Novel molecular targeting strategy against chromosomal maintenance factor FANCJ

• Project/Area Number: 25460390
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kyushu University
• Principal Investigator: KITAO HIROYUKI 九州大学, 医学(系)研究科(研究院), 准教授 (30368617)
• Co-Investigator(Kenkyū-buntansha): IIMORI Makoto 九州大学, 医学研究院, 助教 (20546460) ; MORITA Masaru 独立行政法人国立病院機構(九州がんセンター), その他部局等, 消化器外科部長 (30294937) ; OKI Eiji 九州大学, 大学病院, 講師 (70380392)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 染色体不安定性 / 抗がん剤 / FANCJ / FdUrd / トリフルリジン / ロンサーフ（TFTD,TAS-102） / 抗癌剤

Outline of Final Research Achievements

Chromosomal stability is ensured by the accurate DNA replication and the equal segregation of duplicated chromosomes. In tumors, such mechanism is often disrupted and chromosomal instability, which is represented as high mutation frequency and abnormal number of chromosomes, emerges. In our previous study, we reported that the colorectal cancer patients who exhibited higher expression of chromosomal stability factor FANCJ in their tumors tended to be poor prognosis and less effective with 5-FU-based chemotherapy (Nakanishi et al. Ann Surg Oncol 2012). In this project, we drugged the underlying molecular mechanism of the association between FANCJ expression and 5-FU resistance experimentally and found that the physical interaction between FANCJ and key partners are critical.

