Imaging of VEGF receptor kinase inhibitor-induced antiangiogenic effects in drug-resistant human adenocarcinoma model

Small molecule vascular endothelial growth factor (VEGF) receptor tyrosinase kinase inhibitors (VEGFR-TKIs) 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 and Development) could be reported by magnetic resonance imaging (MRI) during the initial phase of treatment. We used MRI and superparamagnetic nano-particles 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) and were imaged after three consecutive treatments. Relative tumor blood volume fractions were calculated using Delta R-2* maps that were scaled by the known VVF value of an in-plane skeletal muscle (1.9%). There was a pronounced and 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 and 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; and 2) iron oxide nanoparticles and steady-state MRI enable an early detection of tumor response to antiangiogenic therapies.