) the VEGFR-TKI resulted in antiangiogenic effects that were manifested by a decrease or rVVF;, 2) iron oxide nanoparticles, steadystate MRI enable an early detection of tumor response to antiangiogenic therapies.