| Project/Area Number |
19K16437
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | シスプラチン / 腎障害 / 非ステロイド性消炎鎮痛薬 / セレコキシブ / NSAIDs / NSAIDｓ / 腎機能障害 / シクロオキシゲナーゼ |
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| Outline of Research at the Start |
申請者らは過去の研究において抗悪性腫瘍薬シスプラチン(CDDP)の代表的な副作用である腎機能障害が非ステロイド性消炎鎮痛薬(Non-Steroidal Anti-Inflammatory Drugs; NSAIDs)の併用により悪化することを明らかにした．NSAIDsはがん患者の解熱・鎮痛に汎用されるため，CDDPとの併用回避目的の中止は患者の鎮痛・解熱コントロール悪化に直結する．しかしながらNSAIDsによるCDDP起因性腎障害の悪化については詳細が不明である．CDDPとNSAIDsが併用可能となればがん患者の生活の質の向上が期待できるため臨床研究，基礎研究の両面から本問題の解決に取り組む．
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| Outline of Final Research Achievements |
Non-steroidal anti-inflammatory drugs (NSAIDs) are suggested as a risk factor for cisplatin-induced nephrotoxicity (CIN). In this research, we have minutely evaluated the influence of NSAIDs, particularly inhibition manner of cyclooxygenase, on CIN development.
First, we assessed the impact of NSAIDs co-administration on CIN development using meta-analysis, suggesting that NSAIDs co-administration can worsen CIN. Second, we assessed the influence of each NSAIDs on CDDP-induced cytotoxicity in vivo and in vitro, revealing that celecoxib significantly attenuated and flurbiprofen markedly enhanced renal toxicity by CDDP. In addition, celecoxib attenuated cytotoxicity by reducing oxidative stress and increasing autophagy activation.
In conclusion, we have evaluated NSAIDs influence on CIN, and revealed that celecoxib attenuates CIN by regulating oxidative stress and autophagy activation.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究成果よりセレコキシブ特有のCIN予防・軽減作用が示された．本研究はCINマネジメントの観点からCDDPと併用可能なNSAIDsを細分化により探索したものであり，その新規性から学術的意義及び社会的意義は大きいと思われる．さらに，我々のグループはNSAIDsがCDDPの抗腫瘍効果に与える影響も検討しており，その結果も踏まえCDDP投与時のNSAIDsの適正使用に貢献すべくさらなる検討を継続したい．
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