The role of nitric oxide in Photodynamic Therapy of cancer

DI VENOSA G, PEROTTI C, FUKUDA H, CASAS A, BATLLE A

Cambridge, UK

Workshop; Tetrapyrrole discussion group; 2004

In this work we studied the in vitro interactions between aminolevulinic acid (ALA)-mediated Photodynamic Therapy (PDT) and nitric oxide (NO), as well as the interactions between ALA, porphyrins and some NO donors and precursors.  We employed three murine adenocarcinoma cell lines: LM2, which does not produce NO; LM3, which produces NO, and LM3-SNP, a variant of LM3 resistant to NO producing the same amount of NO as the parental.  We did not find cross resistance between NO-induced cytotoxicity and ALA-PDT.  In spite of the lower porphyrin synthesis, LM2 cells show the highest sensitivity to ALA-PDT.  We ignore if this could be related to the lack of endogenous NO production. However, modulation of NO levels did not modify the response to PDT in any of the cell lines. Two unexpected results were found: the enhancement of NO production from the donor sodium nitroprusside (SNP) induced by ALA in both cells and medium, and the inhibition by ALA of NO production from arginine.   This last interaction may have implications in ALA-PDT efficacy in vivo through modulation of blood flood.  We also found that SNP strongly protected the cells from ALA-PDT by impairing porphyrin biosynthesis as a consequence of an inhibition of the enzyme ALA dehyratase, and this feature was not related to NO production.  The complexity of these results is an indication of the possible multiple interactions between ALA, SNP and arginine, either in a physiological or in a therapeutic setting.