Nitric oxide production by tumour tissue: impact on the response to photodynamic therapy

The role of nitric oxide (NO) in the response to Photofrin-based photodynam ic therapy (PDT) was investigated using mouse tumour models characterized b y either relatively high or low endogenous NO production (RIF and SCCVII vs EMT6 and FsaR, respectively). The NO synthase inhibitors N-omega-nitro-L-a rginine (L-NNA) or N-omega-nitro-L-arginine methyl ester (L-NAME), administ ered to mice immediately after PDT light treatment of subcutaneously growin g tumours, markedly enhanced the cure rate of RIF and SCCVII models, but pr oduced no obvious benefit with the EMT6 and FsaR models. Laser Doppler flow metry measurement revealed that both L-NNA and L-NAME strongly inhibit bloo d flow in RIF and SCCVII tumours, but not in EMT6 and FsaR tumours. When in jected intravenously immediately after PDT light treatment, L-NAME dramatic ally augmented the decrease in blood flow in SCCVII tumours induced by PDT. The pattern of blood flow alterations in tumours following PDT indicates t hat, even with curative doses, regular circulation may be restored in some vessels after episodes of partial or complete obstruction. Such conditions are conducive to the induction of ischaemia-reperfusion injury, which is in stigated by the formation of superoxide radical. The administration of supe roxide dismutase immediately after PDT resulted in a decrease in tumour cur e rates, thus confirming the involvement of superoxide in the anti-tumour e ffect. The results of this study demonstrate that NO participates in the ev ents associated with PDT-mediated tumour destruction, particularly in the v ascular response that is of critical importance for the curative outcome of this therapy. The level of endogenous production of NO in tumours appears to be one of the determinants of sensitivity to PDT. (C) 2000 Cancer Resear ch Campaign.