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Anti-Vascular Endothelial Growth Factor Treatment Augments Tumor Radiation Response under Normoxic or Hypoxic Conditions.

 Chang-Geol Lee  ;  Marcus Heijn  ;  Emmanuelle di Tomaso  ;  Genevieve Griffon-Etienne  ;  M. Ancukiewicz  ;  Chieko Koike  ;  K. R. Park  ;  Napoleone Ferrara  ;  Rakesh K. Jain  ;  Herman D. Suit  ;  Yves Boucher 
 Cancer Research, Vol.60(19) : 5565-5570, 2000 
Journal Title
 Cancer Research 
Issue Date
Adenocarcinoma/blood supply ; Adenocarcinoma/metabolism ; Adenocarcinoma/therapy* ; Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacology* ; Apoptosis/drug effects ; Cell Division/drug effects ; Cell Division/radiation effects ; Cell Hypoxia ; Colonic Neoplasms/blood supply ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/therapy* ; Combined Modality Therapy ; Endothelial Growth Factors/antagonists & inhibitors ; Endothelial Growth Factors/immunology* ; Endothelial Growth Factors/metabolism ; Extracellular Space/physiology ; Glioblastoma/blood supply ; Glioblastoma/metabolism ; Glioblastoma/therapy* ; Humans ; Lymphokines/antagonists & inhibitors ; Lymphokines/immunology* ; Lymphokines/metabolism ; Male ; Mice ; Mice, Nude ; Oxygen/metabolism* ; Partial Pressure ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; Xenograft Model Antitumor Assays
Recent studies in experimental animals have shown that combining antiangiogenic therapy with radiation can enhance tumor response. Whether this enhancement is mainly attributable to angiogenesis inhibition, endothelial cell radiosensitivity, tumor cell apoptosis, or a decrease in the number of hypoxic cells (improved oxygenation) is not known. We designed this study to discern the role of tumor oxygenation. We chose an anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody (mAb) which has a known target, human VEGF. We also measured interstitial fluid pressure (IFP) to test the hypothesis that the decreased vascular permeability induced by the anti-VEGF mAb can lower IFP. The effect of anti-VEGF mAb on vascular density, partial oxygen tension (pO2), and apoptosis was also measured. Athymic NCr/Sed nu/nu mice bearing 6-mm xenograft of the human glioblastoma multiforme (U87), or colon adenocarcinoma (LS174T) were treated with anti-VEGF mAb injected i.p. on alternate days for a total of six injections at a dosage of 100 microg/injection/mouse. For combined anti-VEGF and radiation, single radiation doses were given under normal blood flow (20 and 30 Gy) or clamped hypoxic conditions (30 and 40 Gy) 24 h after the sixth injection of mAb. The inhibition of the growth of U87 and LS174T tumors by the anti-VEGF mAb was associated with a significant reduction in tumor vascular density and a relatively small increase in the number of apoptotic cells. Compared with size-matched controls, IFP decreased by 74% in LS174T, and 73% in U87 in mice treated with anti-VEGF mAb. After antibody treatment PO2 increased significantly in U87, but did not change in LS174T tumors. Combined treatment induced in U87 tumors a tumor-growth delay (TGD) which was greater than additive; in LS174T except for the 40-Gy hypoxic group, the effect was only additive. In both U87 and LS174T the TGD induced by the antibody was independent of oxygen levels in the tumor at the time of radiation. The fact that the increase in TGD occurred under both normoxic and hypoxic conditions suggests that anti-VEGF mAb treatment can compensate for the resistance to radiation induced by hypoxia.
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1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Lee, Chang Geol(이창걸) ORCID logo https://orcid.org/0000-0002-8702-881X
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