Combined effect of tumor necrosis factor-alpha and ionizing radiation on the induction of apoptosis in 5637 bladder carcinoma cells
Combined effect of tumor necrosis factor-alpha and ionizing radiation on the induction of apoptosis in 5637 bladder carcinoma cells
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DOI：
10.1007/s00066-006-1475-2
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发表时间：
2006-08-01
影响因子：
3.1
通讯作者：
Roedel, Franz
中科院分区：
文献类型：
--
作者：
Baierlein, Sammy A.;Distel, Luitpold;Roedel, Franz
背景和目的：上睑脱垂可由不同但重叠的途径引起。电离辐射通过线粒体依赖的“内在”途径诱导细胞凋亡。肿瘤坏死因子α、Fas(CD95)或TRAIL受体的结扎是死亡受体介导的外源性途径的典型代表。材料与方法：5637膀胱癌细胞用不同浓度的重组肿瘤坏死因子α(0~10 ng/ml)单次照射、0.5~10Gy射线照射或联合照射，观察其诱导细胞凋亡和克隆存活的作用。用TUNEL法检测治疗后96h的细胞凋亡率，用克隆形成法检测克隆形成细胞的存活率。结果：5637肿瘤细胞受照射后，细胞凋亡率呈不连续的剂量依赖关系，在0~2Gy时明显增加，在2~10Gy时略有增加。肿瘤细胞的凋亡率在较低浓度的肿瘤坏死因子-α处理后持续增加，在5.0-10.0 ng/m L浓度范围内达到平台期。等位图分析表明，照射与肿瘤坏死因子-α之间存在超相加关系。在0.005至0.5 ng/ml的范围内，以及对肿瘤坏死因子-α浓度的相加效应。在克隆生存分析中证实了相加效应，在联合应用肿瘤坏死因子-α和放射治疗后，细胞存活分数降低。结论：联合应用两种诱导方式在诱导5637膀胱癌细胞凋亡方面具有协同作用。虽然放射增敏效应仍需在动物模型中得到证实，但联合治疗可能会增加膀胱癌的放射治疗效果。
Background and Purpose: Apo ptosis can be induced by distinct but overlapping pathways. Ionizing radiation induces apoptosis by an "intrinsic", mitochondria-dependent pathway. Ligation of tumor necrosis factor-(TNF-)alpha, FAS (CD95)or TRAIL receptors are typical representatives of an extrinsic, death-receptor-mediated pathway. In this study the effect of irradiation, treatment with the cytokine TNF-alpha, or a combination of both on the induction of apoptosis and clonogenic survival of bladder carcinoma cells was investigated.Material and Methods: 5637 bladder carcinoma cells were treated with different concentrations of recombinant TNF-alpha (0-10 ng/ml), irradiated with single doses ranging from 0.5 to 10 Gy, or a combination of both modalities. Apoptotic cells were quantified by the TUNEL assay up to 96 h following treatment, clonogenic cell survival by a clonogenic assay. Synergistic effects of both modalities were evaluated using isobotographic analysis.Results: Irradiation of 5637 carcinoma cells resulted in a discontinuous dose dependence of the apoptotic fraction with a pronounced increase in the range of 0-2 Gy and a slighter increase at 2-10 Gy. The percentage of apoptotic carcinoma cells also increased continuously after treatment with Lower concentrations of TNF-alpha reaching a plateau at concentrations of 5.0-10.0 ng/mL Isobolographic analysis revealed a supraadditive interrelationship between irradiation and TNF-alpha. in the range between 0.005 and 0.5 ng/ml, and an additive effect for TNF-alpha concentrations > 0.5 ng/mL. The additive effects were confirmed in clonogenic survival assays with reduced survival fractions following combined TNF-a administration and irradiation.Conclusion:The combination of two apoptosis-inducing modalities resulted in a synergistic effect on the induction of apoptosis in 5637 bladder carcinoma cells. Although a radiosensitizing effect still has to be proven in animal models, combined-modality treatment may increase the therapeutic effectiveness of irradiation in bladder cancer.