title: Usefulness of HIF-1 imaging for determining optimal timing of combining bevacizumab and radiotherapy.
abstract: OBJECTIVE
  To study the relationship between the hypoxia-inducible factor-1 (HIF-1) activity level after bevacizumab treatment and the antitumor effects of radiation to determine the optimal combination schedule of bevacizumab with radiotherapy.
  
  
  METHODS
  The tumor hypoxia changes induced after bevacizumab treatment were evaluated using optical imaging with a HIF-1-dependent reporter gene using the NCI-H441 human lung adenocarcinoma xenograft model. The combined effects of bevacizumab with radiation were evaluated according to the timing of combination.
  
  
  RESULTS
  In vivo imaging experiments revealed that bevacizumab treatment had little effect on intratumoral HIF-1 activity 1 day after bevacizumab treatment, but it dramatically upregulated it thereafter through increases in the hypoxic fractions of the tumors. When bevacizumab treatment was combined with 14 Gy of radiation at 24 h or 72 h after bevacizumab treatment, the former combination delayed, but the latter combination accelerated, tumor growth compared with irradiation alone.
  
  
  CONCLUSIONS
  These data suggest that an optimal window exists for combining bevacizumab with radiotherapy that determines whether the combination will be beneficial and that the imaging of HIF-1 activity would be useful in determining this window.
authors.affiliation: Department of Radiation Oncology, Cancer Hospital Institute, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Guangfei
authors.initials: G
authors.lastname: Ou
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itasaka
authors.forename: Lihua
authors.initials: L
authors.lastname: Zeng
authors.forename: Keiko
authors.initials: K
authors.lastname: Shibuya
authors.forename: Junlin
authors.initials: J
authors.lastname: Yi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiraoka
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D015415:Biomarkers / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D017930:Genes, Reporter; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011897:Random Allocation; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D051793:Hypoxia-Inducible Factor 1; D000068258:Bevacizumab