1: Cancer Res. 2005 Sep 1;65(17):7911-6. 

Tumor radiosensitization by antiinflammatory drugs: evidence for a new mechanism
involving the oxygen effect.

Crokart N, Radermacher K, Jordan BF, Baudelet C, Cron GO, Gregoire V, Beghein N,
Bouzin C, Feron O, Gallez B.

Laboratory of Medicinal Chemistry and Radiopharmacy, Universite Catholique de
Louvain, Brussels, Belgium.

We hypothesized that nonsteroidal antiinflammatory drugs (NSAIDs) might enhance
tumor radiosensitivity by increasing tumor oxygenation (pO2), via either a
decrease in the recruitment of macrophages or from inhibition of mitochondrial
respiration. The effect of four NSAIDs (diclofenac, indomethacin, piroxicam, and
NS-398) on pO2 was studied in murine TLT liver tumors and FSaII fibrosarcomas.
At the time of maximum pO2 (t(max), 30 minutes after administration), perfusion,
oxygen consumption, and radiation sensitivity were studied. Local pO2
measurements were done using electron paramagnetic resonance. Tumor perfusion
and permeability measurements were assessed by dynamic contrast-enhanced
magnetic resonance imaging. The oxygen consumption rate of tumor cells after in
vivo NSAID administration was measured using high-frequency electron
paramagnetic resonance. Tumor-infiltrating macrophage localization was done with
immunohistochemistry using CD11b antibody. All the NSAIDs tested caused a rapid
increase in pO2. At t(max), tumor perfusion decreased, indicating that the
increase in pO2 was not caused by an increase in oxygen supply. Also at t(max),
global oxygen consumption decreased but the amount of tumor-infiltrating
macrophages remained unchanged. Our study strongly indicates that the oxygen
effect caused by NSAIDs is primarily mediated by an effect on mitochondrial
respiration. When irradiation (18 Gy) was applied at t(max), the tumor
radiosensitivity was enhanced (regrowth delay increased by a factor of 1.7).
These results show the potential utility of an acute administration of NSAIDs
for radiosensitizing tumors, and shed new light on the mechanisms of NSAID
radiosensitization. These results also provide a new rationale for the treatment
schedule when combining NSAIDs and radiotherapy.

PMID: 16140962 [PubMed - in process]