title: Targeting Bone Marrow to Potentiate the Anti-Tumor Effect of Tyrosine Kinase Inhibitor in Preclinical Rat Model of Human Glioblastoma.
abstract: Antiangiogenic agents caused paradoxical increase in pro-growth and pro-angiogenic factors and caused tumor growth in glioblastoma (GBM). It is hypothesized that paradoxical increase in pro-angiogenic factors would mobilize Bone Marrow Derived Cells (BMDCs) to the treated tumor and cause refractory tumor growth. The purposes of the studies were to determine whether whole body irradiation (WBIR) or a CXCR4 antagonist (AMD3100) will potentiate the effect of vatalanib (a VEGFR2 tyrosine kinase inhibitor) and prevent the refractory growth of GBM. Human GBM were grown orthotopically in three groups of rats (control, pretreated with WBIR and AMD3100) and randomly selected for vehicle or vatalanib treatments for 2 weeks. Then all animals underwent Magnetic Resonance Imaging (MRI) followed by euthanasia and histochemical analysis. Tumor volume and different vascular parameters (plasma volume (vp), forward transfer constant (Ktrans), back flow constant (kep), extravascular extracellular space volume (ve) were determined from MRI. In control group, vatalanib treatment increased the tumor growth significantly compared to that of vehicle treatment but by preventing the mobilization of BMDCs and interaction of CXCR4-SDF-1 using WBIR and ADM3100, respectively, paradoxical growth of tumor was controlled. Pretreatment with WBIR or AMD3100 also decreased tumor cell migration, despite the fact that ADM3100 increased the accumulation of M1 and M2 macrophages in the tumors. Vatalanib also increased Ktransand vein control animals but both of the vascular parameters were decreased when the animals were pretreated with WBIR and AMD3100. In conclusion, depleting bone marrow cells or CXCR4 interaction can potentiate the effect of vatalanib.
authors.affiliation: Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shaaban
authors.affiliation: Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
authors.forename: M
authors.initials: M
authors.lastname: Alsulami
authors.affiliation: Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Arbab
authors.affiliation: Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ara
authors.affiliation: Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shankar
authors.affiliation: Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
authors.forename: A
authors.initials: A
authors.lastname: Iskander
authors.affiliation: Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
authors.forename: K
authors.initials: K
authors.lastname: Angara
authors.affiliation: Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
authors.forename: M
authors.initials: M
authors.lastname: Jain
authors.affiliation: Department of Radiology, Henry Ford Health System, Detroit, MI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Bagher-Ebadian
authors.affiliation: Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Achyut
authors.affiliation: Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Arbab
keywords: CXCR4 antagonist (AMD3100); Glioblastoma; bone marrow derived cells (BMDC); receptor tyrosine kinase inhibitor (RTKI); whole body irradiation