Development of chemoradiotherapy using TAS-102 for rectal cancer

• Project/Area Number: 20K09051
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Research Institute for Clinical Oncology Saitama Cancer Center
• Principal Investigator: Nishikawa Takeshi 地方独立行政法人埼玉県立病院機構埼玉県立がんセンター(臨床腫瘍研究所), 病院 消化器外科, 医長 (00749799)
• Co-Investigator(Kenkyū-buntansha): 石原 聡一郎 東京大学, 医学部附属病院, 教授 (00376443) ; 野澤 宏彰 東京大学, 医学部附属病院, 准教授 (80529173) ; 川合 一茂 東京大学, 医学部附属病院, 届出研究員 (80571942)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: Trifluridine / 放射線療法 / 大腸癌 / TAS-102 / HIF-1α

Outline of Research at the Start

TAS-102は近年開発された大腸癌に対する新しい抗癌剤であり、最近の我々の研究でその有効成分であるTrifluridineがCPT-11同様放射線感受性を増強する効果を有することが明かとなりつつある。本研究では①大腸癌細胞株にRadiationを行い、Trifluridineの併用によるHIF-1α mRNA / anti-HIF-1α mRNA / HIF-1α蛋白それぞれの発現量の変化を測定する　②HIF-1αにより誘導されるCell cycleの変化を検討する　③動物モデルを用いてTrifluridineの放射線感受性増強効果を検証する。

Outline of Final Research Achievements

Using the HT-29 colon cancer cell line, we showed that trifluridine inhibits cell proliferation in colon cancer cells after irradiation with 4 Gy of radiation. Trifluridine also suppressed cell proliferation by arresting the cell cycle at G2/M, but not by increasing apoptosis. Furthermore, the expression of HIF-1α was quantified by western blotting, and it was confirmed that the expression of HIF-1α was increased by irradiation. Trifluridin was added, and it was confirmed that radiation-induced HIF-1α was suppressed.

Academic Significance and Societal Importance of the Research Achievements

直腸癌に対する放射線治療抵抗性の原因の一つにhypoxia - inducible factor (HIF)-1
αの活性化が挙げられるが、TAS-102によってHIF-1αを抑制することで放射線感受性を高めることができる可能性が示唆された。さらにそのメカニズムの一部を解明することで今後の放射線抵抗性の克服に向けたさらなる研究へとつながる重要な成果が得られたと思われる。

Research Products

• [Journal Article] Impact of the viability assessment of lateral lymph node metastasis in rectal cancer after neoadjuvant chemoradiotherapy (2022)
  • Author(s): Ozaki Kosuke、Kawai Kazushige、Nozawa Hiroaki、Sasaki Kazuhito、Murono Koji、Emoto Shigenobu、Abe Hiroyuki、Ushiku Tetsuo、Ishihara Soichiro
  • Journal Title: International Journal of Colorectal Disease Volume: 37 Issue: 2 Pages: 467-473
  • DOI: 10.1007/s00384-021-04085-4
  • Peer Reviewed
• [Journal Article] Therapeutic effects and limitations of chemoradiotherapy in advanced lower rectal cancer focusing on T4b (2021)
  • Author(s): Ozaki Kosuke、Kawai Kazushige、Nozawa Hiroaki、Sasaki Kazuhito、Murono Koji、Emoto Shigenobu、Iida Yuuki、Ishii Hiroaki、Yokoyama Yuichiro、Anzai Hiroyuki、Sonoda Hirofumi、Sugihara Kenichi、Ishihara Soichiro
  • Journal Title: International Journal of Colorectal Disease Volume: 36 Issue: 7 Pages: 1525-1534
  • DOI: 10.1007/s00384-021-03936-4
  • Peer Reviewed
• [Journal Article] Development of a novel apoptosis-based tumor regression grade to assess the efficacy of preoperative chemoradiotherapy for rectal cancer: a retrospective single-center study (2021)
  • Author(s): Ozaki Kosuke、Kawai Kazushige、Nozawa Hiroaki、Sasaki Kazuhito、Murono Koji、Ishihara Soichiro
  • Journal Title: International Journal of Clinical Oncology Volume: 26 Issue: 9 Pages: 1679-1688
  • DOI: 10.1007/s10147-021-01948-2
  • Peer Reviewed