Effects of Tyrosine Kinase Inhibitors and CXCR4 Antagonist on Tumor Growth and Angiogenesis in Rat Glioma Model: MRI and Protein Analysis Study

Abstract

The aim of the study was to determine the antiangiogenic efficacy of vatalanib, sunitinib, and AMD3100 in an animal model of human glioblastoma (GBM) by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and tumor protein expression analysis. Orthotopic GBM-bearing animals were randomly assigned either to control group or vatalanib, sunitinib, and AMD3100 treatment groups. Following 2 weeks of drug treatment, tumor growth and vascular parameters were measured using DCE-MRI. Expression of different angiogenic factors in tumor extracts was measured using a membrane-based human antibody array kit. Tumor angiogenesis and invasion were determined by immunohistochemistry. DCE-MRI showed a significant increase in tumor size after vatalanib treatment. AMD3100-treated group showed a significant decrease in a number of vascular parameters determined by DCE-MRI. AMD3100 significantly decreased the expression of different angiogenic factors compared to sunitinib or vatalanib; however, there were no significant changes in vascular density among the groups. Sunitinib-treated animals showed significantly higher migration of the invasive cells, whereas in both vatalanib- and AMD3100-treated animals the invasive cell migration distance was significantly lower compared to that of control. Vatalanib and sunitinib resulted in suboptimal therapeutic effect, but AMD3100 treatment resulted in a significant reduction in tumor growth, permeability, interstitial space volume, and invasion of tumor cells in an animal model of GBM.

Targeting Bone Marrow to Potentiate the Anti-Tumor Effect of Tyrosine Kinase Inhibitor in Preclinical Rat Model of Human Glioblastoma

“…The average distance between the MHC-1 positive cells and the tumor margin was determined for vatalanib and vehicle treated animals in each groups. The analysis was done according to our published method (Ali et al, 2013). …”

“…Clinicians are using anti-angiogenic agent in addition to surgery, radiotherapy and chemotherapy (Venur et al, 2015; Rovere, 2014). Both in clinical and preclinical cases of GBM, agents targeting Vascular Endothelial Growth Factor (VEGF)-VEGF Receptor (R) signaling pathways are routinely being used (Ali et al, 2010, 2013; Batchelor et al, 2007; Ferrara et al, 2005; Gerstner et al, 2007; Reardon et al, 2008). Our group have previously used various VEGFR Tyrosine Kinase Inhibitors (TKIs) in preclinical models of human GBM and the results are not encouraging (Ali et al, 2010, 2013).…”

“…Both in clinical and preclinical cases of GBM, agents targeting Vascular Endothelial Growth Factor (VEGF)-VEGF Receptor (R) signaling pathways are routinely being used (Ali et al, 2010, 2013; Batchelor et al, 2007; Ferrara et al, 2005; Gerstner et al, 2007; Reardon et al, 2008). Our group have previously used various VEGFR Tyrosine Kinase Inhibitors (TKIs) in preclinical models of human GBM and the results are not encouraging (Ali et al, 2010, 2013). Our results using vatalanib (a VEGFR2 TKI) indicated the activation of alternative pathways for neovascularization and release of factors/chemokines, such as stromal cell derived factor 1-alpha (SDF-1α), from the tumor cells that mobilize bone marrow cells and enhanced accumulation to the site of GBM (Ali et al, 2010).…”

“…Our group have previously used MRI technique to determine different vascular parameters in GBM with or without anti-angiogenic treatments (AAT) (Ali et al, 2010, 2013). The purpose of the study was to determine the effects of bone marrow manipulation either through whole body irradiation or CXCR4 antagonist treatment on the tumor growth and vascular parameters determined by MRI with or without the treatment of vatalanib.…”

G protein-coupled receptors as oncogenic signals in glioma: Emerging therapeutic avenues

“…Interestingly, AMD3100 significantly decreased tumor volume, tumor cell invasion, and neovascularization while the non-specific RTK inhibitors vatalanib and sunitinib increased tumor volume and cell invasion, respectively (Ali et al, 2013). Moreover, concurrent treatment of intracranial xenograft tumors with radiation and AMD3100 prevented tumor recurrence and neovascularization more effectively than the VEGF neutralizing antibody, DC101 (Kioi et al, 2010).…”