| Project/Area Number |
18K07294
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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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| Review Section |
Basic Section 50020:Tumor diagnostics and therapeutics-related
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| Research Institution | University of Fukui |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
根来 英樹 福井大学, 学術研究院医学系部門(附属病院部), 助教 (40444228)
細野 奈穂子 福井大学, 学術研究院医学系部門(附属病院部), 講師 (50509312)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 化学療法 / 分子標的療法 / 血液腫瘍学 / 急性白血病 / クロファラビン / 抗アポトーシスタンパク / 耐性克服 |
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| Outline of Final Research Achievements |
The aim of our present research was to examine thoroughly the mechanisms of drug resistance in the cultured leukemia cells, which we had developed to be resistant to the key drugs (cytarabine, clofarabine) for treating leukemia. In the resistant cell lines, the active drug metabolite production (triphosphate forms) was reduced due to the suppression of activating enzymes, dCK and dGK. In addition, the anti-apoptotic proteins Bcl-2 and Mcl-1 were overexpressed, while pro-apoptotic proteins were not changed. The Bcl-2 inhibitor, venetoclax, induced apoptosis as a single agent, and the combination exerted a synergistic effect. The effect of venetoclax was reduced by the increased Bcl-2 expression. The combined effect of the Mcl-1 inhibitor, alvocidib, was minimal. Thus, it was found that the introduction of a molecular-targeted drug aiming at anti-apoptosis is effective as a means for pharmacological overcoming drug resistance in leukemia.
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| Academic Significance and Societal Importance of the Research Achievements |
抗がん薬に耐性化した白血病細胞を直截かつ網羅的に解析し、耐性分子病態を解明し克服戦略を確立することが本研究の目的である。その成果として、細胞内薬剤活性化に加えて、抗アポトーシス増強が耐性の主要因であることを突き止めた。アポトーシス経路はほとんどすべての抗がん薬の殺細胞作用に関わっており、それを標的とする戦略は他がん治療に応用できる普遍性を有する（学術的意義）。さらに、白血病では今後世界的に治療体系の核となるベネトクラクスが我が国でも承認された（2021年3月）。本研究は本薬の実臨床での単剤・併用治療法開発・発展のための重要な基礎理論となる（社会的意義）。
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