Tumor reoxygenation following administration of Mitogen-Activated Protein Kinase inhibitors: a rationale for combination with radiation therapy.

Abstract

BACKGROUND AND PURPOSE:

The relevance of Mitogen Activated Protein Kinase (MAPK) inhibitors as co-treatments for radiation therapy is investigated, with special focus on a potential link between the MAPK pathway and tumor hypoxia, which is a critical determinant for response to therapy.

MATERIALS AND METHODS:

The effects of two MAPK inhibitors, Sorafenib and PD0325901, were monitored daily using in vivo EPR (Electron Paramagnetic Resonance) oximetry in FSaII and TLT tumor models in order to identify a window of reoxygenation, during which tumor blood flow, oxygen consumption and radiation sensitivity were assessed.

RESULTS:

Reoxygenation was shown after two days of treatments with Sorafenib or PD0325901 in two tumor models, which was further successfully exploited with Sorafenib for improving the radiation response of FSaII tumors by a factor of 1.5. The increase in tumor oxygenation was shown to be the result of two major factors: (i) an increase in blood flow for Sorafenib, that might be linked to its anti-angiogenic effect (vascular normalization), and (ii) a decrease in oxygen consumption for Sorafenib and PD0325901, due to an alteration of the mitochondrial activity.

CONCLUSION:

We evidenced tumor reoxygenation in vivo following MAPK inhibition and suggest a rationale for the combination of radiation therapy with Sorafenib.

• Authors: Oussama Karroum, Julie Kengen, Pierre Danhier, Julie Magat, Lionel Mignion, Caroline Bouzin, Julien Verrax, Nicolas Charette, Peter Starkel, Pedro Buc Calderon, Pierre Sonveaux, Oliver Feron, Vincent Grégoire, Bernard Gallez, Bénédicte F Jordan
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 105 Issue 1 Pg. 64-71 (Oct 2012) ISSN: 1879-0887 [Electronic] Ireland
• PMID: 22682746 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Angiogenesis Inducing Agents
• Benzamides
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Niacinamide
• mirdametinib
• Diphenylamine
• Sorafenib
• Glutathione

Topics

• Angiogenesis Inducing Agents
• Animals
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Blotting, Western
• Diphenylamine (analogs & derivatives, pharmacology)
• Electron Spin Resonance Spectroscopy
• Fibrosarcoma (metabolism, radiotherapy)
• Glutathione (analysis)
• Liver Neoplasms, Experimental (metabolism, radiotherapy)
• Mice
• Neoplasms, Experimental (metabolism, radiotherapy)
• Niacinamide (analogs & derivatives, pharmacology)
• Oxygen Consumption (drug effects)
• Phenylurea Compounds (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Radiation Tolerance (drug effects, physiology, radiation effects)
• Sorafenib