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 90days 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 1h 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.

• Authors: Shyam S Rao, Chris Thompson, Jin Cheng, Adriana Haimovitz-Friedman, Simon N Powell, Zvi Fuks, Richard N Kolesnick
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 111 Issue 1 Pg. 88-93 (Apr 2014) ISSN: 1879-0887 [Electronic] Ireland
• PMID: 24794795 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Ireland Ltd.

Chemical References

• Imidazoles
• Indazoles
• Protein Kinase Inhibitors
• Radiation-Sensitizing Agents
• Axitinib
• Receptors, Vascular Endothelial Growth Factor

Topics

• Animals
• Apoptosis (radiation effects)
• Axitinib
• Endothelial Cells (drug effects)
• Imidazoles (pharmacology)
• Indazoles (pharmacology)
• Male
• Melanoma, Experimental (drug therapy, metabolism, pathology, radiotherapy)
• Mice
• Mice, Inbred C57BL
• Neovascularization, Pathologic (drug therapy, radiotherapy)
• Protein Kinase Inhibitors (pharmacology)
• Radiation Tolerance (drug effects)
• Radiation-Sensitizing Agents (pharmacology)
• Radiotherapy Dosage
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Sarcoma, Experimental (drug therapy, metabolism, pathology, radiotherapy)
• Signal Transduction (drug effects)