Mechanisms underlying early tumor reoxygenation after irradiation and radiosensitizing properties of anti-inflammatory drugs : consequences of their oxygen effect on radiotherapy time schedule

Tumor oxygenation is a key factor of the radiotherapy treatment efficacy because the efficacy for killing cells in oxygenated conditions is three times more effective than in hypoxic conditions. This tumor oxygenation is a balance between oxygen supply and oxygen consumption rate by cells. We made the hypothesis that a reoxygenation of the tumor could occur in the early time after irradiation, or early after administration of anti-inflammatory or glucocorticoid drugs. In the first part of the thesis, we investigated the early reoxygenation effect in tumors, the mechanisms responsible for this effect and its consequences for tumor radiosensitivity. We demonstrated that tumor oxygenation increases rapidly after irradiation and remains high for several days. The maximal reoxygenation time was achieved 3-4 hours after irradiation. At this time, other hemodynamic parameters were studied in order to determine the underlying mechanisms. It was demonstrated that oxygen consumption and oxygen delivery played a role in this early reoxygenation, since we observed an important decrease in oxygen consumption and an increase in blood flow after irradiation. Contrary to the late reoxygenation effect, the early reoxygenation effect was not NO-mediated. We also found that inflammatory vasodilatation played a role in the early oxygen effect. Finally, we demonstrated that two irradiations of 9 Gy, when the second was applied at the maximal reoxygenation time, was more effective than one irradiation of 18 Gy. In the second part of the thesis, we investigated the impact of Non steroidal anti-inflammatory drugs (NSAIDs). In particular, we studied the effects of a selective COX-2 inhibitor (NS-398) on tumor oxygenation. The underlying mechanisms and the impact on radiosensitivity were also studied. We demonstrated that all NSAIDS increased tumor oxygenation rapidly after the administration. At the time of maximal reoxygenation (30 minutes after administration), the oxygen effect was demonstrated to be due to a decrease in tumor oxygen consumption. This decrease in consumption was probably due to the uncoupling of mitochondrial respiration, since this effect was described for NSAIDs in the literature. On the other hand, tumor perfusion was decreased at the same time. Finally, the regrowth delay was much larger (i.e., treatment was more effective) when irradiation was applied at the maximal reoxygenation time. This increase in treatment effectiveness was comparable to that observed for carbogen. The last part of the thesis focused on the effect of glucocorticoid administration on tumor oxygenation. The tumor oxygenation was increased after the administration of these drugs, with maximal reoxygenation time occurring after 30 minutes. At this time the perfusion and the tumor oxygen consumption rate were significantly decreased. The effect on oxygen consumption could be correlated to an effect on the mitochondrial respiratory chain, both via a direct effect on specific mitochondrial complexes or via prostaglandin inhibition (as prostaglandins play important role in mitochondrial respiration). Moreover, this latter effect could explain the surprisingly analogy of timing in oxygenation between glucocorticoids and NSAIDs. Finally, when irradiation was applied at the maximal reoxygenation time, the regrowth delay was much larger (i.e., treatment was more effective) than for irradiation aloneThèse de doctorat en sciences pharmaceutiques (FARM 3) --UCL, 200