Folylpolyglutamate synthase and γ-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity
Folylpolyglutamate synthase and γ-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity
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DOI：
10.1016/j.bbrc.2007.11.043
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发表时间：
2008-01-25
影响因子：
3.1
通讯作者：
Oka, Tatsuzo
中科院分区：
文献类型：
--
作者：
Sakamoto, Etsuko;Tsukioka, Sayaka;Oka, Tatsuzo
尽管5-氟尿嘧啶(5-FU)联合亚叶酸钙(LV)是治疗结直肠癌的标准化疗方案，但决定LV增强5-FU抗肿瘤活性的因素尚不清楚。我们研究了叶酸代谢的主要酶叶基多谷氨酸合成酶(FPGS)和γ-谷氨酰水解酶(GGH)在LV作用中的作用。LV可增强5-FU的抗癌活性和人结肠癌细胞内还原型叶酸水平。将小干扰RNA(SiRNA)导入DLD-1细胞，下调FPGS，可降低LV诱导的基础叶酸水平和LV处理后的叶酸水平，并增强5-氟-2‘-脱氧尿苷(FdUrd)诱导的细胞毒性。相反，siRNA下调GGH可增加细胞对FdUrd和LV的敏感性。这些结果表明，肿瘤组织中FPGS和GGH的表达水平是LV增强5-FU抗肿瘤活性的决定因素。(C)2007 Elsevier Inc.保留所有权利。
Although 5-fluorouracil (5-FU) plus leucovorin (LV) is a standard chemotherapy regimen for colorectal cancer, the factors that determine the LV-mediated enhancement of the antitumor activity of 5-FU have remained unknown. We investigated the roles of folylpolyglutamate synthase (FPGS) and gamma-glutamyl hydrolase (GGH), which are the main enzymes involved in folate metabolism, in the effect of LV. LV enhanced the anticancer activity of 5-FU and the level of reduced folate in human colon cancer cells. Small-interfering RNA (siRNA) transfected into DLD-1 cells to downregulate FPGS reduced the basal level of reduced folate, the folate level after LV treatment, and the enhancement of 5-fluoro-2'-deoxyuridine (FdUrd)-induced cytotoxicity elicited by LV. By contrast, the downregulation of GGH by siRNA increased cellular sensitivity to FdUrd combined with LV. These results suggest that FPGS and GGH expression levels in tumors are determinants of the efficacy of LV in enhancing the antitumor activity of 5-FU. (C) 2007 Elsevier Inc. All rights reserved.