Research Products

• [Journal Article] Trifluridine Induces p53-Dependent Sustained G2 Phase Arrest with Its Massive Misincorporation into DNA and Few DNA Strand Breaks (2015)
  • Author(s): Matsuoka K, Iimori M, Niimi S, Tsukihara H, Watanabe S, Kiyonari S, Kiniwa M, Ando K, Tokunaga E, Saeki H, Oki E, Maehara Y, Kitao H.
  • Journal Title: Molecular Cancer Therapeutics Volume: 14 Issue: 4 Pages: 1004-1013
  • DOI: 10.1158/1535-7163.mct-14-0236
  • Peer Reviewed / Open Access
• [Journal Article] The 1,2-diaminocyclohexane carrier ligand in oxaliplatin induces p53-dependent transcriptional repression of factors involved in thymidylate biosynthesis. (2015)
  • Author(s): Kiyonari S, Iimori M, Matsuoka K, Watanabe S, Morikawa-Ichinose T, Miura D, Niimi S, Saeki H, Tokunaga E, Oki E, Morita M, Kadomatsu K, Maehara Y, Kitao H
  • Journal Title: Mol Cancer Ther Volume: 14 Issue: 10 Pages: 2332-42
  • DOI: 10.1158/1535-7163.mct-14-0748
  • Peer Reviewed / Open Access
• [Journal Article] Chromosomal instability associated with global DNA hypomethylation is associated with the initiation and progression of esophageal squamous cell carcinoma (2014)
  • Author(s): Kawano H, Saeki H, Kitao H, Tsuda Y, Otsu H, Ando K, Ito S, Egashira A, Oki E, Morita M, Oda Y, Maehara Y.
  • Journal Title: Annals of Surgical Oncology Volume: 4 Issue: S4 Pages: 696-702
  • DOI: 10.1245/s10434-014-3818-z
  • Peer Reviewed / Open Access
• [Journal Article] Oxidative DNA damage in human esophageal cancer: clinicopathological analysis of 8-hydroxydeoxyguanosine and its repair enzyme. (2014)
  • Author(s): Kubo N, Morita M, Nakashima Y, Kitao H, Egashira A, Saeki H, Oki E, Kakeji Y, Oda Y, Maehara Y.
  • Journal Title: Dis Esophagus. Volume: 27 Issue: 3 Pages: 285-293
  • DOI: 10.1111/dote.12107
  • Peer Reviewed / Open Access
• [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
  • Journal Title: PLoS One Volume: 8巻(2号) Issue: 2 Pages: 55361-55361
  • DOI: 10.1371/journal.pone.0055361
  • Peer Reviewed
• [Journal Article] Involvement of ribonucleotide reductase-M1 in 5-fluorouracil induced DNA damage in esophageal cancer cell lines. (2013)
  • Author(s): Aoki Y, Sakogawa K, Hihara J, Emi M, Hamai Y, Kono K, Shi L, Sun J, Kitao H, Ikura T, Niida H, Nakanishi M, Okada M, Tashiro S.
  • Journal Title: Int J Oncol. Volume: 42(6) Issue: 6 Pages: 1951-60
  • DOI: 10.3892/ijo.2013.1899
  • Peer Reviewed
• [Presentation] The 1,2-diaminocyclohexane carrier ligand in oxaliplatin induces p53-dependent transcriptional repression of factors involved in thymidylate biosynthesis (2015)
  • Author(s): 北尾洋之
  • Organizer: 27th AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
  • Place of Presentation: Hynes Convention Center, Boston, MA, USA
  • Year and Date: 2015-11-05
  • Int'l Joint Research
• [Presentation] Cellular response to a fluorinated thymidine analogue trifluridine, a key component of the novel oral antitumor drug TAS-102. (2015)
  • Author(s): Hiroyuki Kitao
  • Organizer: Gordon Research Conference
  • Place of Presentation: Rockport, RI
  • Year and Date: 2015-06-28 – 2015-07-03
• [Presentation] Cellular response to a fluorinated thymidine analogue trifluridine, a key component of the novel oral antitumor drug TAS-102 (2015)
  • Author(s): 北尾洋之
  • Organizer: Gordon Research Conference on Nucleosides, Nucleotides and Oligonucleotides
  • Place of Presentation: Salva Regina University, Newport, RI, USA
  • Year and Date: 2015-06-28
  • Int'l Joint Research
• [Presentation] Trifluridine induces p53-dependent sustained G2 phase arrest with its massive misincorporation into DNA and few DNA strand breaks (2015)
  • Author(s): Kazuaki Matsuoka, Hiroyuki Kitao
  • Organizer: American Association of Cancer Research (AACR) Annual Meeting 2015
  • Place of Presentation: Philadelphia, PA
  • Year and Date: 2015-04-20
• [Presentation] 新規経口ヌクレオシド型抗腫瘍薬「ロンサーフ」の作用機序 (2015)
  • Author(s): 北尾 洋之
  • Organizer: 九州大学先端融合医療レドックスナビ研究拠点若手研究者主催シンポジウム
  • Place of Presentation: 福岡
  • Year and Date: 2015-01-27
  • Invited
• [Presentation] Trifluorothymidine induces p53-dependent sustained G2 arrest without extensive DNA strand-breaks (2013)
  • Author(s): Kazuaki Matsuoka, Makoto Iimori, Hiroshi Tsukihara, Shinichi Kiyonari, Sugiko Watanabe, Eiji Oki, Hiroyuki Kitao, Yoshihiko Maehara
  • Organizer: 第３６回日本分子生物学会総会
  • Place of Presentation: 神戸
• [Remarks] 九州大学消化器・総合外科（第二外科）
  • URL: http://www.kyudai2geka.com
• [Remarks] 九州大学大学院 消化器・総合外科（第二外科）
  • URL: http://www.kyudai2geka.com/
• [Remarks] 九州大学先端融合医療レドックスナビ研究拠点 先端がん診断・創薬グループ
  • URL: http://redoxnavi.kyushu-u.ac.jp/group4/
• [Remarks] 九州大学大学院 消化器・総合外科（第二外科）
  • URL: http://www.kyudai2geka.com/
• [Remarks] 九州大学先端融合医療レドックスナビ研究拠点 先端がん診断・創薬グループ
  • URL: http://redoxnavi.kyushu-u.ac.jp/group4/
• [Patent(Industrial Property Rights)] 検出剤、該検出剤を含むキット、被験試料中のＤＮＡに取り込まれたトリフルリジンを検出する方法およびトリフルリジンまたはトリフルリジンを含む抗悪性腫瘍剤の抗腫瘍効果を判定する方法 (2015)
  • Inventor(s): 北尾洋之、諸富洋介、木庭守、前原喜彦
  • Industrial Property Rights Holder: 北尾洋之、諸富洋介、木庭守、前原喜彦
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-10-08