Axitinib sensitization of high Single Dose Radiotherapy

Shyam Rao, Chris Thompson, Jin Cheng, Adriana Haimovitz-Friedman, Simon N. Powell, Zvi Fuks, Richard N. Kolesnick

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Background and purpose Single Dose Radiation Therapy (SDRT) provides remarkably high rates of control even for tumors resistant to fractionated radiotherapy. SDRT tumor control depends on acute acid sphingomyelinase-mediated endothelial cell injury and monoclonal antibodies targeting Vascular Endothelial Cell Growth Factor (VEGF) signaling radiosensitized tumor endothelium when delivered immediately prior to irradiation. Here we evaluate the ability of the oral VEGF receptor inhibitor, axitinib, to sensitize tumor endothelium and increase tumor control with SDRT. Methods and materials Axitinib was added to primary cultured endothelial cells, or administered orally to Sv129/BL6 mice bearing radiosensitive MCA/129 sarcoma or radioresistant B16F1 melanoma flank tumors, followed by SDRT. Endothelial apoptosis was assessed by TUNEL assay or bis-benzamide staining. Mice with irradiated tumors were followed for 90 days to evaluate the impact of axitinib on SDRT tumor control. Results Pre-treatment with axitinib increased acute endothelial cell apoptosis following SDRT in vitro, and in vivo for both MCA/129 and B16F1 tumors. Axitinib correspondingly increased SDRT tumor growth delay and complete response rate (by 40%) for both tumors. Administration precisely 1 h before SDRT was critical for radiosensitization. Conclusions Axitinib radiosensitizes tumor endothelial cells and enhances tumor cure with SDRT, which may permit dose de-escalation and significantly expand the range of clinical indications for SDRT.

Original languageEnglish (US)
Pages (from-to)88-93
Number of pages6
JournalRadiotherapy and Oncology
Volume111
Issue number1
DOIs
StatePublished - Jan 1 2014

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Keywords

  • Acid sphingomyelinase
  • Anti-angiogenic
  • Ceramide
  • Radiosurgery
  • Stereotactic body radiation therapy
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Radiology Nuclear Medicine and imaging

Cite this

Rao, S., Thompson, C., Cheng, J., Haimovitz-Friedman, A., Powell, S. N., Fuks, Z., & Kolesnick, R. N. (2014). Axitinib sensitization of high Single Dose Radiotherapy. Radiotherapy and Oncology, 111(1), 88-93. https://doi.org/10.1016/j.radonc.2014.02.010