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Nitric oxide production by tumour tissue: impact on the response to photodynamic therapy
M Korbelik1, C S Parkins, H Shibuya
1Cancer Imaging Department, British Columbia Cancer Agency, Vancouver, Canada.
Abstract:
The role of nitric oxide (NO) in the response to Photofrin-based photodynamic therapy (PDT) was investigated using mouse tumour models characterized by either relatively high or low endogenous NO production (RIF and SCCVII vs EMT6 and FsaR, respectively). The NO synthase inhibitors Nomega-nitro-L-arginine (L-NNA) or Nomega-nitro-L-arginine methyl ester (L-NAME), administered to mice immediately after PDT light treatment of subcutaneously growing tumours, markedly enhanced the cure rate of RIF and SCCVII models, but produced no obvious benefit with the EMT6 and FsaR models. Laser Doppler flowmetry measurement revealed that both L-NNA and L-NAME strongly inhibit blood flow in RIF and SCCVII tumours, but not in EMT6 and FsaR tumours. When injected intravenously immediately after PDT light treatment, L-NAME dramatically augmented the decrease in blood flow in SCCVII tumours induced by PDT. The pattern of blood flow alterations in tumours following PDT indicates that, 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 instigated by the formation of superoxide radical. The administration of superoxide dismutase immediately after PDT resulted in a decrease in tumour cure rates, thus confirming the involvement of superoxide in the anti-tumour effect. The results of this study demonstrate that NO participates in the events associated with PDT-mediated tumour destruction, particularly in the vascular 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.
Insights
Nitric oxide (NO) enhances photodynamic therapy (PDT) effectiveness by influencing tumor blood flow. Inhibiting NO production improved PDT cure rates in specific mouse models, highlighting NO
Area of Science:
- Oncology
- Vascular Biology
- Photomedicine
Background:
- Photodynamic therapy (PDT) utilizes photosensitizers and light to generate cytotoxic effects.
- Nitric oxide (NO) plays a complex role in physiological responses, including inflammation and vascular function.
- Tumor characteristics, such as endogenous nitric oxide (NO) production, may influence treatment outcomes.
Purpose of the Study:
- To investigate the role of endogenous nitric oxide (NO) in the therapeutic response to Photofrin-based photodynamic therapy (PDT).
- To determine if modulating NO levels impacts PDT efficacy in different mouse tumor models.
- To elucidate the mechanisms underlying NO's influence on PDT-induced tumor destruction.
Main Methods:
- Utilized mouse tumor models with varying endogenous NO production levels (RIF/SCCVII - high; EMT6/FsaR - low).
- Administered NO synthase inhibitors (Nomega-nitro-L-arginine [L-NNA] or Nomega-nitro-L-arginine methyl ester [L-NAME]) post-PDT light treatment.
- Measured tumor blood flow using Laser Doppler flowmetry and assessed cure rates.
- Investigated the role of superoxide radicals by administering superoxide dismutase post-PDT.
Main Results:
- NO synthase inhibitors (L-NNA, L-NAME) significantly enhanced PDT cure rates in high-NO producing tumors (RIF, SCCVII) but not in low-NO producing tumors (EMT6, FsaR).
- Inhibitors strongly reduced tumor blood flow in RIF and SCCVII models, while having minimal effect on EMT6 and FsaR.
- L-NAME exacerbated PDT-induced blood flow reduction in SCCVII tumors.
- Superoxide dismutase administration decreased tumor cure rates, indicating superoxide's involvement in the anti-tumor effect.
Conclusions:
- Endogenous nitric oxide (NO) production is a key determinant of sensitivity to Photofrin-based PDT.
- NO modulates the vascular response to PDT, which is critical for therapeutic outcome.
- Targeting NO levels or managing ischemia-reperfusion injury may optimize PDT efficacy.