Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors
Elevated interstitial fluid pressure, a hallmark of solid tumors, can compromise the delivery of therapeutics to tumors. Here we show that blocking vascular endothelial growth factor (VEGF) signaling by DC101 (a VEGF-receptor-2 antibody) decreases interstitial fluid pressure, not by restoring lympha...
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| Published in | Cancer research (Chicago, Ill.) Vol. 64; no. 11; pp. 3731 - 3736 |
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| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Philadelphia, PA
American Association for Cancer Research
01.06.2004
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Elevated interstitial fluid pressure, a hallmark of solid tumors, can compromise the delivery of therapeutics to tumors. Here we show that blocking vascular endothelial growth factor (VEGF) signaling by DC101 (a VEGF-receptor-2 antibody) decreases interstitial fluid pressure, not by restoring lymphatic function, but by producing a morphologically and functionally “normalized” vascular network. We demonstrate that the normalization process prunes immature vessels and improves the integrity and function of the remaining vasculature by enhancing the perivascular cell and basement membrane coverage. We also show that DC101 induces a hydrostatic pressure gradient across the vascular wall, which leads to a deeper penetration of molecules into tumors. Thus, vascular normalization may contribute to the improved survival rates in tumor-bearing animals and in colorectal carcinoma patients treated with an anti-VEGF antibody in combination with cytotoxic therapies. |
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| AbstractList | Elevated interstitial fluid pressure, a hallmark of solid tumors, can compromise the delivery of therapeutics to tumors. Here we show that blocking vascular endothelial growth factor (VEGF) signaling by DC101 (a VEGF-receptor-2 antibody) decreases interstitial fluid pressure, not by restoring lymphatic function, but by producing a morphologically and functionally "normalized" vascular network. We demonstrate that the normalization process prunes immature vessels and improves the integrity and function of the remaining vasculature by enhancing the perivascular cell and basement membrane coverage. We also show that DC101 induces a hydrostatic pressure gradient across the vascular wall, which leads to a deeper penetration of molecules into tumors. Thus, vascular normalization may contribute to the improved survival rates in tumor-bearing animals and in colorectal carcinoma patients treated with an anti-VEGF antibody in combination with cytotoxic therapies. Elevated interstitial fluid pressure, a hallmark of solid tumors, can compromise the delivery of therapeutics to tumors. Here we show that blocking vascular endothelial growth factor (VEGF) signaling by DC101 (a VEGF-receptor-2 antibody) decreases interstitial fluid pressure, not by restoring lymphatic function, but by producing a morphologically and functionally "normalized" vascular network. We demonstrate that the normalization process prunes immature vessels and improves the integrity and function of the remaining vasculature by enhancing the perivascular cell and basement membrane coverage. We also show that DC101 induces a hydrostatic pressure gradient across the vascular wall, which leads to a deeper penetration of molecules into tumors. Thus, vascular normalization may contribute to the improved survival rates in tumor-bearing animals and in colorectal carcinoma patients treated with an anti-VEGF antibody in combination with cytotoxic therapies.Elevated interstitial fluid pressure, a hallmark of solid tumors, can compromise the delivery of therapeutics to tumors. Here we show that blocking vascular endothelial growth factor (VEGF) signaling by DC101 (a VEGF-receptor-2 antibody) decreases interstitial fluid pressure, not by restoring lymphatic function, but by producing a morphologically and functionally "normalized" vascular network. We demonstrate that the normalization process prunes immature vessels and improves the integrity and function of the remaining vasculature by enhancing the perivascular cell and basement membrane coverage. We also show that DC101 induces a hydrostatic pressure gradient across the vascular wall, which leads to a deeper penetration of molecules into tumors. Thus, vascular normalization may contribute to the improved survival rates in tumor-bearing animals and in colorectal carcinoma patients treated with an anti-VEGF antibody in combination with cytotoxic therapies. |
| Author | Kozin, Sergey V. Winkler, Frank Hicklin, Daniel J. Tong, Ricky T. Boucher, Yves Jain, Rakesh K. |
| Author_xml | – sequence: 1 givenname: Ricky T. surname: Tong fullname: Tong, Ricky T. – sequence: 2 givenname: Yves surname: Boucher fullname: Boucher, Yves – sequence: 3 givenname: Sergey V. surname: Kozin fullname: Kozin, Sergey V. – sequence: 4 givenname: Frank surname: Winkler fullname: Winkler, Frank – sequence: 5 givenname: Daniel J. surname: Hicklin fullname: Hicklin, Daniel J. – sequence: 6 givenname: Rakesh K. surname: Jain fullname: Jain, Rakesh K. |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16102210$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/15172975$$D View this record in MEDLINE/PubMed |
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| CODEN | CNREA8 |
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| Cites_doi | 10.1172/JCI200318549 10.1152/physrev.1993.73.1.1 10.1016/B978-0-12-168561-4.50333-4 10.1006/mvre.1996.2005 10.1007/BF00047468 10.1007/BF00437479 10.1073/pnas.95.8.4607 10.1172/JCI5028 10.1172/JCI8829 10.1038/nm0603-685 10.1073/pnas.93.25.14765 10.1126/science.1071420 10.1038/89997 10.1038/nm0901-987 10.1038/nm988 10.1073/pnas.96.6.3137 10.1016/S0140-6736(03)13603-3 10.1016/S0002-9440(10)64920-6 10.1038/sj.bjc.6601005 10.1006/mvre.1996.0041 |
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| Snippet | Elevated interstitial fluid pressure, a hallmark of solid tumors, can compromise the delivery of therapeutics to tumors. Here we show that blocking vascular... |
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| SubjectTerms | Animals Antibodies - immunology Antibodies - pharmacology Antineoplastic agents Biological and medical sciences Capillary Permeability - drug effects Cell Line, Tumor Humans Hydrostatic Pressure Medical sciences Mice Mice, SCID Neoplasms - blood supply Neoplasms - drug therapy Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - therapy Pharmacology. Drug treatments Serum Albumin, Bovine - pharmacokinetics Tumors Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 - immunology |
| Title | Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors |
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