| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Neurosurgical Laboratories and Brain Tumor Center, Brigham and Women's Hospital, Children's Hospital, Dana-Farber Cancer Institute, Joint Center for Radiation Therapy, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115
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 down-regulation 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.
1 Supported by a fellowship grant by the Deutsche Forschungsgemeinschaft (to M. K.).
2 These authors contributed equally to this work.
3 Requests for reprints should be addressed either to: Matthias Kirsch at Klinik und Poliklinik für Neurochirurgie, Fetscherstraße 74, 01307 Dresden, Federal Republic of Germany. Phone: 49-351-458-2883; Fax: 49-351-458-4304; or Peter McL. Black at Neurosurgery, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. Phone: (617) 732-6842; Fax: (617) 232-9029.
Received 5/11/98. Accepted 8/17/98.
This article has been cited by other articles:
|
|
 |
|
  J. Ma and D. J. Waxman Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib Mol. Cancer Ther., January 1, 2008; 7(1): 79 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. X. Zhang, J. J. Wang, K. Lu, R. Mott, R. Longeras, and J.-x. Ma Therapeutic Potential of Angiostatin in Diabetic Nephropathy J. Am. Soc. Nephrol., February 1, 2006; 17(2): 475 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Perri, J. Nalbantoglu, B. Annabi, Z. Koty, L. Lejeune, M. Francois, M. R. Di Falco, R. Beliveau, and J. Galipeau Plasminogen Kringle 5-Engineered Glioma Cells Block Migration of Tumor-Associated Macrophages and Suppress Tumor Vascularization and Progression Cancer Res., September 15, 2005; 65(18): 8359 - 8365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kirsch, P. Weigel, T. Pinzer, R. S. Carroll, P. McL. Black, H.-K. Schackert, and G. Schackert Therapy of Hematogenous Melanoma Brain Metastases with Endostatin Clin. Cancer Res., February 1, 2005; 11(3): 1259 - 1267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, J. Zhu, J. Chen, and Y. Shang Effects of Nicotine on the Number and Activity of Circulating Endothelial Progenitor Cells J. Clin. Pharmacol., August 1, 2004; 44(8): 881 - 889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Bello, V. Lucini, F. Costa, M. Pluderi, C. Giussani, F. Acerbi, G. Carrabba, M. Pannacci, D. Caronzolo, S. Grosso, et al. Combinatorial Administration of Molecules That Simultaneously Inhibit Angiogenesis and Invasion Leads to Increased Therapeutic Efficacy in Mouse Models of Malignant Glioma Clin. Cancer Res., July 1, 2004; 10(13): 4527 - 4537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. O. Schmidt, M. Ziu, G. Carrabba, C. Giussani, L. Bello, Y. Sun, K. Schmidt, M. Albert, P. Mcl. Black, and R. S. Carroll Antiangiogenic Therapy by Local Intracerebral Microinfusion Improves Treatment Efficiency and Survival in an Orthotopic Human Glioblastoma Model Clin. Cancer Res., February 15, 2004; 10(4): 1255 - 1262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Wachsberger, R. Burd, and A. P. Dicker Tumor Response to Ionizing Radiation Combined with Antiangiogenesis or Vascular Targeting Agents: Exploring Mechanisms of Interaction Clin. Cancer Res., June 1, 2003; 9(6): 1957 - 1971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Giussani, G. Carrabba, M. Pluderi, V. Lucini, M. Pannacci, D. Caronzolo, F. Costa, M. Minotti, G. Tomei, R. Villani, et al. Local Intracerebral Delivery of Endogenous Inhibitors by Osmotic Minipumps Effectively Suppresses Glioma Growth in Vivo Cancer Res., May 15, 2003; 63(10): 2499 - 2505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Kim, Y.-K. Hong, Y. A. Joe, Y. Lee, J.-Y. Shin, H.-E. Park, I.-H. Lee, S.-Y. Lee, D.-K. Kang, S.-I. Chang, et al. Anti-angiogenic Activity of the Recombinant Kringle Domain of Urokinase and Its Specific Entry into Endothelial Cells J. Biol. Chem., March 21, 2003; 278(13): 11449 - 11456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Takano, K. Tsuboi, A. Matsumura, and T. Nose Anti-vascular endothelial growth factor antibody and nimustine as combined therapy: Effects on tumor growth and angiogenesis in human glioblastoma xenografts Neuro-oncol, January 1, 2003; 5(1): 1 - 7. [Abstract] [PDF]
|
|
|
|
|
|
L. Bello, C. Giussani, G. Carrabba, M. Pluderi, V. Lucini, M. Pannacci, D. Caronzolo, G. Tomei, R. Villani, F. Scaglione, et al. Suppression of Malignant Glioma Recurrence in a Newly Developed Animal Model by Endogenous Inhibitors Clin. Cancer Res., November 1, 2002; 8(11): 3539 - 3548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Rosser and R. J. Packer Review Article : Neurofibromas in Children With Neurofibromatosis 1 J Child Neurol, August 1, 2002; 17(8): 585 - 591. [Abstract] [PDF]
