Investigation for preventive method of cyclophosphamide induced cardiomyopathy from the viewpoint of aldehyde metabolism

• Project/Area Number: 16K10034
• 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: Nishikawa Takuro 鹿児島大学, 医歯学域附属病院, 講師 (90535725)
• Co-Investigator(Kenkyū-buntansha): 河野 嘉文 鹿児島大学, 医歯学域医学系, 教授 (20260680) ; 岡本 康裕 鹿児島大学, 医歯学域医学系, 准教授 (30398002) ; 児玉 祐一 鹿児島大学, 医歯学域附属病院, 講師 (20535695)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: cyclophosphamide / cardiotoxicity / aldehyde metabolism / acrolein / Cyclophosphamide / aldehyde dehydrogenase / 心筋障害 / シクロフォスファミド / 抗がん剤 / アルデヒド / アクロレイン / 造血細胞移植 / アルデヒド代謝

Outline of Final Research Achievements

In our previous in vitro study, we reported that acrolein is implicated in an onset of cardiotoxicity after exposure to cyclophosphamide (CY). Aldehyde dehydrogenase 1 (ALDH1) decrease the production of acrolein from CY whereas increase the induction of inactive metabolite o-carboxyethyl phosphoramide mustard (CEPM). Therefore, ALDH1 plays a crucial role in CY-induced cardiotoxicity. To reveal the role of ALDH1 in CY metabolism, we assessed whether knockdown (KD) of Aldh1a1 gene expression sensitizes mice to CY. Aldh1a1 KD-mice exhibit lower concentration of CEPM in their plasma compared to the control group. Furthermore, knockdown of Aldh1a1 gene expression resulted in marked cardiomyopathy. It suggested that even in in vivo experiments, acrolein is responsible for CY-induced cardiotoxicity.

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。今回、in vivoの系でもacroleinがCY心筋障害の主因である可能性が示唆されたことで、acrolein除去薬の投与やacrolein産生を抑える薬剤投与などで予防につながる可能性がみいだせた。

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
• [Journal Article] Gene expression ratio as a predictive determinant of nelarabine chemosensitivity in T-lymphoblastic leukemia/lymphoma. (2017)
  • Author(s): Sripornsawan P, Okamoto Y, Nishikawa T, Kodama Y, Yamaki Y, Kurauchi K, Tanabe T, Nakagawa S, Shinkoda Y, Imuta N, Kawano Y.
  • Journal Title: Pediatr Blood Cancer. Volume: 64 Issue: 2 Pages: 250-253
  • DOI: 10.1002/pbc.26214
  • Peer Reviewed
• [Journal Article] Decrease of Cardiac Base Rotation in 2D Speckle Tracking Indicates Drug-induced Cardiomyopathy After Chemotherapy in Children With Cancer. (2017)
  • Author(s): Yanagimoto K, Okamoto Y, Kodama Y, Nishikawa T, Tanabe T, Kawano Y.
  • Journal Title: J Pediatr Hematol Oncol. Volume: 39 Issue: 1 Pages: 10-14
  • DOI: 10.1097/mph.0000000000000683
  • Peer Reviewed
• [Journal Article] DIC Complicating APL Successfully Treated With Recombinant Thrombomodulin Alfa. (2016)
  • Author(s): Saito A, Okamoto Y, Seki Y, Matsunaga M, Nakagawa S, Kodama Y, Nishikawa T, Tanabe T, Kawano Y.
  • Journal Title: J Pediatr Hematol Oncol. Volume: 38 Issue: 6 Pages: e189-e190
  • DOI: 10.1097/mph.0000000000000585
  • Peer Reviewed
• [Journal Article] Conservative treatment of massive hemothorax in a girl with neuroblastoma. (2016)
  • Author(s): Shiokawa N, Okamoto Y, Kodama Y, Nishikawa T, Tanabe T, Mukai M, Yoshioka T, Kawano Y.
  • Journal Title: Pediatr Int. Volume: 58 Issue: 10 Pages: 1090-1092
  • DOI: 10.1111/ped.13094
  • Peer Reviewed
• [Journal Article] Central nervous system EBV lymphoproliferative disorder in a patient with rhabdomyosarcoma. (2016)
  • Author(s): Nakashima K, Kodama Y, Nishikawa T, Nishimura M, Ito N, Fukano R, Nomura Y, Ueba T, Inoue T, Oshima K, Okamura J, Inagaki J.
  • Journal Title: Pediatr Int. Volume: 58 Issue: 5 Pages: 388-390
  • DOI: 10.1111/ped.12812
  • Peer Reviewed
• [Presentation] 移植後シクロフォスファミドを用いた小児HLA半合致末梢血細胞移植におけるシクロフォスファミド薬物動態解析 (2017)
  • Author(s): 西川拓朗，猪川和朗，棈松貴成，中川俊輔，倉内宏一郎，児玉祐一，田邊貴幸，新小田雄一，岡本 康裕，河野嘉文．
  • Organizer: 第39回日本造血細胞移植学会総会
  • Place of Presentation: くにびきメッセ・島根県民会館（島根県松江市）
  • Year and Date: 2017-03-02
• [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, Kawano Y
  • Organizer: 2017 BMT Tandem Meetings
  • Place of Presentation: Orlando, Florida
  • Year and Date: 2017-02-22
  • Int'l Joint Research
• [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
• [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