Mechanism of cyclophosphamide-induced fatal cardiotoxicity on cardiomyocytes derived from human iPS cells

• Project/Area Number: 16H07088
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Hygiene and public health
• Research Institution: Kagoshima University
• Principal Investigator: MIYAHARA Emiko 鹿児島大学, 医歯学総合研究科, 特任研究員 (20778427)
• Project Period (FY): 2016-08-26 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 毒性学 / 抗がん剤 / シクロホスファミド / 心筋障害 / アクロレイン / 薬剤反応性

Outline of Final Research Achievements

Administration of cyclophosphamide (CY) increased the acrolein-lysine adducts in mice plasma. Aldehyde dehydrogenase 1 (ALDH1) in mice white blood cells were activated by N-acetylcysteine (NAC). And under the active ALDH1, CY was metabolized to carboxyethylphosphoramide mustard, which is noncytotoxic metabolite of CY. Furthermore, vacuole degeneration or eosinophilic generation in the hearts and livers in mice were suppressed by NAC treatment.
In these results indicate that the concentration of acrolein in the blood after administration of CY and ALDH1 activity are important factor on CY-induced cardiotoxicity. Therefore, these factors may contribute to prevent the CY-induced cardiotoxicity.

Research Products

• [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
• [Presentation] Pharmacokinetics of cyclophosphamide and its metabolites in Pediatric Hematopoietic Stem Cll Transplant Recipients: A comparative study of two conditioning regimens, and one post transplantation 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: 2017 BMT Tandem Meetings
  • Place of Presentation: Orlando, Florida, (USA)
  • Year and Date: 2017-02-22
  • Int'l Joint Research
• [Presentation] Pharmacokinetics and toxicological evaluation of cyclophosphamide in mice (2017)
  • Author(s): Emiko Miyahara, Takuro, Nishikawa, Kazuro Ikawa, Miharu Ushikai, Hiroaki Kawaguchi, Yasuhiro Okamoto, Norifumi Morikawa, Masahisa Horiuchi, Yoshifumi Kawano
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring 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、黒田 英志、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
• [Presentation] Pharmacokinetics of cyclophosphamide and its metabolites in HSCT recipients. (2016)
  • Author(s): Nishikawa T, Ikawa K, Miyahara E, Abematsu T, Nakagawa S, Kurauchi K, Kodama Y, Tanabe T, Shinkoda Y, Okamoto Y, Morikawa N, Kawano Y.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-13