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

2015 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

小児血液・腫瘍