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Nitric oxide production by tumour tissue: impact on the response to photodynamic therapy
Authors
Andrade SP
Athar M
+59 more
Athar M
Beckman JS
Blough NV
Bredt DS
C S Parkins
Cecic I
D J Chaplin
Dougherty TJ
Durand RE
Evans TJ
Fukumura D
Gaboury JP
Gilissen MJ
Gollnick SO
Grisham MB
Gupta S
H Shibuya
Henderson BW
Horsman MR
I Cecic
Jenkins DC
Kimura H
Korbelik M
Korbelik M
Korbelik M
Korbelik M
Krosl G
Kubes P
Lala PK
M Korbelik
M R L Stratford
McCall TB
Mehta JL
Moilanen E
Moulder JE
Moulder JE
Nakazono K
Ochsner M
Orucevic A
Parkins CS
Parkins CS
Parkins CS
Rees DD
Rockwell SC
Schmidt HHH
Schulz R
Shepherd AP
Stratford MRL
Suit HD
Tozer GM
Tozer GM
Twentyman PR
van Geel IPJ
van Geel IPJ
Vanhoutte PM
Volpe JP
Wolin MS
Wood PJ
Xie K
Publication date
1 January 2000
Publisher
Nature Publishing Group
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PubMed
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 Nω-nitro- L -arginine (L-NNA) or Nω-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. © 2000 Cancer Research Campaig
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