Mechanisms of dUTPase downregulation by oxaliplatin and its applications to combination chemotherapy

奥沙利铂下调dUTPase的机制及其在联合化疗中的应用

• 批准号: 24701028
• 负责人: KIYONARI Shinichi
• 金额: $ 2.08万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24701028/
• 关键词: オキサリプラチン; 5-フルオロウラシル; 併用化学療法; 大腸癌

Oxaliplatin is used in 5-fluorouracil-based combination chemotherapy. Interestingly, the dUTPase gene expression was reportedly suppressed by p53 stabilization after oxaliplatin treatment, however, the detailed molecular mechanisms were unclear. We found that the suppression was not observed when colon cancer cells were treated with cisplatin and carboplatin. Because oxaliplatin and its analog, dachplatin, can suppress dUTPase expression, the DNA damage response induced by 1,2-diaminocyclohexane (DACH) carrier ligand would be critical for the suppression effect. Our results suggested that oxaliplatin could enhance the cytotoxicity of 5-fluorouracil by regulating the expression of the genes that are implicated in thymidylate biosynthesis.

奥沙利铂用于以5-氟尿嘧啶为基础的联合化疗。有趣的是，据报道，奥沙利铂治疗后dUTPase基因的表达受到p53稳定剂的抑制，然而，具体的分子机制尚不清楚。我们发现，当顺铂和卡铂处理结肠癌细胞时，没有观察到这种抑制。由于奥沙利铂及其类似物Dachplatin可以抑制dUTPase的表达，1，2-二氨基环己烷(DACH)载体配体诱导的DNA损伤反应将是抑制作用的关键。我们的结果提示，奥沙利铂可能通过调节胸腺嘧啶生物合成相关基因的表达来增强5-氟尿嘧啶的细胞毒性。

项目成果

オキサリプラチンによるdUTPase遺伝子発現抑制の分子メカニズム

奥沙利铂抑制 dUTPase 基因表达的分子机制

• 发表时间: 2013
• 作者: 鷹取 元;林武弘;山田和俊;荒井邦明;加賀谷尚史;山下竜也;金子周一;清成信一
• 通讯作者: 清成信一

Rad9, Rad17, TopBP1 and claspin play essential roles in heat-induced activation of ATR kinase and heat tolerance.

• DOI: 10.1371/journal.pone.0055361
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Tuul M;Kitao H;Iimori M;Matsuoka K;Kiyonari S;Saeki H;Oki E;Morita M;Maehara Y
• 通讯作者: Maehara Y