Eda H, Fujimoto K, Watanabe S, Ishikawa T, Ohiwa T, Tatsuno K, Tanaka Y, Ishitsuka H
Department of Oncology, Nippon Roche Research Center, Kanagawa.
Jpn J Cancer Res. 1993 Mar;84(3):341-7. doi: 10.1111/j.1349-7006.1993.tb02876.x.
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 alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), and interferon gamma (IFN gamma) 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. TNF alpha, IL-1 alpha, IFN gamma, 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 TNF alpha 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.
研究了5-氟尿嘧啶（5-FUra）和5'-脱氧-5-氟尿苷（5'-dFUrd）与典型细胞因子和生长因子联合使用时对小鼠结肠26癌细胞的抗增殖活性。低剂量的肿瘤坏死因子α（TNFα）、白细胞介素-1α（IL-1α）和干扰素γ（IFNγ）单独使用时对细胞生长的抑制率<50%，但它们增强了细胞对5'-dFUrd活性的敏感性。特别是，这些细胞因子的混合物分别使5'-dFUrd和5-FUra的活性大大增强，增幅高达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敏感性，但仅对5'-dFUrd有作用。5'-dFUrd活性的这种优先增强可能是由于细胞因子诱导尿苷磷酸化酶（Urd Pase），通过该酶5'-dFUrd被转化为5-FUra。TNFα、IL-1α、IFNγ以及这些因子的混合物使结肠26细胞中的该酶活性增加了高达3.7倍。因此，TNFα处理增加了结肠26细胞中5'-dFUrd向氟核苷酸的合成代谢以及5-FUra掺入RNA的过程。此外，尿苷磷酸化酶抑制剂2,2'-脱水-5-乙基尿苷消除了细胞因子混合物对5'-dFUrd敏感性的增加。这些结果表明，细胞因子诱导尿苷磷酸化酶活性是增加对5'-dFUrd敏感性的关键事件。
