Mechanisms of fatal cardiotoxicity following high-dose cyclophosphamide therapy and a method for its prevention

• Project/Area Number: 26870460
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hygiene and public health; Pediatrics
• Research Institution: Kagoshima University
• Principal Investigator: Nishikawa Takuro 鹿児島大学, 医学部・歯学部附属病院, 助教 (90535725)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: シクロフォスファミド / 心筋障害 / 造血細胞移植 / 代謝 / 活性酸素 / 抗酸化剤 / アルデヒド脱水素酵素 / グルタチオン / acrolein / アポトーシス / アクロレイン

Outline of Final Research Achievements

We investigated the poorly understood cardiotoxic mechanisms of high-dose cyclophosphamide (CY). A rat cardiac myocardial cell line, H9c2, was exposed to CY metabolized by S9 fraction of rat liver homogenate mixed with co-factors (CYS9). CYS9 exhibited myocardial cytotoxicity when CY concentration was 250 μM or more. Inhibition of CYS9-induced cytotoxicity occurred with N-acetylcysteine (NAC). Pre-treatment with NAC, however, did not inhibit the metabolism of CY: compared to control samples, we observed no difference in 4-hydroxy-cyclophosphamide (HCY), a significant increase of o-carboxyethyl-phosphoramide (CEPM), and a significant decrease of acrolein. Furthermore, NAC pre-treatment did not affect intracellular amounts of ROS produced by CYS9. Since acrolein seems to be heavily implicated in the onset of cardiotoxicity, any competitive metabolic processing of CY that reduces its transformation to acrolein is likely to be an important mechanism for preventing cardiotoxicity.

Research Products

• [Journal Article] Mechanisms of Fatal Cardiotoxicity following High-Dose Cyclophosphamide Therapy and a Method for Its Prevention. (2015)
  • Author(s): Nishikawa T, Miyahara E, Kurauchi K, Watanabe E, Ikawa K, Asaba K, Tanabe T, Okamoto Y, Kawano Y.
  • Journal Title: PLoS One Volume: 26;10(6） Issue: 6 Pages: e0131394-e0131394
  • DOI: 10.1371/journal.pone.0131394
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration-time curve in pediatric hematopoietic stem cell transplant recipients. (2015)
  • Author(s): Watanabe E, Nishikawa T, Ikawa K, Yamaguchi H, Abematsu T, Nakagawa S, Kurauchi K, Kodama Y, Tanabe T, Shinkoda Y, Matsumoto K, Okamoto Y, Takeda Y, Kawano Y.
  • Journal Title: International Journal of Hematology Volume: 102 Issue: 5 Pages: 611-616
  • DOI: 10.1007/s12185-015-1853-6
  • Peer Reviewed / Open Access
• [Journal Article] Long-Term Morbidity and Mortality in Children with Chronic Graft-versus-Host Disease Classified by National Institutes of Health Consensus Criteria after Allogeneic Hematopoietic Stem Cell Transplantation. (2015)
  • Author(s): Inagaki J, Moritake H, Nishikawa T, Hyakuna N, Okada M, Suenobu S, Nagai K, Honda Y, Shimomura M, Fukano R, Noguchi M, Kurauchi K, Tanioka S, Okamura J.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 21(11) Issue: 11 Pages: 1973-1980
  • DOI: 10.1016/j.bbmt.2015.07.025
  • Peer Reviewed
• [Journal Article] Acute encephalomyelitis complicated with severe neurological sequelae after intrathecal administration of methotrexate in a patient with acute lymphoblastic leukemia. (2014)
  • Author(s): Nishikawa T, Okamoto Y, Maruyama S, Tanabe T, Kurauchi K, Kodama Y, Nakagawa S, Shinkoda Y, Kawano Y.
  • Journal Title: Rinsho Ketsueki. Volume: 55(11) Pages: 2306-2310
  • NAID: 130004705980
  • Peer Reviewed
• [Journal Article] Bone marrow transplant for a girl with bone marrow failure and cerebral palsy. (2014)
  • Author(s): Kodama Y, Okamoto Y, Shinkoda Y, Tanabe T, Nishikawa T, Yamaki Y, Kurauchi K, Kawano Y.
  • Journal Title: Pediatr Int. Volume: 56(3) Issue: 3 Pages: 424-426
  • DOI: 10.1111/ped.12297
  • Peer Reviewed
• [Journal Article] Effect of myeloperoxidase inhibition on gene expression profiles in HL-60 cells exposed to 1, 2, 4,-benzenetriol. (2014)
  • Author(s): Miyahara E, Nishikawa T, Takeuchi T, Yasuda K, Okamoto Y, Kawano Y, Horiuchi M.
  • Journal Title: Toxicology Volume: 317 Pages: 50-57
  • DOI: 10.1016/j.tox.2014.01.007
  • Peer Reviewed
• [Presentation] 移植後シクロフォスファミドを用いたHLA半合致末梢血細胞移植とハプロDLIを施行した急性骨髄性白血病． (2015)
  • Author(s): 引地美菜子，西川拓朗，中村達郎，棈松貴成，中川俊輔，児玉祐一，田邊貴幸，新小田雄一，岡本康裕，河野嘉文．
  • Organizer: 第57回日本小児血液・がん学会学術集会
  • Place of Presentation: 甲府富士屋ホテル（山梨県甲府市）
  • Year and Date: 2015-11-27
• [Presentation] High-dose cyclophosphamide induced cardiotoxicity: the roles of acrolein and ALDH1 activity. (2015)
  • Author(s): Nishikawa T, Miyahara E, Kurauchi K, Okamoto Y, Kawano Y.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
  • Year and Date: 2015-10-16
• [Presentation] シクロフォスファミド大量療法施行患児における薬物動態－CY、CY代謝物濃度とCYP遺伝子多型および急性心筋障害発症との関係－ (2015)
  • Author(s): 西川拓朗，渡辺英里香，猪川和朗，宮原恵弥子，倉内宏一郎，棈松貴成，中川俊輔，児玉祐一，田邊貴幸，新小田雄一，松元一明，岡本康裕，森川則文，武田泰生，河野嘉文．
  • Organizer: 第32回日本TDM学会・学術大会
  • Place of Presentation: キッセイ文化ホール（長野県松本市）
  • Year and Date: 2015-05-23
• [Presentation] シクロフォスファミド心筋障害のメカニズムとその予防法の探求． (2015)
  • Author(s): 西川拓朗，宮原恵弥子，倉内宏一郎，岡本康裕，河野嘉文．
  • Organizer: 第85回日本衛生学会学術集会
  • Place of Presentation: 和歌山(和歌山県民文化会館、ホテルアバローム紀の国）
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] シクロフォスファミド（CY）、CY代謝物濃度と大量CY投与後の急性心筋障害の検討． (2015)
  • Author(s): 西川拓朗，渡辺英里香，岡本康裕，児玉祐一，田邊貴幸，中川俊輔，倉内宏一郎，棈松貴成，新小田雄一，武田泰生，河野嘉文．
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸（神戸国際会議場、神戸ポートピアホテル）
  • Year and Date: 2015-03-05 – 2015-03-07
• [Presentation] Mechanisms and prevention of fatal cardiotoxicity forrowing high-dose cyclophosphamide therapy. (2014)
  • Author(s): Nishikawa T, Miyahara E, Kurauchi K, Okamoto Y, Kawano Y.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪（大阪国際会議場）
  • Year and Date: 2014-10-31 – 2014-11-02