Cytokines Induce Uridine Phosphorylase in Mouse Colon 26 Carcinoma Cells and Make the Cells More Susceptible to 5′‐Deoxy‐5‐fluorouridine
Cytokines Induce Uridine Phosphorylase in Mouse Colon 26 Carcinoma Cells and Make the Cells More Susceptible to 5′‐Deoxy‐5‐fluorouridine
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DOI：
10.1111/j.1349-7006.1993.tb02876.x
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发表时间：
1993-03
期刊：
影响因子：
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通讯作者：
H. Eda;K. Fujimoto;Shin‐ichi Watanabe;T. Ishikawa;T. Ohiwa;K. Tatsuno;Yutaka Tanaka;H. Ishitsuka
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文献类型：
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作者：
H. Eda;K. Fujimoto;Shin‐ichi Watanabe;T. Ishikawa;T. Ohiwa;K. Tatsuno;Yutaka Tanaka;H. Ishitsuka
研究了5-氟尿嘧啶（5-FUra）和5′-脱氧-5-氟尿嘧啶核苷（5′-dFUrd）与典型细胞因子和生长因子联合应用对小鼠结肠癌26细胞的抗增殖活性。低剂量的肿瘤坏死因子α（TNFα）、白细胞介素-1 α（IL-1α）和干扰素γ（IFNγ）本身对细胞生长的抑制< 50%，增强了细胞对5′-dFUrd活性的敏感性。特别是，这些细胞因子的混合物大大增强了5′-dFUrd和5-FUra的活性，分别高达12.4倍和2.7倍，而其他细胞抑制剂的活性仅略有变化（< 1.5倍）。碱性成纤维细胞生长因子也增加了易感性，但仅对5′-dFUrd。这种5′-dFUrd活性的优先增强可能是由于细胞因子诱导尿苷磷酸化酶（Urd β）将5′-dFUrd转化为5-FUra。TNFα、IL-1α、IFNγ和这些因子的混合物使结肠26细胞中的酶活性增加高达3.7倍。因此，TNFα处理增加了结肠26细胞中5′-dFUrd对荧光素的拮抗作用和5-FUra掺入RNA中。此外，细胞因子混合物对5′-dFUrd敏感性的增加被Urd抑制剂2，2 ′-脱水-5-乙基尿苷消除。这些结果表明，细胞因子诱导Urd活性是增加对5′-dFUrd敏感性的关键事件。
The antiproliferative activity of 5‐fluorouracil (5‐FUra) and 5′‐deoxy‐5‐fluorouridine (5′‐dFUrd), used in combination with typical cytokines and growth factors, was investigated in mouse colon 26 carcinoma cells. Tumor necrosis factor α (TNFα), interleukin‐1a (IL‐1α), and interferon γ (IFNγ) at low doses showing < 50% inhibition of cell growth by themselves enhanced the susceptibility of the cells to the activity of 5′‐dFUrd. In particular, a mixture of these cytokines greatly enhanced the activity of 5′‐dFUrd and 5‐FUra by up to 12.4‐ and 2.7‐fold, respectively, whereas the activity of other cytostatics was only slightly changed (< 1.5‐fold). Basic fibroblast growth factor also increased the susceptibility, but only to 5′‐dFUrd. This preferential enhancement of the activity of 5′‐dFUrd would be due to induction by the cytokines of uridine phosphorylase (Urd Pase), by which 5′‐dFUrd is converted to 5‐FUra. TNFα, IL‐1α, IFNγ, and a mixture of these factors increased the enzyme activity by up to 3.7‐fold in colon 26 cells. Consequently, the anabolism of 5′‐dFUrd to fluoronucleotides and the incorporation of 5‐FUra into RNA in colon 26 cells were increased by TNFα treatment. In addition, the increase by the cytokine mixture in the susceptibility to 5′‐dFUrd was abolished by an inhibitor of Urd Pase, 2,2′‐anhydro‐5‐ethyluridine. These results indicate that induction of Urd Pase activity by cytokines is a critical event that increases the susceptibility to 5′‐dFUrd.