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Prediction of response to anticancer therapy by thymidine phosphorylase imaging: pre-clinical proof of concept

Research Project

Project/Area Number 16K10335
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Radiation science
Research InstitutionFukushima Medical University

Principal Investigator

Zhao Songji  福島県立医科大学, 公私立大学の部局等, 教授 (80374239)

Co-Investigator(Kenkyū-buntansha) 久下 裕司  北海道大学, アイソトープ総合センター, 教授 (70321958)
東川 桂  北海道大学, アイソトープ総合センター, 助教 (10756878)
志水 陽一  京都大学, 医学研究科, 助教 (90634212)
志賀 哲  北海道大学, 医学研究院, 准教授 (80374495)
北川 善政  北海道大学, 歯学研究院, 教授 (00224957)
大倉 一枝  北海道医療大学, 薬学部, 教授 (60094827)
秋澤 宏行  昭和薬科大学, 薬学部, 教授 (90311795)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsチミジンホスホリラーゼ(TP) / ヨウ素標識IIMU / 核医学診断薬 / SPECTイメージング / 5-フルオロウラシル(5-FU) / プロドラッグ / 抗がん剤Paclitaxel / 担癌モデル動物 / 5-フルオロウラシル(5-FU) / 5-FUプロドラッグ / がんの核医学的分子イメージング / IIMU / PET/SPECT / 5-フルオロウラシル
Outline of Final Research Achievements

Thymidine phosphorylase (TP) is a key enzyme in the pyrimidine nucleoside salvage pathway, and its expression is upregulated in a wide variety of solid tumors. TP expression correlates well with tumor malignancy and is essential for the bioactivation of 5-fluorouracil and its prodrugs including capecitabine in tumors. Capecitabine-based chemotherapies have been reported to be effective in tumors expressing high TP levels. Radio- and chemotherapies including paclitaxel may induce the expression of TP in tumors. We have developed a radio-iodinated uracil derivative with TP inhibitory potency (125/123I-IIMU). In this study, we evaluated whether TP imaging could predict the response to an anticancer therapy by estimating TP expression levels in tumor tissues. In vivo studies showed that paclitaxel increased TP expression levels and 125I-IIMU uptake in tumor tissues. Therefore, TP imaging could be used for predicting the response to an anticancer therapy.

Academic Significance and Societal Importance of the Research Achievements

我々が開発した123I-IIMUを用いたTP画像化法は、核医学の特徴である非侵襲性、かつ腫瘍組織のTP発現量を感度よく定量的に評価できるため、世界で初めての5-FUやそのプロドラッグの治療効果を予測可能にすることが本研究の学術的意義がある。本研究において、IIMUを用いたTP画像化によって、5-FUやそのプロドラッグによる治療効果予測が可能なことが示されれば、速やかに臨床応用を開始できるため、効果のない無駄な治療を避け、速やかに他の治療方針を決定することで、患者ごとに最適な個別化医療が実現できるとともに、医療経済効果、医療の質の向上にも貢献ができるし、医療戦略の革新となることが期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (18 results)

All 2019 2018 2017

All Journal Article (8 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 8 results,  Open Access: 3 results) Presentation (10 results) (of which Int'l Joint Research: 7 results,  Invited: 3 results)

  • [Journal Article] Elimination of tumor hypoxia by eribulin demonstrated by 18F-FMISO hypoxia imaging in human tumor xenograft models2019

    • Author(s)
      Zhao S, Yu W, Ukon N, Tan C, Nishijima K, Shimizu Y, Higashikawa K, Shiga T, Yamashita H, Tamaki N, Kuge Y.
    • Journal Title

      EJNMMI Res

      Volume: in press

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Comparative evaluation of 18F-DiFA and its analogues as novel hypoxia positron emission tomography and 18F-FMISO as the standard.2019

    • Author(s)
      Nakata N, Kiriu M, Okumura Y, Zhao S, Nishijima K, Shiga T, Tamaki N, Kuge Y, Matsumoto H.
    • Journal Title

      Nucl Med Biol

      Volume: 70 Pages: 39-45

    • DOI

      10.1016/j.nucmedbio.2019.01.008

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A novel PET probe [18F]DiFA accumulates in hypoxic region via glutathione conjugation following reductive metabolism.2019

    • Author(s)
      Shimizu Y, Zhao S, Yasui H, Nishijima K, Matsumoto H, Siga T, Tamaki N, Ogawa M, Kuge Y.
    • Journal Title

      Mol Imaging Biol

      Volume: 21 Issue: 1 Pages: 122-129

    • DOI

      10.1007/s11307-018-1214-y

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] [18F]DPA-714 PET imaging shows immunomodulatory effect of intravenous administration of bone marrow stromal cells after transient focal ischemia2018

    • Author(s)
      Tan C, Zhao S, Higashikawa K, Wang Z, Kawabori M, Abumiya T, Nakayama N, Kazumata K, Ukon N, Yasui H, Tamaki N, Kuge Y, Shichinohe H, Houkin K
    • Journal Title

      EJNMMI Res

      Volume: 8 Issue: 1 Pages: 35-35

    • DOI

      10.1186/s13550-018-0392-6

    • NAID

      120006482581

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel PET probe [18F]DiFA accumulates in hypoxic region via glutathione conjugation following reductive metabolism2018

    • Author(s)
      Shimizu Y, Zhao S, Yasui H, Nishijima K, Matsumoto H, Siga T, Tamaki N, Ogawa M, Kuge Y.
    • Journal Title

      Mol Imaging Biol

      Volume: in press

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] In vitro uptake and metabolism of [14C]acetate in rabbit atherosclerotic arteries: biological basis for atherosclerosis imaging with [11C]acetate.2018

    • Author(s)
      Yamasaki K, Yamashita A, Zhao Y, Shimizu Y, Nishii R, Kawai K, Tamaki N, Zhao S, Asada Y, Kuge Y.
    • Journal Title

      Nucl Med Biol.

