Anti-angiogenic therapy for malignant gliomas using hypoxia-responsive soluble VEGF receptor

VEGF受体的可溶性形式、sFlt1和缺氧诱导因子（HIF）是恶性胶质瘤抗血管生成治疗的关键分子。sFlt1和HIF在胶质瘤组织中的作用：VEGF/sFlt1比值大于1和HIF高表达是胶质瘤患者预后不良的因素。2 .过表达sFlt1的抗胶质瘤作用：将sFlt1基因转染U87人恶性胶质瘤细胞系，肿瘤体积比对照减少30%。3 . CPT-11的抗血管生成作用：CPT-11通过抑制胶质瘤细胞HIF和VEGF的表达，抑制内皮细胞增殖和小管形成，具有强效的血管抑制作用。CPT-11节律计划对胶质瘤生长的影响：低剂量（1mg/kg）和长期（77天）给药CPT-11导致胶质瘤生长，与中剂量（40mg/kg）和短期（10天）给药相似，无全身副作用。JTT治疗不仅能增强胶质瘤小鼠的免疫功能，还能抑制血管生成。使用CPT-11节律化疗通过抑制HIF和VEGF表达以及抑制内皮细胞增殖和管形成，对胶质瘤生长有效。sFlt1和JTT也是神经胶质瘤血管抑制剂的候选药物。

Soluble form of VEGF receptor, sFlt1 and hypoxia indutible factor(HIF) were focused on the key molecules of antiangiogenic therapy for malignant gliomas.1.The role of sFlt1 and HIF in glioma tissues : The VEGF/sFlt1 ration over than 1 and high expression of HIF were bad prognostic factors in the patients with gliomas.2.Anti-glioma effect of over expression of sFlt1 : sFlt1 gene transfection into U87 human malignant glioma cell lines resulted in 30% decrease of tumor volume compared to control.3.Anti-angiogenic effect of CPT-11 : CPT-11 had potent angiosuppressive agent by inhibiting HIF and VEGF expression of glioma cells and inhibiting endothelial cell proliferation and tube formation.4.The effect of metronomic schedule of CPT-11 for glioma growth : Low dose (1mg/kg) and long term (77 days) administration of CPT-11 resulted in glioma growth which was similar to moderate dose (40mg/kg) and short term (10 days) administration without systemic side effect.5.JTT treatment caused to not only enhance immune function but also inhibit angiogenesis in mouse bearing glioma.Metronomic chemotherapy using CPT-11 is effective for glioma growth by inhibiting HIF and VEGF expression and by inhibiting endothelial cell proliferation and tube formation. sFlt1 and JTT are also candidates as angiosuppressive agent for glioma.