A Fas-dependent component in 5-fluorouracil/leucovorin-induced cytotoxicity in colon carcinoma cells.
A Fas-dependent component in 5-fluorouracil/leucovorin-induced cytotoxicity in colon carcinoma cells.
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发表时间：
1999-02
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通讯作者：
D. Tillman;I. Peták;J. Houghton
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作者：
D. Tillman;I. Peták;J. Houghton
我们已经证明了（J。霍顿等人，Proc. Natl. Acad. Sci.美国，94：8144-8149，1997），胸苷酸脱氢酶缺陷（TS-）结肠癌细胞中的无胸腺嘧啶死亡是在脱氧胸苷（dThd）剥夺后通过Fas/FasL相互作用介导的，并且人结肠癌细胞系的Fas依赖性敏感性可能依赖于Fas表达的水平。本研究的目的是阐明是否存在Fas依赖的组件在5-氟尿嘧啶（FUra）/亚叶酸（LV）诱导的细胞毒性的结肠癌细胞，这是否可能是加强IFN-γ诱导的Fas表达的升高，使用HT 29细胞系作为模型。FUra/LV的细胞毒活性被HT 29细胞中的dThd抑制，并且还部分地被阻止Fas/FasL相互作用的NOK-1+NOK-2单克隆抗体抑制。FUra/LV诱导的细胞毒性被IFN-γ显著增强，通过暴露于NOK-1+NOK-2抗体逆转，并且与IFN-γ存在下Fas表达的4倍诱导和FasL表达的显著升高相关。使用另外五种人结肠癌细胞系，FUra/LV诱导的细胞毒性在GC 3/c1、VRC 5/c1和Caco 2中是dThd依赖性的，但在HCT 8或HCT 116细胞中不是。与HT 29细胞一样，IFN-γ在GC 3/c1和VRC 5/c1中增强了这种细胞毒性，但在Caco 2中没有增强，Caco 2不表达Fas，在HCT 8和HCT 116中也没有增强，在HCT 8和HCT 116中没有证实dThd依赖性FUra诱导的细胞毒性。数据表明，Fas依赖性成分，增强IFN-γ，存在于FURA/LV诱导的细胞毒性，但需要FURA/LV诱导的DNA损伤IFN-γ诱导的增强发生。
We have shown previously (J. A. Houghton et al., Proc. Natl. Acad. Sci. USA, 94: 8144-8149, 1997) that thymineless death in thymidylate synthase-deficient (TS-) colon carcinoma cells is mediated via Fas/FasL interactions after deoxythymidine (dThd) deprivation, and that Fas-dependent sensitivity of human colon carcinoma cell lines may be dependent upon the level of Fas expressed. The objective of this study was to elucidate whether a Fas-dependent component exists in 5-fluorouracil (FUra)/leucovorin (LV)-induced cytotoxicity of colon carcinoma cells, and whether this may be potentiated by IFN-gamma-induced elevation in Fas expression, using the HT29 cell line as a model. The cytotoxic activity of FUra/LV was inhibited by dThd in HT29 cells and also, in part, by NOK-1+NOK-2 MoAbs that prevent Fas/FasL interactions. FUra/LV-induced cytotoxicity was significantly potentiated by IFN-gamma, reversed by exposure to NOK-1+NOK-2 antibodies, and correlated with a 4-fold induction of Fas expression in the presence of IFN-gamma and significant elevation in expression of FasL. Using five additional human colon carcinoma cell lines, FUra/LV-induced cytotoxicity was dThd-dependent in GC3/c1, VRC5/c1, and Caco2 but not in HCT8 or HCT116 cells. Like HT29 cells, this cytotoxicity was potentiated by IFN-gamma in GC3/c1 and VRC5/c1 but not in Caco2, which fails to express Fas, nor in HCT8 and HCT116, in which no dThd-dependent FUra-induced cytotoxicity was demonstrated. Data suggest that a Fas-dependent component, potentiated by IFN-gamma, exists in FUra/LV-induced cytotoxicity but requires FUra/LV-induced DNA damage for IFN-gamma-induced potentiation to occur.