Enhancement of 5-fluorouracil-induced cytotoxicity by leucovorin in 5-fluorouracil-resistant gastric cancer cells with upregulated expression of thymidylate synthase.
Enhancement of 5-fluorouracil-induced cytotoxicity by leucovorin in 5-fluorouracil-resistant gastric cancer cells with upregulated expression of thymidylate synthase.
复制标题
DOI：
10.1007/s10120-013-0249-7
复制
发表时间：
2014-01
期刊：
影响因子：
7.4
通讯作者：
Hayashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Nakamura, Ayako;Nakajima, Go;Okuyama, Ryuji;Kuramochi, Hidekazu;Kondoh, Yurin;Kanemura, Toshinori;Takechi, Teiji;Yamamoto, Masakazu;Hayashi, Kazuhiko
阐明胃癌细胞获得5-氟尿嘧啶（5FU）耐药的机制可能为开发5FU耐药胃癌的有效化疗提供重要线索，通过将细胞持续暴露于逐渐增加的5FU浓度约1年，建立了4个5FU耐药细胞系（MKN45/5FU、MKN74/5FU、NCI-N87/5FU和KATOIII/5FU）。通过实时逆转录-聚合酶链式反应，定量评价与5FU代谢相关的4个基因胸腺苷酸合成酶（TS）、二氢嘧啶脱氢酶、胸腺苷磷酸化酶和羊角酸磷酸核糖基转移酶的mRNA表达水平。Western blot法检测TS蛋白表达。与亲本细胞系相比，5FU抗性细胞系对5FU的抗性高3.8 ~ 11.6倍，TS mRNA表达量高1.9 ~ 3.5倍，TS蛋白表达量高1.6 ~ 7.1倍。而其他基因的表达在不同细胞系间无显著差异。亚叶酸素（LV）对4种5FU耐药细胞系中的3种的细胞毒性增强2.3 ~ 2.8倍。综上所述，LV不仅增强了5FU对亲本胃癌细胞系的细胞毒性，而且增强了5FU耐药细胞系的细胞毒性，即使是那些TS表达水平升高的细胞系。这些结果表明，在以5FU为基础的治疗后复发的胃癌患者中，5FU和LV联合应用的临床研究是有必要的。
Elucidation of the mechanisms by which gastric cancer cells acquire resistance to 5-fluorouracil (5FU) may provide important clues to the development of effective chemotherapy for 5FU-resistant gastric cancer Four 5FU-resistant cell lines (MKN45/5FU, MKN74/5FU, NCI-N87/5FU, and KATOIII/5FU) were established by continuous exposure of the cells to progressively increasing concentrations of 5FU for about 1 year. Then, mRNA expression levels of four genes associated with 5FU metabolism, i.e., thymidylate synthase (TS), dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase, were quantitatively evaluated by real-time reverse transcriptase-polymerase chain reaction. In addition, TS protein expression was measured by Western blot analysis. As compared with the parent cell lines, the 5FU-resistant cell lines showed 3.8- to 11.6-fold higher resistance to 5FU, as well as 1.9- to 3.5-fold higher TS mRNA expression and 1.6- to 7.1-fold higher TS protein expression. In contrast, the expressions of other genes did not differ significantly among the cell lines. The cytotoxicity of 5FU was enhanced 2.3- to 2.8 fold by leucovorin (LV) against three of the four 5FU-resistant cell lines. Collectively, LV enhanced the cytotoxicity of 5FU not only against the parent gastric cancer cell lines, but also against the 5FU-resistant cell lines, even those with elevated TS expression levels. These results suggest that clinical studies of a combination of 5FU and LV are warranted in patients who have recurrent gastric cancer after 5FU-based therapy.
登录
查看更多内容
影响因子：
8.4
作者：
Fukushima, M;Fujioka, A;Takechi, T
通讯作者：
Takechi, T
影响因子：
11.2
作者：
Mizuarai, Shinji;Yamanaka, Kazunori;Kotani, Hidehito
通讯作者：
Kotani, Hidehito
影响因子：
3.7
作者：
Kim HP;Yoon YK;Kim JW;Han SW;Hur HS;Park J;Lee JH;Oh DY;Im SA;Bang YJ;Kim TY
通讯作者：
Kim TY
DOI：
10.1111/j.1349-7006.2000.tb00866.x
发表时间：
2000-01
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Ishikawa Y;Kubota T;Otani Y;Watanabe M;Teramoto T;Kumai K;Takechi T;Okabe H;Fukushima M;Kitajima M
通讯作者：
Kitajima M
DOI：
10.1016/j.bbrc.2007.11.043
发表时间：
2008-01-25
影响因子：
3.1
作者：
Sakamoto, Etsuko;Tsukioka, Sayaka;Oka, Tatsuzo
通讯作者：
Oka, Tatsuzo