Ischaemia-reperfusion injury in photodynamic therapy-treated mouse tumours

Abstract

Prompted by the observation of ischaemia development during the treatment of tumours by photodynamic therapy (PDT) that is typically followed by a restoration of tumour blood flow and by the indications of secondary superoxide generation after PDT, we aimed in this study to obtain evidence of the induction of ischaemia-reperfusion (I/R) injury in PDT-treated tumours. Using subcutaneous mouse FsaR fibrosarcoma model and Photofrin-based PDT treatment, we have examined the activity of xanthine oxidase (XO, a key enzyme in the I/R injury development) in tumours before and after the therapy. Compared to the levels in nontreated tumours, there was a five-fold increase in the activity of this enzyme in tumours excised immediately after PDT. This burst of elevated XO activity declined rapidly, returning to the pretreatment levels within the next 30 min. Visible reflectance spectroscopy confirmed the occurrence of a PDT-induced strong but temporary reduction in tumour oxygenation. The administration of XO inhibitor oxypurinol prevented this PDT-induced rise in XO activity. The oxypurinol treatment also decreased the extent of neutrophil accumulation in PDT-treated tumours and reduced the level of PDT-mediated cures. These results demonstrate the induction of I/R injury in PDT-treated tumours, and show that it can contribute to the therapy outcome. Since I/R injury is a wellrecognised proinflammatory insult, we suggest that its induction in PDT-treated tumours promotes the development of inflammatory response that has become established as a key element of the antitumour effect of PDT.

PDT‐associated host response and its role in the therapy outcome

“…2), which confirms the participation of this humoral effector system of innate immunity [40] in the anti-tumor effect of PDT. Other elements, including the activity of nitric oxide [41] and events such as ischemia-reperfusion injury [42] can have important roles in the vascular effects of PDT [4]. Therefore, although the described events in the vasculature of PDT-treated tumors can be prompted by direct photooxidative lesions inflicted in endothelial cells, they can be also effectively initiated by PDT damage produced in perivascular regions of tumor tissue that instigates chemotactic gradients across the vascular endothelium.…”

Correlation of real-time haemoglobin oxygen saturation monitoring during photodynamic therapy with microvascular effects and tissue necrosis in normal rat liver

“…When oxygen is reintroduced, it enables XO to induce the formation of xanthine from hypoxanthine, resulting in the release of reactive oxygen species, primarily superoxide anions and hydroxyl radicals. There is growing evidence from experiments with other photosensitisers such as porfimer sodium and ALA that reperfusion ischaemia injury may be important Korbelik et al, 2003).…”

Activation of Poly(adenosine diphosphate-ribose) Polymerase in Mouse Tumors Treated by Photodynamic Therapy¶

“…This may reflect the contribution of secondary PDT effects (occurring after photodynamic illumination) to PARP activation in treated tumors. Such effects may, for instance, include the ischemia‐reperfusion insult that we have recently demonstrated in PDT‐treated FsaR tumors (24), which is known to induce PARP activation (38).…”