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

2013 Fiscal Year Final Research Report

• Project/Area Number: 24701028
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Clinical oncology
• Research Institution: Nagoya University
• Principal Investigator: KIYONARI Shinichi 名古屋大学, 医学(系)研究科(研究院), 助教 (70570836)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: 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

Research Abstract

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.

Research Products

• [Journal Article] Rad9, Rad17, TopBP1 and claspin play essential roles in heat-induced activation of ATR kinase and heat tolerance (2013)
  • Author(s): Tuul M, Kitao H, Iimori M, Matsuoka K, Kiyonari S, Saeki H, Oki E, Morita M, Maehara Y.
  • Journal Title: PLoS One Volume: 8 Pages: e55361
  • DOI: 10.1371/journal.pone.0055361
  • Peer Reviewed
• [Journal Article] CtIP- and ATR-dependent FANCJ phosphorylation in response to DNA strand breaks mediated by DNA replication (2012)
  • Author(s): Sakasai R, Sakai A, Iimori M, Kiyonari S, Matsuoka K, Kakeji Y, Kitao H, Maehara Y.
  • Journal Title: Genes to Cells Volume: 17 Pages: 962-970
  • DOI: 10.1111/gtc.12011
  • Peer Reviewed
• [Presentation] 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 (2013)
  • Author(s): 清成信一
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド、神戸市
  • Year and Date: 2013-12-04
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/biochem/