Personalized therapy for mercaptopurine by measuring metabolites in DNA in children with leukemia

• Project/Area Number: 18K06756
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: National Institute of Health Sciences (2020); Kitasato University (2018-2019)
• Principal Investigator: Tanaka Yoichi 国立医薬品食品衛生研究所, 医薬安全科学部, 主任研究官 (40525341)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 6-メルカプトプリン / 白血病 / 小児 / DNA / deoxy thioguanosine / NUDT15 / LC-MS/MS / deoxy thioguanine / DNA-dTG / 小児白血病 / メルカプトプリン / 代謝物 / 濃度

Outline of Final Research Achievements

To adjust 6-mercaptopurine (6-MP) therapy for children with acute lymphoblastic leukemia, we measured 6-MP metabolite in blood cells and DNA during maintenance therapy and evaluated the association among 6-MP metabolite levels, genetic variations of 6-MP metabolism enzymes and 6-MP dose. 6-MP metabolite levels were associated with 6-MP intolerability in each cells. And 6-MP metabolite level inserted into DNA was influence on NUDT15 genetic variants.

Academic Significance and Societal Importance of the Research Achievements

小児急性リンパ性白血病における6-MPによる治療の感受性には、DNAに取り込まれた6-MP代謝物量が関連している。また患者の持つNUDT15遺伝子多型によって、DNAへの取り込まれやすさが異なる。患者の持つNUDT15遺伝子多型および6-MP代謝物濃度の測定を併せて検討する事で、治療効果が期待できるが副作用が少ない患者個々に合わせた6-MPによる治療を提供することができると考えられる。

Research Products

• [Presentation] 6-メルカプトプリン投与小児白血病患者におけるDNA中 deoxythioguanosineの定量と有害事象との関連性に関する検討 (2021)
  • Author(s): 田中庸一、小野林太郎、足洗美穂、細谷要介、櫻井彩子、渡邊敦、長谷川大輔、斎藤嘉朗
  • Organizer: 日本薬学会第141年会
• [Presentation] Efficacy of mercaptopurine sensitivity test after long-term exposure of leukemia cells (2020)
  • Author(s): Somazu S, Tanaka Y, Thao N, Keiko Kagami K, Kasai S, Tamai M, Murakami Y, Watanabe A, Akahane K, Sato H, Kojika S, Goi K, Inukai T
  • Organizer: 第82会日本血液学会学術集会
• [Presentation] Association of NUDT15 gene polymorphism with cellular metabolism of thiopurine in BCP-ALL cell lines (2019)
  • Author(s): Shinpei Somazu, Yoichi Tanaka, Masako Abe, Keiko Kagami, Daisuke Harama, Yasushi Murakami, Atsushi Watanabe, Koushi Akahane, Kumiko Goi, Takaya Moriyama, Jun Yang , Takeshi Inukai
  • Organizer: 第61回日本小児血液・がん学会学術集会