Inhibition of Tumor Growth, Angiogenesis, and Microcirculation by the Novel Flk-1 Inhibitor SU5416 as Assessed by Intravital Multi-fluorescence Videomicroscopy
Vascular endothelial growth factor (VEGF) plays a fundamental role in mediating tumor angiogenesis and tumor growth. Here we investigate the direct effect of a novel small molecule inhibitor of the Flk-1-mediated signal transduction pathway of VEGF, SU5416, on tumor angiogenesis and microhemodynamic...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
1999-04-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558699800335 |
| _version_ | 1828294702346010624 |
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| author | Peter Vajkoczy Michael D. Menger Brigitte Vollmar Lothar Schilling Peter Schmiedek K. Peter Hirth Axel Ullrich T.Annie T. Fong |
| author_facet | Peter Vajkoczy Michael D. Menger Brigitte Vollmar Lothar Schilling Peter Schmiedek K. Peter Hirth Axel Ullrich T.Annie T. Fong |
| author_sort | Peter Vajkoczy |
| collection | DOAJ |
| description | Vascular endothelial growth factor (VEGF) plays a fundamental role in mediating tumor angiogenesis and tumor growth. Here we investigate the direct effect of a novel small molecule inhibitor of the Flk-1-mediated signal transduction pathway of VEGF, SU5416, on tumor angiogenesis and microhemodynamics of an experimental glioblastoma by using intravital multifluorescence videomicroscopy. SU5416 treatment significantly suppressed tumor growth. In parallel, SU5416 demonstrated a potent antiangiogenic activity, resulting in a significant reduction of both the total and functional vascular density of the tumor microvasculature, which indicates an impaired vascularization as well as significant perfusion failure in treated tumors. This malperfusion was not compensated for by changes in vessel diameter or recruitment of nonperfused vessels. Analyses of the tumor microcirculation revealed significant microhemodynamic changes after angiogenesis blockage such as a higher red blood cell velocity and blood flow in remnant tumor vessels when compared with controls. Our results demonstrate that the novel antiangiogenic concept of targeting the tyrosine kinase of Flk-1/KDR by means of a small molecule inhibitor represents an efficient strategy to control growth and progression of angiogenesis-dependent tumors. This study provides insight into microvascular consequences of Flk-1/KDR targeting in vivo and may have important implications for the future treatment of angiogenesis-dependent neoplasms. |
| first_indexed | 2024-04-13T11:42:07Z |
| format | Article |
| id | doaj.art-9a42472f19d94ff8a358d24b5e68f03b |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-04-13T11:42:07Z |
| publishDate | 1999-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-9a42472f19d94ff8a358d24b5e68f03b2022-12-22T02:48:17ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80021999-04-0111314110.1038/sj.neo.7900006Inhibition of Tumor Growth, Angiogenesis, and Microcirculation by the Novel Flk-1 Inhibitor SU5416 as Assessed by Intravital Multi-fluorescence VideomicroscopyPeter Vajkoczy0Michael D. Menger1Brigitte Vollmar2Lothar Schilling3Peter Schmiedek4K. Peter Hirth5Axel Ullrich6T.Annie T. Fong7Department of Neurosurgery, Klinikum Mannheim, University of Heidelberg, MannheimInstitute for Clinical and Experimental Surgery, University of Saarland, Homburg/SaarInstitute for Clinical and Experimental Surgery, University of Saarland, Homburg/SaarDepartment of Molecular Biology, Max-Planck-Institut für Biochemie, Martinsried, GermanyDepartment of Neurosurgery, Klinikum Mannheim, University of Heidelberg, MannheimSUGEN Inc, South San FranciscoDepartment of Molecular Biology, Max-Planck-Institut für Biochemie, Martinsried, GermanySUGEN Inc, South San FranciscoVascular endothelial growth factor (VEGF) plays a fundamental role in mediating tumor angiogenesis and tumor growth. Here we investigate the direct effect of a novel small molecule inhibitor of the Flk-1-mediated signal transduction pathway of VEGF, SU5416, on tumor angiogenesis and microhemodynamics of an experimental glioblastoma by using intravital multifluorescence videomicroscopy. SU5416 treatment significantly suppressed tumor growth. In parallel, SU5416 demonstrated a potent antiangiogenic activity, resulting in a significant reduction of both the total and functional vascular density of the tumor microvasculature, which indicates an impaired vascularization as well as significant perfusion failure in treated tumors. This malperfusion was not compensated for by changes in vessel diameter or recruitment of nonperfused vessels. Analyses of the tumor microcirculation revealed significant microhemodynamic changes after angiogenesis blockage such as a higher red blood cell velocity and blood flow in remnant tumor vessels when compared with controls. Our results demonstrate that the novel antiangiogenic concept of targeting the tyrosine kinase of Flk-1/KDR by means of a small molecule inhibitor represents an efficient strategy to control growth and progression of angiogenesis-dependent tumors. This study provides insight into microvascular consequences of Flk-1/KDR targeting in vivo and may have important implications for the future treatment of angiogenesis-dependent neoplasms.http://www.sciencedirect.com/science/article/pii/S1476558699800335antiangiogenic therapyprotein tyrosine kinasegliomavascularizationvascular endothelial growth factor (VEGF) |
| spellingShingle | Peter Vajkoczy Michael D. Menger Brigitte Vollmar Lothar Schilling Peter Schmiedek K. Peter Hirth Axel Ullrich T.Annie T. Fong Inhibition of Tumor Growth, Angiogenesis, and Microcirculation by the Novel Flk-1 Inhibitor SU5416 as Assessed by Intravital Multi-fluorescence Videomicroscopy Neoplasia: An International Journal for Oncology Research antiangiogenic therapy protein tyrosine kinase glioma vascularization vascular endothelial growth factor (VEGF) |
| title | Inhibition of Tumor Growth, Angiogenesis, and Microcirculation by the Novel Flk-1 Inhibitor SU5416 as Assessed by Intravital Multi-fluorescence Videomicroscopy |
| title_full | Inhibition of Tumor Growth, Angiogenesis, and Microcirculation by the Novel Flk-1 Inhibitor SU5416 as Assessed by Intravital Multi-fluorescence Videomicroscopy |
| title_fullStr | Inhibition of Tumor Growth, Angiogenesis, and Microcirculation by the Novel Flk-1 Inhibitor SU5416 as Assessed by Intravital Multi-fluorescence Videomicroscopy |
| title_full_unstemmed | Inhibition of Tumor Growth, Angiogenesis, and Microcirculation by the Novel Flk-1 Inhibitor SU5416 as Assessed by Intravital Multi-fluorescence Videomicroscopy |
| title_short | Inhibition of Tumor Growth, Angiogenesis, and Microcirculation by the Novel Flk-1 Inhibitor SU5416 as Assessed by Intravital Multi-fluorescence Videomicroscopy |
| title_sort | inhibition of tumor growth angiogenesis and microcirculation by the novel flk 1 inhibitor su5416 as assessed by intravital multi fluorescence videomicroscopy |
| topic | antiangiogenic therapy protein tyrosine kinase glioma vascularization vascular endothelial growth factor (VEGF) |
| url | http://www.sciencedirect.com/science/article/pii/S1476558699800335 |
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