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

S Shaaban, M Alsulami, S A Arbab, R Ara, A Shankar, A Iskander, K Angara, M Jain, H Bagher-Ebadian, B R Achyut, A S Arbab

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 (K(trans)), 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 K(trans) and ve in 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.

Original languageEnglish (US)
Pages (from-to)69-81
Number of pages13
JournalInternational Journal of Cancer Research
Volume12
Issue number2
DOIs
StatePublished - Jul 19 2016
Externally publishedYes

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Glioblastoma
Whole-Body Irradiation
Protein-Tyrosine Kinases
Bone Marrow
Growth
Bone Marrow Cells
Neoplasms
Angiogenesis Inducing Agents
Blood Vessels
Magnetic Resonance Imaging
Control Groups
Angiogenesis Inhibitors
Euthanasia
Plasma Volume
Extracellular Space
Tumor Burden
Cell Communication
Cell Movement
Therapeutics
Macrophages

Cite this

Targeting Bone Marrow to Potentiate the Anti-Tumor Effect of Tyrosine Kinase Inhibitor in Preclinical Rat Model of Human Glioblastoma. / Shaaban, S; Alsulami, M; Arbab, S A; Ara, R; Shankar, A; Iskander, A; Angara, K; Jain, M; Bagher-Ebadian, H; Achyut, B R; Arbab, A S.

In: International Journal of Cancer Research, Vol. 12, No. 2, 19.07.2016, p. 69-81.

Research output: Contribution to journalArticle

Shaaban, S ; Alsulami, M ; Arbab, S A ; Ara, R ; Shankar, A ; Iskander, A ; Angara, K ; Jain, M ; Bagher-Ebadian, H ; Achyut, B R ; Arbab, A S. / Targeting Bone Marrow to Potentiate the Anti-Tumor Effect of Tyrosine Kinase Inhibitor in Preclinical Rat Model of Human Glioblastoma. In: International Journal of Cancer Research. 2016 ; Vol. 12, No. 2. pp. 69-81.
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AU - Shankar, A

AU - Iskander, A

AU - Angara, K

AU - Jain, M

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AB - 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 (K(trans)), 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 K(trans) and ve in 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.

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