Kirsch M, Strasser J, Allende R, Bello L, Zhang J, Black P M
Brigham and Women's Hospital, Dana-Farber Cancer Institute, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cancer Res. 1998 Oct 15;58(20):4654-9.
Human malignant gliomas are among the most malignant and most intensely vascularized solid tumors. Angiostatin, an internal fragment of plasminogen, was recently discovered as an endogenous inhibitor of tumor-related angiogenesis by selective inhibition of endothelial cell growth. Using xenograft transplants of rat and primary human glioma cells in immunodeficient mice we investigated the effects of systemic administration of angiostatin purified from human plasma on tumor growth. The rat C6 and 9L glioma and the human U87 glioma cell lines implanted either s.c. or intracranially in Swiss nude mice responded to angiostatin in a dose-dependent fashion with growth inhibition to 11% of controls (P < 0.01), without detectable signs of toxicity. The inhibition of treated tumors was accompanied by a marked reduction of vascularity to 38% of controls (P < 0.01) in the presence of an up to 6-fold increased apoptotic index (P < 0.01), consistent with the hypothesis that angiostatin acts tumoristatic by inhibiting tumor-induced endothelial cell proliferation. Expression analysis of growth factors in angiostatin-treated tumors revealed an up to 3-fold decrease in vascular endothelial growth factor-mRNA and an up to 4-fold increase in basic fibroblast growth factor-mRNA, as compared with untreated controls in rat gliomas (P < 0.01). This suggests that inhibition of the tumorigenic phenotype may be mediated in part by a downregulation of vascular endothelial growth factor expression within the tumor. Our data demonstrate that systemic administration of angiostatin efficiently suppresses malignant glioma growth in vivo. The tumoristatic activity against intracranial tumors independent of the blood brain barrier suggests that targeting the vascular compartment may offer novel therapeutic strategies against malignant gliomas.
人类恶性胶质瘤是最具侵袭性且血管化程度最高的实体肿瘤之一。血管抑素是纤溶酶原的一个内部片段，最近被发现是一种通过选择性抑制内皮细胞生长来抑制肿瘤相关血管生成的内源性抑制剂。我们利用免疫缺陷小鼠体内大鼠和原发性人类胶质瘤细胞的异种移植，研究了从人血浆中纯化得到的血管抑素全身给药对肿瘤生长的影响。在瑞士裸鼠皮下或颅内植入的大鼠C6和9L胶质瘤以及人类U87胶质瘤细胞系，对血管抑素呈剂量依赖性反应，生长受到抑制，仅为对照组的11%（P < 0.01），且未检测到毒性迹象。在凋亡指数增加高达6倍（P < 0.01）的情况下，经治疗的肿瘤血管明显减少，仅为对照组的38%（P < 0.01），这与血管抑素通过抑制肿瘤诱导的内皮细胞增殖发挥肿瘤抑制作用的假说一致。血管抑素治疗的肿瘤中生长因子的表达分析显示，与大鼠胶质瘤未治疗的对照组相比，血管内皮生长因子 - mRNA最多降低3倍，碱性成纤维细胞生长因子 - mRNA最多增加4倍（P < 0.01）。这表明肿瘤发生表型的抑制可能部分是由肿瘤内血管内皮生长因子表达的下调介导的。我们的数据表明，血管抑素全身给药可有效抑制体内恶性胶质瘤的生长。对颅内肿瘤具有独立于血脑屏障的肿瘤抑制活性表明，针对血管成分可能为恶性胶质瘤提供新的治疗策略。
