Changes in the expression of 5-fluorouracil metabolism associated enzyme genes by regulation of methylation

甲基化调节5-氟尿嘧啶代谢相关酶基因表达的变化

• 批准号: 17591423
• 负责人: TERASHIMA Masanori
• 金额: $ 2.24万
• 依托单位: Fukushima Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591423/
• 关键词: Methylation; 5-fluorouracil; thymidylate synthase; 5-aza-deoxy citidine; 5-aza-2'-deoxycitidine

We investigated the changes in drug sensitivity against 5-fluorouracil by adding 5-aza-2'-deoxycitidine (5-aza) (2 μM) in a total of 7 gastrointestinal cancer cell lines (MKN-1, MKN-45, MKN-74, C-1, Panc-1, MIaPaCa-2, HuH-7) using MTT assay and found that sensitivity to 5-FU significantly decreased in MKN-1, MKN-74, Panc-1, MIaPaCa-2. We also investigated the changes in 5-FU metabolism associated enzyme gene (thymidylate synthase (TS), dihydropyrimidine dehydroohgenase (DPD), orotatephosphoribosyl transferase (OPRT), thymidine phospholyrsase (TP), ribonucleotide reductase (RNR)) by adding 2 μM or 10μM of 5-aza using real-time RT-PCR. The expression levels were upregulated by 5-aza in a dose dependent manner in most of genes except for DPD. From these results, it is suggested that 5-FU metabolism associated enzyme gene are highly methylated in human gastrointestinal cancer cell lines. We further investigated the correlation between the changes in gene expression level and drug sensitivity. It is found that up-regulation of TS significantly correlated with the decreased drug sensitivity.

通过加入5-氮-2‘-脱氧胞苷(5-aza-2’-deoxcitidine，2-μM)，用四甲基偶氮唑蓝比色法检测了7种胃肠道癌细胞株(MKN-1、MKN-45、MKN-74、C-1、PANC-1、MIaPaCa-2、HH-7)对5-氟尿嘧啶(5-FU)敏感性的变化。用实时荧光定量RT-PCR法检测加入2μM和10μM的5-氮杂氮对5-FU代谢相关酶基因(胸苷合成酶、二氢嘧啶脱氢酶、核糖核糖基转移酶、胸苷磷酸解酶、核糖核苷酸还原酶)的影响。除DPD外，5-aza可剂量依赖地上调大多数基因的表达水平。这些结果表明，5-FU代谢相关酶基因在人胃肠道癌细胞系中高度甲基化。我们进一步研究了基因表达水平的变化与药物敏感性的相关性。研究发现，TS上调与药物敏感性降低显著相关。

项目成果

Phase II study of docetaxel and S-1 combination therapy for advanced or recurrent gastric cancer

• DOI: 10.1158/1078-0432.ccr-05-2425
• 发表时间: 2006-06-01
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Yoshida, Kazuhiro;Ninomiya, Motoki;Nishiyama, Masahiko
• 通讯作者: Nishiyama, Masahiko

Activation o human dendritic cells by streptococcal preparation OK-432.

通过链球菌制剂 OK-432 激活人树突状细胞。

• 发表时间: 2005
• 期刊: Anti Cancer Research 25(6)
• 作者: Norio Kanzaki;Masanori Terashima;et al.
• 通讯作者: et al.

Phase II study of a 4-week capecitabine regimen in advanced or recurrent gastric cancer

• DOI: 10.1097/00001813-200602000-00016
• 发表时间: 2006-02-01
• 期刊: ANTI-CANCER DRUGS
• 影响因子: 2.3
• 作者: Sakamoto, J;Chin, K;Koizumi, W
• 通讯作者: Koizumi, W

Detection of cancer cells disseminated in bone marrow using real-time quantitative RT-PCR of CEA, CK19, and CK20 in patients with gastric cancer.

使用实时定量 RT-PCR 检测胃癌患者中 CEA、CK19 和 CK20 的骨髓中播散的癌细胞。

• 发表时间: 2006
• 期刊: Gastric Cancer 9・4
• 作者: Masafumi;Inomata;Junichi Sakamoto;Yasuki Fujita
• 通讯作者: Yasuki Fujita

Gene expression profiles in human gastric cancer: expression of maspin correlates with lymph node metastasis.

人类胃癌中的基因表达谱：Maspin的表达与淋巴结转移相关。

• DOI: 10.1038/sj.bjc.6602429
• 发表时间: 2005-03-28
• 期刊: BRITISH JOURNAL OF CANCER
• 影响因子: 8.8
• 作者: Terashima, M;Maesawa, C;Oyama, K;Ohtani, S;Akiyama, Y;Ogasawara, S;Takagane, A;Saito, K;Masuda, T;Kanzaki, N;Matsuyama, S;Hoshino, Y;Kogure, M;Gotoh, M;Shirane, M;Mori, K
• 通讯作者: Mori, K