de Boüard Sophie, Herlin Paulette, Christensen James G, Lemoisson Edwige, Gauduchon Pascal, Raymond Eric, Guillamo Jean-Sébastien
GRECAN, Centre François Baclesse, Universié de Caen Basse-Normandie, 14076 Caen, France.
Neuro Oncol. 2007 Oct;9(4):412-23. doi: 10.1215/15228517-2007-024. Epub 2007 Jul 10.
Angiogenesis inhibitors appear to be promising therapies for highly vascularized tumors such as glioblastoma multiforme (GBM). Sunitinib is an oral multitargeted tyrosine kinase inhibitor with both antiangiogenic and antitumor activities due to selective inhibition of various receptor tyrosine kinases, including those important for angiogenesis (vascular endothelial growth factor receptors and platelet-derived growth factor receptors). Here we evaluated the antitumor activities of sunitinib on orthotopic models of GBM in vitro and in vivo. Sunitinib potently inhibited angiogenesis that was stimulated by implantation of U87MG and GL15 cells into organotypic brain slices at concentrations as low as 10 nM. At high dose (10 microM), sunitinib induced direct antiproliferative and proapoptotic effects on GL15 cells and decreased invasion of these cells implanted into brain slices by 49% (p < 0.001). Treatment was associated with decreases in Src (35%) and focal adhesion kinase (44%) phosphorylation. However, anti-invasive activity was not observed in vivo at the highest dose level utilized (80 mg/kg per day). Survival experiments involving athymic mice bearing intracerebral U87MG GBM demonstrated that oral administration of 80 mg/kg sunitinib (five days on, two days off) improved median survival by 36% (p < 0.0001). Sunitinib treatment caused a 74% reduction in microvessel density (p < 0.05), an increase in tumor necrosis, and a decrease in number of GBM cells positive for MIB antibody. Sunitinib exhibited potent antiangiogenic activity that was associated with a meaningful prolongation of survival of mice bearing intracerebral GBM. These data support the potential utility of sunitinib in the treatment of GBM.
血管生成抑制剂似乎是治疗多形性胶质母细胞瘤（GBM）等高血管化肿瘤的有前景的疗法。舒尼替尼是一种口服多靶点酪氨酸激酶抑制剂，由于其对多种受体酪氨酸激酶的选择性抑制作用，包括对血管生成重要的那些受体酪氨酸激酶（血管内皮生长因子受体和血小板衍生生长因子受体），因而具有抗血管生成和抗肿瘤活性。在此，我们在体外和体内的GBM原位模型中评估了舒尼替尼的抗肿瘤活性。舒尼替尼在低至10 nM的浓度下就能有效抑制将U87MG和GL15细胞植入器官型脑切片所刺激的血管生成。在高剂量（10 microM）时，舒尼替尼对GL15细胞具有直接的抗增殖和促凋亡作用，并使植入脑切片的这些细胞的侵袭减少49%（p<0.001）。治疗与Src（35%）和粘着斑激酶（44%）磷酸化的降低有关。然而，在所使用的最高剂量水平（每天80 mg/kg）下，未在体内观察到抗侵袭活性。涉及携带脑内U87MG GBM的无胸腺小鼠的生存实验表明，口服80 mg/kg舒尼替尼（连续五天给药，停药两天）可使中位生存期提高36%（p<0.0001）。舒尼替尼治疗使微血管密度降低74%（p<0.05），肿瘤坏死增加，MIB抗体阳性的GBM细胞数量减少。舒尼替尼表现出强大的抗血管生成活性，这与携带脑内GBM的小鼠生存期的显著延长相关。这些数据支持了舒尼替尼在治疗GBM方面的潜在效用。
