Abstract A10: Antiangiogenic therapy (VEGF-R1–3 and PDGFR inhibitor) increases tumor hemoglobin saturation and decreases interstitial pressure, and microvessel density
Hanna, G; Tailor, T; Palmer, G; Herbert, J; Vlahovic, G; Dewhirst, M
Published in: Molecular Cancer Therapeutics
Methods: We evaluate the effects of pazopanib, a novel multi-targeted tyrosine kinase inhibitor, by examining its effects on tumor oxygenation, interstitial pressure (IFP), and vascularity as compared to an untreated control group.Nude mice (n=35) were injected with A-549 NSCLC tumor cells. Tumors reached an average volume of 650 mm3 before treatment with pazobanib 100mg/kg/day, Pazobanib 30mg/kg/day. or Vehicle (Control). Animals were treated daily for 14 days.Spectroscopic Measurements: A novel Skinskan spectrofluorometer was used to obtain non-invasive measurements of hemoglobin saturation (Hbsat) and total Hb for each tumor. Measurements were performed every other day, starting the day of treatment. These values were analyzed by a custom MATLAB program.IFP Measurements: IFP was measured on the last day of treatment(day 14), prior to sacrifice.Immunohistochemical staining: The number of vessels, determined by positive CD31 staining, was averaged over 6–8 image fields to obtain microvessel density (MVD).Results:Optical Spectroscopy: A significant increase in Hbsat was observed at day 8 for the low and high pazopanib dose groups, compared to control (p=0.0109, p=0.0290, respectively). After the 8th treatment day, Hbsat trended downward toward baseline.Tumor IFP: Tumor IFP for animals treated with pazopanib 100mg/kg was significantly reduced, compared to control (p=0.0026). Treatment with pazopanib 30mg/kg also demonstrated a strong trend towards IFP reduction, compared to control (p=0.0645).MVD: MVD was significantly reduced in mice treated with low and high dose pazopanib, compared to control (p=0.0271, p=0.0107, respectively).Conclusions: Treatment with pazopanib lead to a significant reduction in IFP, MVD, and increase in tumor Hb sat. This result demonstrates that pazopanib enhances efficiency of tumor perfusion which could lead to better drug distribution into the tumor, and increased of tumor Hb saturation would correlate with better oxygenation and predicts better response to radiotherapy.Work supported by a grant from GlaxoSmithKline.Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A10.
