Axitinib sensitization of high Single Dose Radiotherapy Journal Article

Authors: Rao, S. S.; Thompson, C.; Cheng, J.; Haimovitz-Friedman, A.; Powell, S. N.; Fuks, Z.; Kolesnick, R. N.
Article Title: Axitinib sensitization of high Single Dose Radiotherapy
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. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: controlled study; treatment response; nonhuman; cancer radiotherapy; treatment indication; animal cell; mouse; animal tissue; melanoma; apoptosis; animal experiment; animal model; in vitro study; sarcoma; endothelium cell; radiosurgery; staining; vascular endothelial growth factor; radiosensitivity; tumor growth; cancer control; axitinib; stereotactic body radiation therapy; nick end labeling; endothelium; radiosensitization; sensitization; ceramide; sphingomyelin phosphodiesterase; acid sphingomyelinase; anti-angiogenic; male; priority journal; article; benzamide; single dose radiation therapy
Journal Title: Radiotherapy and Oncology
Volume: 111
Issue: 1
ISSN: 0167-8140
Publisher: Elsevier Inc.  
Date Published: 2014-04-01
Start Page: 88
End Page: 93
Language: English
DOI: 10.1016/j.radonc.2014.02.010
PROVIDER: scopus
PUBMED: 24794795
PMCID: PMC4278650
Notes: Radiother. Oncol. -- Export Date: 8 July 2014 -- CODEN: RAOND -- Source: Scopus
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MSK Authors
  1. Simon Nicholas Powell
    185 Powell
  2. Zvi Fuks
    344 Fuks
  3. Richard N Kolesnick
    246 Kolesnick
  4. Shyam S Rao
    83 Rao
  5. Jin Cheng
    5 Cheng