Janssens M Y, Van den Berge D L, Verovski V N, Monsaert C, Storme G A
Department of Radiotherapy, Oncology Center, Academic Hospital, Free University Brussels, Belgium.
Cancer Res. 1998 Dec 15;58(24):5646-8.
EMT-6 cells treated for 16 h with 1-10 units/ml IFN-gamma showed a gradual activation of inducible nitric oxide synthase (iNOS) in Western and Northern blots, a simultaneous raise in NO output, and an increase in hypoxic cell radiosensitivity almost to the level of aerobic cells. Both the NO signal and radiosensitization were counteracted by the NO scavenger oxyhemoglobin, by the specific iNOS inhibitor aminoguanidine, and by the L-arginine analogue N(G)-monomethyl-L-arginine. Collectively, these data demonstrate that IFN-gamma can radiosensitize EMT-6 cells through iNOS induction and that NO is the effector molecule responsible for radiosensitization. Compared with the spontaneous NO releaser (2)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium -1,2-diolate], the iNOS-generated NO signal appeared to be 10 times lower yet resulting in the same enhancement ratio of 2.4. Direct stimulation of NO synthesis in tumor cells through the L-arginine/iNOS pathway represents a novel approach to exploit the radiosensitizing properties of NO.
用1-10单位/毫升的γ干扰素处理16小时的EMT-6细胞，在蛋白质免疫印迹法和Northern印迹法中显示出诱导型一氧化氮合酶（iNOS）的逐渐激活，一氧化氮（NO）产量同时增加，并且缺氧细胞的放射敏感性增加，几乎达到需氧细胞的水平。NO信号和放射增敏作用都被NO清除剂氧合血红蛋白、特异性iNOS抑制剂氨基胍以及L-精氨酸类似物N（G）-单甲基-L-精氨酸所抵消。总体而言，这些数据表明γ干扰素可通过诱导iNOS使EMT-6细胞产生放射增敏作用，并且NO是负责放射增敏的效应分子。与自发NO释放剂（2）-1-[N-（3-氨丙基）-N-（正丙基）氨基]重氮-1,2-二醇盐相比，iNOS产生的NO信号似乎低10倍，但导致相同的2.4增强率。通过L-精氨酸/iNOS途径直接刺激肿瘤细胞中的NO合成代表了一种利用NO放射增敏特性的新方法。
