2018 Fiscal Year Final Research Report
Investigation for preventive method of cyclophosphamide induced cardiomyopathy from the viewpoint of aldehyde metabolism
| Project/Area Number |
16K10034
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kagoshima University |
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Principal Investigator |
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| 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)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | cyclophosphamide / cardiotoxicity / aldehyde metabolism / acrolein |
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| 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.
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| Free Research Field |
小児血液・腫瘍学
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| 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。
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