Establishment of safe and effective pediatric hematopoietic cell transplantation by pharmacokinetic analysis and metabolic enzyme activity analysis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10033
• 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: Kawano Yoshifumi 鹿児島大学, 医歯学域医学系, 教授 (20260680)
• Co-Investigator(Kenkyū-buntansha): 児玉 祐一 鹿児島大学, 医歯学域附属病院, 講師 (20535695) ; 岡本 康裕 鹿児島大学, 医歯学域医学系, 准教授 (30398002) ; 西川 拓朗 鹿児島大学, 医歯学域附属病院, 講師 (90535725)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: cyclophosphamide / 心毒性 / acrolein / glutathione

Outline of Final Research Achievements

4-hydroxy-cyclophosphamide (HCY) is an active metabolite of cyclophosphamide (CY). It is converted to cytotoxic metabolite acrolein. Human hepatoblastoma cell line HepG2 were exposed to HCY and the concentration of acrolein in cell culture supernatant were measured. Interestingly, the detected acrolein was higher than we expected. Furthermore, glutathione (GSH), an acrolein scavenger were reduced gradually in HepG2 cells. And then, to inhibit the production of acrolein, ALDH1 were knock downed by RNA interference. Against our expectations, the production of acrolein is not increased when ALDH1 knockdown HepG2 cells were exposed to HCY. It indicates that acrolein is not only produced directly by CY, but also is produced in another pathway.

Free Research Field

小児血液腫瘍

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。CY心毒性の主因であるacrolein産生量はその除去剤でもあるglutathionの量が関係することが示唆された。glutathion産生能の個体差が、CY心毒性発症の個体差に繋がる可能性がある。