| During photodynamic therapy (PDT) adequate tissue oxygenation is required for cytotoxicity, but the PDT process can deplete oxygen levels through consumption of ground state oxygen during production of cytotoxic singlet oxygen. The fluence rate of illumination may affect PDT oxygen consumption, with lower fluency rates predicted to favor tumor oxygenation and production of singlet oxygen. In Photofrin{dollar}spcircler{dollar} PDT of radiation induced fibrosarcoma murine tumors, pO{dollar}sb2{dollar} values fell significantly during the first minute of treatment at all fluence rates. However, during delivery of {dollar}sim{dollar}20-50 J/cm{dollar}sp2{dollar} tumor pO{dollar}sb2{dollar} recovered to control levels or better at a fluence rate of 30 mW/cm{dollar}sp2,{dollar} while pO{dollar}sb2{dollar} remained significantly depleted at a fluence rate of 150 mW/cm{dollar}sp2.{dollar} In conjunction with enhanced tumor pO{dollar}sb2{dollar} during treatment, 30 mW/cm{dollar}sp2{dollar} 100 J/cm{dollar}sp2{dollar} produced significantly better tumor responses than the same fluence delivered at 150 mW/m{dollar}sp2.{dollar} Increased efficiency at lower fluence rates enabled the use of smaller total fluences than those required for equivalent tumor responses at higher fluence rates. The increased efficiency, though, could not completely compensate for the need to use longer treatment times at lower fluence rates. Fluence rate also affected normal tissue toxicity and improvements in treatment selectivity may be possible at low fluence rates if their enhanced efficiency is compensated for by lowering treatment fluence. Possible mechanisms contributing to improved tumor response at low fluence rate include increases in direct tumor cell kill and enhanced vascular damage in peri-tumor skin. Studies utilizing an inhibitor of the vascular modulator nitric oxide indicate that tumor cures are associated with treatment conditions capable of disrupting skin vascular function. However, fluence rate did not affect tumor vascular responses to PDT; vascular perfusion and pO{dollar}sb2{dollar} values in tumors were similarly reduced following both high and low fluence rate treatments. PDT-induced tumor hypoxia did not increase expression of the hypoxia-sensitive, angiogenic cytokine, vascular endothelial growth factor. Preliminary clinical studies in basal cell carcinomas indicate that oxygen depletion may not necessarily occur during high fluence rate PDT; these results may be related to low Photofrin{dollar}spcircler{dollar} doses. Overall, the preclinical studies have indicated that lower fluence rates can improve tumor oxygenation and responses to Photofrin{dollar}spcircler{dollar} PDT. The applicability of these findings to the clinic is under investigation. |
