Usefulness of HIF-1 imaging for determining optimal timing of combining bevacizumab and radiotherapy.
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.
Ou
Guangfei
G
Department of Radiation Oncology, Cancer Hospital Institute, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People's Republic of China.
Itasaka
Satoshi
S
Zeng
Lihua
L
Shibuya
Keiko
K
Yi
Junlin
J
Harada
Hiroshi
H
Hiraoka
Masahiro
M
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
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D051793:Hypoxia-Inducible Factor 1; D000068258:Bevacizumab