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 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) and were imaged after three consecutive treatments. Relative tumor blood volume fractions were calculated using deltaR2* 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.
Reichardt
Wilfried
W
Center for Molecular Imaging Research, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129-2060, USA.
Hu-Lowe
Dana
D
Torres
Denise
D
Weissleder
Ralph
R
Bogdanov
Alexei
A
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001810:Blood Volume / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D005290:Ferric Compounds; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
C508051:AG 013925; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005290:Ferric Compounds; D007191:Indazoles; D047428:Protein Kinase Inhibitors; C000499:ferric oxide; D040301:Vascular Endothelial Growth Factor Receptor-2