Mechanism of reoxygenation after antiangiogenic therapy using SU5416 and its importance for guiding combined antitumor therapy.
Emerging preclinical studies support the concept of a transient "normalization" of tumor vasculature during the early stage of antiangiogenic treatment, with possible beneficial effects on associated radiotherapy or chemotherapy. One key issue in this area of research is to determine whether this feature is common to all antiangiogenic drugs and whether the phenomenon occurs in all types of tumors. In the present study, we characterized the evolution of the tumor oxygenation (in transplantable liver tumor and FSAII tumor models) after administration of SU5416, an antagonist of the vascular endothelial growth factor receptor. SU5416 induced an early increase in tumor oxygenation [measured by electronic paramagnetic resonance (EPR)], which did not correlate with remodeling of the tumor vasculature (assessed by CD31 labeling using immunohistochemistry) or with tumor perfusion (measured by dynamic contrast enhanced-magnetic resonance imaging). Inhibition of mitochondrial respiration (measured by EPR) was responsible for this early reoxygenation. Consistent with these unique findings in the tumor microenvironment, we found that SU5416 potentiated tumor response to radiotherapy but not to chemotherapy. In addition to the fact that the characterization of the tumor oxygenation is essential to enable correct application of combined therapies, our results show that the long-term inhibition of oxygen consumption is a potential novel target in this class of compounds.
Ansiaux
Réginald
R
Laboratory of Biomedical Magnetic Resonance, Université Catholique de Louvain, Brussels, Belgium.
Baudelet
Christine
C
Jordan
Bénédicte F
BF
Crokart
Nathalie
N
Martinive
Philippe
P
DeWever
Julie
J
Grégoire
Vincent
V
Feron
Olivier
O
Gallez
Bernard
B
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015687:Cell Hypoxia / Q000187:drug effects*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D051379:Mice; D008809:Mice, Inbred C3H; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D011838:Radiation-Sensitizing Agents; C116890:Semaxinib; D003520:Cyclophosphamide; D010100:Oxygen