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
Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA.
Department of Radiology, Henry Ford Health System, Detroit, MI, USA.
Int J Cancer Res. 2016;12(2):69-81. doi: 10.3923/ijcr.2016.69.81. Epub 2016 Mar 15.
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 (v), forward transfer constant (K), back flow constant (k), extravascular extracellular space volume (v) 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 and v 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.
抗血管生成药物导致促生长和促血管生成因子出现反常增加，并致使胶质母细胞瘤（GBM）发生肿瘤生长。据推测，促血管生成因子的反常增加会促使骨髓源性细胞（BMDCs）迁移至接受治疗的肿瘤部位，并导致难治性肿瘤生长。这些研究的目的在于确定全身照射（WBIR）或CXCR4拮抗剂（AMD3100）是否会增强凡他尼布（一种VEGFR2酪氨酸激酶抑制剂）的疗效，并预防GBM的难治性生长。将人GBM原位种植于三组大鼠体内（对照组、经WBIR预处理组和AMD3100预处理组），并随机选择给予赋形剂或凡他尼布治疗2周。然后，所有动物接受磁共振成像（MRI）检查，随后实施安乐死并进行组织化学分析。根据MRI确定肿瘤体积和不同的血管参数（血浆容积（v）、正向转移常数（K）、回流常数（k）、血管外细胞外间隙容积（v））。在对照组中，与赋形剂治疗相比，凡他尼布治疗显著增加了肿瘤生长，但分别通过使用WBIR和ADM3100阻止BMDCs的迁移以及CXCR4-SDF-1的相互作用，肿瘤的反常生长得到了控制。尽管ADM3100增加了肿瘤中M1和M2巨噬细胞的积聚，但WBIR或AMD3100预处理也减少了肿瘤细胞迁移。凡他尼布还增加了对照动物的K和v，但当动物经WBIR和AMD3100预处理时，这两个血管参数均降低。总之，消耗骨髓细胞或CXCR4相互作用可增强凡他尼布的疗效。
