Usefulness of HIF-1 Imaging for Determining Optimal Timing of Combining Bevacizumab and Radiotherapy

Purpose: 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 and Materials: 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. Conclusion: 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.