トポイソメラーゼ阻害薬
トポイソメラーゼ阻害薬
出典: フリー百科事典『ウィキペディア(Wikipedia)』 (2024/02/02 09:27 UTC 版)
トポイソメラーゼ阻害薬(トポイソメラーゼそがいやく、英: topoisomerase inhibitor)は、トポイソメラーゼの作用を遮断する化合物である。トポイソメラーゼは、大きくI型トポイソメラーゼ(TopI)とII型トポイソメラーゼ(TopII)に分けられる[1][2][3]。トポイソメラーゼは細胞の複製過程やDNAの組織化に重要な役割を果たしており、DNAの一本鎖または二本鎖を切断することで、超らせん構造の緩和やカテナン構造の解消、真核細胞の染色体の脱凝集などの過程を媒介している[1][2][3]。トポイソメラーゼ阻害剤は、こうした生存に必須の細胞過程に影響を与える。一部のトポイソメラーゼ阻害剤はDNA二本鎖切断を妨げ、他のものはトポイソメラーゼ-DNA複合体に結合して再ライゲーションの段階を妨げる[3]。一本鎖・二本鎖切断が未修復のまま残されることでアポトーシスと細胞死が引き起こされるため、こうしたトポイソメラーゼ-DNA-阻害剤複合体は細胞傷害性因子となる[2][3]。このように、トポイソメラーゼ阻害剤はアポトーシス誘導能を有し、感染細胞やがん細胞に対する治療薬として大きな関心を集めている。
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- 1 トポイソメラーゼ阻害薬とは
- 2 トポイソメラーゼ阻害薬の概要
- 3 トポイソメラーゼII阻害薬
- 4 WRNの発現欠乏との合成致死性
トポイソメラーゼ阻害薬
出典: フリー百科事典『ウィキペディア(Wikipedia)』 (2022/06/01 15:35 UTC 版)
I型トポイソメラーゼは1本鎖DNAのらせん制御、II型トポイソメラーゼは2本鎖DNAのらせん制御をすると考えられており、作用が複雑で多目的な働きをするII型トポイソメラーゼを阻害したほうが効果があると考えられている。 カンプトテシンとその誘導体(I型トポイソメラーゼを阻害する)イリノテカン(CPT-11、カンプト) ノギテカン(NGT ハイカムチン) 用量規定因子は消化器毒性と骨髄抑制である。特に下痢は致死的になることもある。FOLFIRIでは止痢剤としてロペミンを併用することがしばしばある。骨髄抑制も非常に強い。 アントラサイクリン系 アントラサイクリン系はDNA構造を直接破壊する。化学療法で最も細胞障害性が高いもののひとつであると考えている。ドキソルビシン(DER、ADR、アドリアシン)が含まれる。DNA内へ挿入(インターカレーション)することによって、II型トポイソメラーゼ阻害を行う。心筋内でフリーラジカル産出を促し、心筋細胞膜を破壊、鬱血性心不全を招くことが有名である。DXR投与中は100mg/m2ごとに心電図、200mg/m2ごとに心エコーを実施し、心毒性をチェックする。 エピポドフィロトキシン系 アントラサイクリン系と同様に、II型トポイソメラーゼ阻害を行う。エトポシド(VP-16、ETP、ラステッド、ベプシド)が含まれる。一般にシスプラチンといったアルキル化薬とII型トポイソメラーゼ阻害薬を併用すると、シナジーを得る。理由は、傷害されたDNAを修復するにはトポイソメラーゼの作用が必要(ポリメラーゼとの相互作用のため)なのだが、そこまでブロックされるとアポトーシスされやすいということである。 キノロン系薬物 レボフロキサシン(クラビット)やシプロフロキサシン(シプロキサン)などが含まれる。原核細胞のII型トポイソメラーゼ(これをDNAジャイレースという)とIV型トポイソメラーゼを阻害し、細菌を傷害する。一応はグラム陽性菌にはIV型トポイソメラーゼ、グラム陰性菌にはII型トポイソメラーゼ阻害が効いていると考えられている。AUCに比例して効果を示す抗菌薬なので、1日1回投与のほうが効果的である。
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