Department of Neurosurgery, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba city, Ibaraki 305-8575, Japan.
J Neurooncol. 2010 Sep;99(2):177-85. doi: 10.1007/s11060-010-0118-8. Epub 2010 Jan 12.
Irinotecan (CPT-11) has shown emerging promise in the treatment of malignant gliomas. It is believed the mechanism of action of irinotecan is to sensitize glioma cells to the cytotoxic action of radiation therapy and alkylating agents. However, clinical trials using weekly or three-weekly doses of CPT-11 have demonstrated imaging responses in only 10-15% of patients. In this study, we evaluated another mechanism of action, angiosuppression by CPT-11 of ACNU-resistant gliomas, using a metronomic administration schedule. Two different types of treatment, (1) conventional and (2) metronomic, were applied to the subcutaneous U87 model. We found that metronomic administration of CPT-11 significantly inhibited malignant glioma growth by inhibiting angiogenesis; this treatment procedure reduced the number of tumor vessels and the area of hypoxic lesions and reduced expression of VEGF and HIF-1alpha, the most important angiogenic factors in gliomas. Metronomic treatment was superior to conventional treatment with regard to the severe systemic side effect of body weight loss. The growth inhibitory effect was very similar for both low and high doses of CPT-11. These angiosuppressive effects of CPT-11 show promise for another use of CPT-11 in metronomic and scheduled angiosuppressive chemotherapy with low dose and long-term administration for malignant gliomas without systemic side effects.
伊立替康（CPT-11）在治疗恶性脑胶质瘤方面显示出了新的前景。人们认为伊立替康的作用机制是使脑胶质瘤细胞对放射治疗和烷化剂的细胞毒性作用敏感。然而，使用每周或每三周剂量的 CPT-11 的临床试验仅在 10-15%的患者中显示出影像学反应。在这项研究中，我们使用节拍式给药方案评估了 CPT-11 抑制 ACNU 耐药性脑胶质瘤的另一种作用机制，血管生成抑制作用。我们发现，CPT-11 的节拍式给药通过抑制血管生成显著抑制恶性脑胶质瘤的生长；这种治疗方法减少了肿瘤血管的数量和缺氧病灶的面积，并降低了血管内皮生长因子（VEGF）和缺氧诱导因子-1α（HIF-1α）的表达，VEGF 和 HIF-1α 是脑胶质瘤中最重要的血管生成因子。与常规治疗相比，节拍式治疗在体重减轻这一严重的全身副作用方面具有优势。低剂量和高剂量的 CPT-11 均具有相似的生长抑制作用。CPT-11 的这些血管生成抑制作用表明，CPT-11 可用于节拍式和计划的血管生成抑制性化疗，以低剂量和长期给药的方式治疗恶性脑胶质瘤，而无全身副作用。
