Establishment of safe and effective pediatric hematopoietic cell transplantation by pharmacokinetic analysis and metabolic enzyme activity analysis

• Project/Area Number: 16K10033
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kagoshima University
• Principal Investigator: Kawano Yoshifumi 鹿児島大学, 医歯学域医学系, 教授 (20260680)
• Co-Investigator(Kenkyū-buntansha): 児玉 祐一 鹿児島大学, 医歯学域附属病院, 講師 (20535695) ; 岡本 康裕 鹿児島大学, 医歯学域医学系, 准教授 (30398002) ; 西川 拓朗 鹿児島大学, 医歯学域附属病院, 講師 (90535725)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: cyclophosphamide / 心毒性 / acrolein / glutathione / busulfan / Aldehyde dehydrogenase 1 / シクロフォスファミド / ブスルファン / 抗がん剤 / グルタチオン / アクロレイン / 造血細胞移植術 / GST / 移植前大量化学療法 / 毒性

Outline of Final Research Achievements

4-hydroxy-cyclophosphamide (HCY) is an active metabolite of cyclophosphamide (CY). It is converted to cytotoxic metabolite acrolein. Human hepatoblastoma cell line HepG2 were exposed to HCY and the concentration of acrolein in cell culture supernatant were measured. Interestingly, the detected acrolein was higher than we expected. Furthermore, glutathione (GSH), an acrolein scavenger were reduced gradually in HepG2 cells. And then, to inhibit the production of acrolein, ALDH1 were knock downed by RNA interference. Against our expectations, the production of acrolein is not increased when ALDH1 knockdown HepG2 cells were exposed to HCY. It indicates that acrolein is not only produced directly by CY, but also is produced in another pathway.

Academic Significance and Societal Importance of the Research Achievements

Cyclophosphamide (CY)大量投与で生じる急性心筋障害はその数%が致死的であり、臨床上大きな問題である。そして、その発症機序は未だ不明でありその予防法も確立されていない。CY心毒性の主因であるacrolein産生量はその除去剤でもあるglutathionの量が関係することが示唆された。glutathion産生能の個体差が、CY心毒性発症の個体差に繋がる可能性がある。

Research Products

• [Journal Article] Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children. (2019)
  • Author(s): Nishikawa T, Yamaguchi H, Ikawa K, Nakayama K, Higashi E, Miyahara E, Abematsu T, Nakagawa S, Kodama Y, Tanabe T, Shigemi A, Shinkoda Y, Okamoto Y, Takeda Y, Kawano Y.
  • Journal Title: Pediatr Int. Volume: - Issue: 6 Pages: 558-565
  • DOI: 10.1111/ped.13859
  • Peer Reviewed
• [Journal Article] Giant radiation-induced cavernous haemangioma before reduced-intensity bone marrow transplantation for acute lymphoblastic leukaemia. (2019)
  • Author(s): Saito A, Nishikawa T, Oyoshi T, Nakagawa S, Kodama Y, Yamada A, Kinoshita M, Okamoto Y, Arita K, Moritake H, Kawano Y.
  • Journal Title: Bone Marrow Transplant. Volume: 54 Issue: 2 Pages: 312-315
  • DOI: 10.1038/s41409-018-0272-8
  • Peer Reviewed
• [Journal Article] Role of metabolites of cyclophosphamide in cardiotoxicity. (2017)
  • Author(s): Kurauchi K, Nishikawa T, Miyahara E, Okamoto Y, Kawano Y.
  • Journal Title: BMC Res Notes. Volume: 14 Issue: 1 Pages: 406-406
  • DOI: 10.1186/s13104-017-2726-2
  • Peer Reviewed / Open Access
• [Journal Article] Maternal T and B cell engraftment in two cases of X-linked severe combined immunodeficiency with IgG1 gammopathy. (2017)
  • Author(s): Okano T, Nishikawa T, Watanabe E, Watanabe T, Takashima T, Yeh TW, Yamashita M, Tanaka-Kubota M, Miyamoto S, Mitsuiki N, Takagi M, Kawano Y, Mochizuki Y, Imai K, Kanegane H, Morio T.
  • Journal Title: Clin Immunol. Volume: 183 Pages: 112-120
  • DOI: 10.1016/j.clim.2017.08.003
  • Peer Reviewed / Open Access
• [Journal Article] Persistent positive metaiodobenzylguanidine scans after autologous peripheral blood stem cell transplantation may indicate maturation of stage 4 neuroblastoma. (2017)
  • Author(s): Okamoto Y, Kodama Y, Nishikawa T, Rindiarti A, Tanabe T, Nakagawa S, Yoshioka T, Takumi K, Kaji T, Kawano Y.
  • Journal Title: Pediatr Hematol Oncol. Volume: 34 Issue: 3 Pages: 157-164
  • DOI: 10.1080/08880018.2017.1348414
  • Peer Reviewed
• [Presentation] Pharmacokinetics of cyclophosphamide and its metabolites in Pediatric Hematopoietic Stem Cell Transplant Recipients: A comparative study of two conditioning regimens, and one posttransplantation regimen. (2017)
  • Author(s): Nishikawa T, Ikawa K, Miyahara E, Abematsu T, Nakagawa S, Kurauchi K, Kodama Y, Tanabe T, Shinkoda Y, Okamoto Y, Kawano Y.
  • Organizer: IATDMCT(International association of TDM and Clinical Toxicology)
  • Int'l Joint Research
• [Presentation] マウスにおける大量シクロホスファミドの薬物動態及び毒性の評価． (2017)
  • Author(s): 宮原恵弥子，西川拓朗，猪川和朗，牛飼美晴，川口博明，岡本康裕，森川則文，堀内正久，河野嘉文．
  • Organizer: 第79回日本血液学会学術集会