      Volume: 56 Pages: 21-25

    • DOI

      10.1016/j.nucmedbio.2017.08.003

    • NAID

      120006546743

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Redesign of negatively charged 111In-DTPA-octreotide derivative to reduce renal radioactivity2017

    • Author(s)
      Oshima N., Akizawa H., Kawashima H., Zhao S., Zhao Y., Nishijima K. I., Kitamura Y., Arano Y., Kuge Y. and Ohkura K.
    • Journal Title

      Nuclear medicine and biology

      Volume: 48 Pages: 16-25

    • DOI

      10.1016/j.nucmedbio.2017.01.006

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Changes in tumor oxygen states after sorafenib therapy evaluated by 18F-fluoromisonidazole hypoxia imaging in a renal cell cancer xenograft2017

    • Author(s)
      Yu W, Zhao S*, Zhao Y, Fatema CN, Murakami M, Nishijima K, Kitagawa Y, Tamaki N, Kuge Y
    • Journal Title

      Oncol Lett

      Volume: 14 Issue: 2 Pages: 2341-2346

    • DOI

      10.3892/ol.2017.6371

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Investigation of the influence of intratumoral glutathione status on the distribution of a hypoxic probe [18F]FMISO.2018

    • Author(s)
      Yasui H, Higashikawa K, Shimizu Y, Shibata Y, Zhao S, Matsumoto H, Shiga T, Tamaki N, Kuge Y.
    • Organizer
      WFNMB 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Potentials of a thymidine phosphorylase imaging agent in the diagnosis of nonalcoholic steatohepatitis.2018

    • Author(s)
      Higashikawa K, Horiguchi S, Uehara R, Tarisawa M, Shibata Y, Kitaura H, Yasui H, Takeda H, Kuge Y.
    • Organizer
      The Tenth China-Japan-Korea Symposium on Radiopharmaceutical Sciences
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Feasibility and potentials of thymidine phosphorylase (TP) as an imaging biomarker and its nuclear medicine imaging for the diagnosis of non-alcoholic steatohepatitis.2018

    • Author(s)
      Higashikawa K, Horiguchi S, Ebita Y, Tarisawa M, Komatsu Y, Ohkura K, Yasui H, Takeda H, Kuge Y.
    • Organizer
      Society of Nuclear Medicine and Molecular Imaging 2018 Annual Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Biodistribution of free 211At and meta-[211At]astatobenzylguanidine (MABG) in normal mice.2018

    • Author(s)
      Zhao S, Aoki M, Washiyaoyma K, Ukon N, Tan C, Shimama S, Kubo H, Oriuchi N, Takahashi K, Ito H, Takenoshita S.
    • Organizer
      第58回日本核医学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] チミジンホスホリラーゼイメージングプローブによる非アルコール性脂肪肝炎の診断法の開発研究。2018

    • Author(s)
      東川 桂、堀口 紗和子、足澤 誠、小松由紀子、大倉一枝、安井 博宣、武田 宏司、久下 裕司。
    • Organizer
      第13回日本分子イメージング学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Preclinical and Translational Research on a Novel Thymidine Phophorylase (TP) Imaging Probe, 123I-IIMU Using SPECT2017

    • Author(s)
      Songji Zhao
    • Organizer
      BIT's 11th World Congress of Regenerative Medicine & Stem Cell 2017 in Singapore
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 小動物インビボイメージングの有用性2017

    • Author(s)
      趙 松吉、久下 裕司、玉木 長良
    • Organizer
      第26回日本バイオイメージング学会 シンポジウム
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 日本甲状腺癌治療の現状及び展望2017

    • Author(s)
      趙 松吉
    • Organizer
      2017年国家級継続医学教育項目‐分化型甲状腺癌治療新進展。中国延辺大学医学部附属医院核医学国際シンポジウム
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Effect of eribulin on remodeling of tumor vasculature confirmed by FMISO PET imaging-Small-animal PET study in human breast cancer cell xenograft-2017

    • Author(s)
      Zhao S, Yu W, Ukon N, Nishijima K, Shimizu Y, Higashikawa K, Yamashita H, Tamaki N, Kuge Y.
    • Organizer
      The 64th Society of Nuclear Medicine Annual Meeting in Denver
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Accumulation mechanism of novel PET imaging probe “[18F]DiFA” in hypoxic cells revealed by imaging mass spectrometry.2017

    • Author(s)
      Shimizu Y, Zhao S, Kishi R, Yasui H, Nishijima K, Matsumoto H, Tamaki N, Ogawa M, Kuge Y.
    • Organizer
      The 64th Society of Nuclear Medicine Annual Meeting in Denver
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2020-03-30  

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