|
|
|
|
|
|
J. I. Izawa, P. Sweeney, P. Perrotte, D. Kedar, Z. Dong, J. W. Slaton, T. Karashima, K. Inoue, W. F. Benedict, and C. P. N. Dinney Inhibition of Tumorigenicity and Metastasis of Human Bladder Cancer Growing in Athymic Mice by Interferon-{beta} Gene Therapy Results Partially from Various Antiangiogenic Effects Including Endothelial Cell Apoptosis Clin. Cancer Res., April 1, 2002; 8(4): 1258 - 1270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-I Ma, P. Guo, J. Li, S.-Z. Lin, Y.-H. Chiang, X. Xiao, and S.-Y. Cheng Suppression of Intracranial Human Glioma Growth after Intramuscular Administration of an Adeno-associated Viral Vector Expressing Angiostatin Cancer Res., February 1, 2002; 62(3): 756 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Bello, G. Carrabba, C. Giussani, V. Lucini, F. Cerutti, F. Scaglione, J. Landre, M. Pluderi, G. Tomei, R. Villani, et al. Low-dose Chemotherapy Combined with an Antiangiogenic Drug Reduces Human Glioma Growth in Vivo Cancer Res., October 1, 2001; 61(20): 7501 - 7506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Indraccolo, M. Morini, E. Gola, F. Carrozzino, W. Habeler, S. Minghelli, L. Santi, L. Chieco-Bianchi, Y. Cao, A. Albini, et al. Effects of Angiostatin Gene Transfer on Functional Properties and in Vivo Growth of Kaposi's Sarcoma Cells Cancer Res., July 1, 2001; 61(14): 5441 - 5446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Teicher, K. Menon, E. Alvarez, E. Galbreath, C. Shih, and M. Faul Antiangiogenic and Antitumor Effects of a Protein Kinase C{beta} Inhibitor in Human T98G Glioblastoma Multiforme Xenografts Clin. Cancer Res., March 1, 2001; 7(3): 634 - 640. [Abstract] [Full Text]
|
|
|
|
|
|
I. Ding, J. Z. Sun, B. Fenton, W. M. Liu, P. Kimsely, P. Okunieff, and W. Min Intratumoral Administration of Endostatin Plasmid Inhibits Vascular Growth and Perfusion in MCa-4 Murine Mammary Carcinomas Cancer Res., January 1, 2001; 61(2): 526 - 531. [Abstract] [Full Text]
|
|
|
|
|
|
C.-G. Lee, M. Heijn, E. di Tomaso, G. Griffon-Etienne, M. Ancukiewicz, C. Koike, K. R. Park, N. Ferrara, R. K. Jain, H. D. Suit, et al. Anti-Vascular Endothelial Growth Factor Treatment Augments Tumor Radiation Response under Normoxic or Hypoxic Conditions Cancer Res., October 1, 2000; 60(19): 5565 - 5570. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Yokoyama, J. E. Green, V. P. Sukhatme, and S. Ramakrishnan Effect of Endostatin on Spontaneous Tumorigenesis of Mammary Adenocarcinomas in a Transgenic Mouse Model Cancer Res., August 1, 2000; 60(16): 4362 - 4365. [Abstract] [Full Text]
|
|
|
|
|
|
M. Volm, J. Mattern, and R. Koomägi Angiostatin Expression in Non-Small Cell Lung Cancer Clin. Cancer Res., August 1, 2000; 6(8): 3236 - 3240. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Yokoyama, M. Dhanabal, A. W. Griffioen, V. P. Sukhatme, and S. Ramakrishnan Synergy between Angiostatin and Endostatin: Inhibition of Ovarian Cancer Growth Cancer Res., April 1, 2000; 60(8): 2190 - 2196. [Abstract] [Full Text]
|
|
|
|
|
|
T. A. Drixler, I. H. M. B. Rinkes, E. D. Ritchie, T. J. M. V. van Vroonhoven, M. F. B. G. Gebbink, and E. E. Voest Continuous Administration of Angiostatin Inhibits Accelerated Growth of Colorectal Liver Metastases after Partial Hepatectomy Cancer Res., March 1, 2000; 60(6): 1761 - 1765. [Abstract] [Full Text]
|
|
|
|
|
|
H. Ito, I. I. Rovira, M. L. Bloom, K. Takeda, V. J. Ferrans, A. A. Quyyumi, and T. Finkel Endothelial Progenitor Cells as Putative Targets for Angiostatin Cancer Res., December 1, 1999; 59(23): 5875 - 5877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ambs, S. Dennis, J. Fairman, M. Wright, and J. Papkoff Inhibition of Tumor Growth Correlates with the Expression Level of a Human Angiostatin Transgene in Transfected B16F10 Melanoma Cells Cancer Res., November 1, 1999; 59(22): 5773 - 5777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. I. Meneses, L. E. Abrey, K. A. Hajjar, S. H. Gultekin, R. M. Duvoisin, K. I. Berns, and M. R. Rosenfeld Simplified Production of a Recombinant Human Angiostatin Derivative That Suppresses Intracerebral Glial Tumor Growth Clin. Cancer Res., November 1, 1999; 5(11): 3689 - 3694. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Manfredi, S. Lim, K. P. Claffey, and T. N. Seyfried Gangliosides Influence Angiogenesis in an Experimental Mouse Brain Tumor Cancer Res., October 1, 1999; 59(20): 5392 - 5397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Cha, E. A. Knopp, G. Johnson, S. G. Wetzel, A. W. Litt, and D. Zagzag Intracranial Mass Lesions: Dynamic Contrast-enhanced Susceptibility-weighted Echo-planar Perfusion MR Imaging Radiology, April 1, 2002; 223(1): 11 - 29. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
