Abstract
Purpose
Large doses of radiation (8–20 Gy) preferentially target tumor vasculature. This vascular response is suggested to regulate tumor response to radiotherapy. Here, we investigate the relative contributions of direct cell killing by radiation versus tumor cell death due to radiation effects on the vasculature. We also examine Sunitinib’s mechanism of action as a tumor radiosensitizer.
Experimental Design
MDA-MB-231 xenografts were treated with radiation doses of 2–16 Gy alone, or in combination with bFGF (endothelial radio-protector) or Sunitinib as pharmacological modulators of the vasculature. Sunitinib was orally administered for 2 weeks at 30 mg/kg before radiotherapy; bFGF was intravenously injected 1 h prior to irradiation. Three-dimensional high-frequency power Doppler ultrasound was used to assess relative changes in tumor vasculature. Immunohistochemistry, clonogenic and tumor growth assays were used to quantify tumor response.
Results
Significant reductions in power Doppler signal of up to 50 % were observed for 8 and 16 Gy treatments, along with a dose-dependent increase in cell death. No significant change in power Doppler signal and minimal tumor cell death were noted for tumors treated with radiation and bFGF. Treatments where Sunitinib was combined with radiation demonstrated a significant increase in flow signal at doses equal or greater than 8 Gy. This was accompanied with a significant increase in cell death when compared to radiation or Sunitinib alone.
Conclusion
We confirm that tumor response to high doses of radiation is regulated by its vasculature. We also posit that the response observed when radiation is combined with Sunitinib is linked to a vascular “normalization” effect.
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Acknowledgments
This work was supported by the CBCF and the Terry Fox Foundation through a program project grant “Ultrasound for Cancer Therapy”. Aspects of the work were also supported by a cancer care Ontario (CCO) research grant in experimental therapeutics and imaging. We would like to thank Clinton Hupple for his help in the technical development of the power Doppler imaging set-up. I would also like to thank Dr. Kolios for scientific insight. Finally, the authors thank Dr. Kerbel for his generous donation of MDA-MB-231 cells. Dr. Gregory Czarnota is supported by a CCO Research Chair in Experimental Therapeutics and Imaging. All animal experiments presented in this paper were conducted in compliance with protocols approved by the Sunnybrook Health Science Centre Institutional Animal Care and Use Committee.
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El Kaffas, A., Giles, A. & Czarnota, G.J. Dose-dependent response of tumor vasculature to radiation therapy in combination with Sunitinib depicted by three-dimensional high-frequency power Doppler ultrasound. Angiogenesis 16, 443–454 (2013). https://doi.org/10.1007/s10456-012-9329-2
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DOI: https://doi.org/10.1007/s10456-012-9329-2