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


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.


CONCLUSIONS
We evidenced tumor reoxygenation in vivo following MAPK inhibition and suggest a rationale for the combination of radiation therapy with Sorafenib.
Université Catholique de Louvain, Brussels, Belgium.
Oussama
O
Karroum
Julie
J
Kengen
Pierre
P
Danhier
Julie
J
Magat
Lionel
L
Mignion
Caroline
C
Bouzin
Julien
J
Verrax
Nicolas
N
Charette
Peter
P
Starkel
Pedro Buc
PB
Calderon
Pierre
P
Sonveaux
Oliver
O
Feron
Vincent
V
Grégoire
Bernard
B
Gallez
Bénédicte F
BF
Jordan
D043925:Angiogenesis Inducing Agents; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D005354:Fibrosarcoma / Q000378:metabolism / Q000532:radiotherapy; D005978:Glutathione / Q000032:analysis; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000532:radiotherapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000532:radiotherapy*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects*; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D000077157:Sorafenib
D043925:Angiogenesis Inducing Agents; D001549:Benzamides; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; C506614:mirdametinib; D004159:Diphenylamine; D000077157:Sorafenib; D005978:Glutathione