Angiogenesis and antiangiogenic therapy for malignant gliomas.
Angiogenesis is crucial to the growth of malignant gliomas. Therefore, antiangiogenic therapy represents a new, promising therapeutic modality for malignant gliomas. This study was designed to define the malignant glioma cases most suitable for antiangiogenic therapy in humans and to demonstrate the efficacy of antiangiogenic therapy in animals. Protein expression of the most potent angiogenic factor, vascular endothelial growth factor (VEGF), and its specific natural inhibitor, soluble Flt-1, as well as vessel architecture, including vessel density, area, and diameter, was evaluated in human malignant glioma samples (24 glioblastomas, 13 anaplastic astrocytomas). Among these, VEGF >1000ng/ml, VEGF/soluble Fltl ratio >1, vessel density >30, and vessel area >7% were prognostic factors for malignant gliomas. Based on these results, we performed three different antiangiogenic experiments targeted to inhibit VEGF expression in a human malignant glioma (U87) mouse model: anti-VEGF neutralized antibody intraperitoneal injection; interferon-beta intramusclar injection; and transfection of an endogenous nonspecific angiogenesis inhibitor, thrombospondin-1, into glioma cells caused inhibition of VEGF secretion and/or mRNA expression and resulted in glioma growth inhibition of 70%, 84%, and 50%, respectively, compared with control. We conclude that malignant gliomas with high degrees of VEGF expression and vessel areas are good candidates for antiangiogenic therapy, especially that designed to inhibit VEGF expression.
Takano
Shingo
S
Department of Neurosurgery, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan. shingo4@md.tsukuba.ac.jp
Kamiyama
Hiroshi
H
Tsuboi
Koji
K
Matsumura
Akira
A
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005910:Glioma / Q000098:blood supply* / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D016899:Interferon-beta / Q000627:therapeutic use; D051379:Mice; D018995:Myosin Heavy Chains; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D024501:Nonmuscle Myosin Type IIB; D011379:Prognosis; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000276:immunology; D040281:Vascular Endothelial Growth Factor Receptor-1
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D016326:Extracellular Matrix Proteins; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D016899:Interferon-beta; C501162:FLT1 protein, human; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains