Di Venosa Gabriela, Perotti Christian, Fukuda Haydée, Batlle Alcira, Casas Adriana
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP) FCEN (University of Buenos Aires and CONICET), Ciudad Universitaria, Pabellón II, 2do piso, 1428 Buenos Aires, Capital Federal, Argentina.
J Photochem Photobiol B. 2005 Sep 1;80(3):195-202. doi: 10.1016/j.jphotobiol.2005.05.001.
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. However, we hypothesised that this is not related to the lack of endogenous NO production, because 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. 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 dehydratase. We were not able to evaluate the action of NO derived from SNP because of the unexpected porphyrin impairment. On the other hand, impairment of NO from Arginine driven by ALA, although not modulating in vitro the ALA-PDT response, by increasing in vivo blood flow, may be contributing to the mechanism of tumour cures.
在本研究中，我们探究了氨基乙酰丙酸（ALA）介导的光动力疗法（PDT）与一氧化氮（NO）之间的体外相互作用，以及ALA、卟啉与一些NO供体和前体之间的相互作用。我们使用了三种小鼠腺癌细胞系：不产生NO的LM2；产生NO的LM3；以及LM3-SNP，它是LM3的一个变体，对NO具有抗性，但产生的NO量与亲本相同。我们未发现NO诱导的细胞毒性与ALA-PDT之间存在交叉抗性。尽管LM2细胞的卟啉合成较低，但对ALA-PDT表现出最高的敏感性。然而，我们推测这与内源性NO的缺乏无关，因为调节NO水平并未改变任何细胞系对PDT的反应。我们发现了两个意外结果：ALA在细胞和培养基中均能增强供体硝普钠（SNP）产生NO的能力，以及ALA对精氨酸产生NO的抑制作用。我们还发现，SNP通过抑制ALA脱水酶，损害卟啉生物合成，从而强烈保护细胞免受ALA-PDT的影响。由于意外的卟啉损伤，我们无法评估SNP衍生的NO的作用。另一方面，ALA对精氨酸产生NO的损害，虽然在体外未调节ALA-PDT反应，但通过增加体内血流量，可能有助于肿瘤治愈机制。
