Early reoxygenation in tumors after irradiation: determining factors and consequences for radiotherapy regimens using daily multiple fractions.
OBJECTIVE
To characterize changes in the tumor microenvironment early after irradiation and determine the factors responsible for early reoxygenation.


METHODS
Fibrosarcoma type II (FSaII) and hepatocarcinoma transplantable liver tumor tumor oxygenation were determined using electron paramagnetic resonance oximetry and a fiberoptic device. Perfusion was assessed by laser Doppler, dynamic contrast-enhanced MRI, and dye penetration. Oxygen consumption was determined by electron paramagnetic resonance. The interstitial fluid pressure was evaluated by the wick-in-needle technique.


RESULTS
An increase in oxygen partial pressure was observed 3-4 h after irradiation. This increase resulted from a decrease in global oxygen consumption and an increase in oxygen delivery. The increase in oxygen delivery was due to radiation-induced acute inflammation (that was partially inhibited by the antiinflammatory agent diclofenac) and to a decrease in interstitial fluid pressure. The endothelial nitric oxide synthase pathway, identified as a contributing factor at 24 h after irradiation, did not play a role in the early stage after irradiation. We also observed that splitting a treatment of 18 Gy into two fractions separated by 4 h (time of maximal reoxygenation) had a greater effect on tumor regrowth delay than when applied as a single dose.


CONCLUSIONS
Although the cell cycle redistribution effect is important for treatment protocols using multiple daily radiation fractions, the results of this work emphasize that the oxygen effect must be also considered to optimize the treatment strategy.
Crokart
Nathalie
N
Laboratory of Medicinal Chemistry and Radiopharmacy, Université Catholique de Louvain, Brussels, Belgium.
Jordan
Bénédicte F
BF
Baudelet
Christine
C
Ansiaux
Reginald
R
Sonveaux
Pierre
P
Grégoire
Vincent
V
Beghein
Nelson
N
DeWever
Julie
J
Bouzin
Caroline
C
Feron
Olivier
O
Gallez
Bernard
B
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000378:metabolism / Q000532:radiotherapy; D019583:Dose Fractionation, Radiation; D045604:Extracellular Fluid / Q000502:physiology; D005354:Fibrosarcoma / Q000098:blood supply / Q000378:metabolism / Q000532:radiotherapy; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000532:radiotherapy*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010092:Oximetry / Q000379:methods; D010101:Oxygen Consumption / Q000502:physiology / Q000528:radiation effects*; D010313:Partial Pressure; D011836:Radiation Tolerance; D013997:Time Factors
D052250:Nitric Oxide Synthase Type III