抗がん治療のスケジュール依存の相互作用

Sheng-Hong Chen¹, William Forrester², Galit Lahav¹

¹Department of Systems Biology, Harvard Medical School, Boston, MA, USA.

Science (New York, N.Y.)

|March 12, 2016

まとめ

腫瘍抑制剤p53を活性化させるが,がん細胞死に対する効果はp53に依存する.

科学分野:

腫瘍学
分子生物学
細胞シグナリング

背景:

多くのがんではMDMXが過剰発現し,腫瘍抑制剤p53を抑制する.
MDMX阻害剤はp53を再活性化し,DNAを損傷する薬剤の有効性を高める可能性があります.
p53シグナル伝達とDNA損傷に対するMDMX阻害の影響に関する定量的な理解は欠けている.

研究の目的:

MDMXの抑制がp53信号経路にどのように影響するかを定量的に調査する.
癌細胞がDNAを損傷する物質に対するMDMX抑制の影響を決定する.

主な方法:

MDMXの枯渇後の単細胞におけるp53蓄積の動態を観察するために,生細胞画像を用いた.
この研究では,p53蓄積の異なる段階におけるDNA損傷に対する細胞の異なる反応を分析した.

主要な成果:

MDMXの枯渇は,p53の蓄積の2つの異なる段階を誘導した:最初のポスミトスパルスと,その後の低幅の振動.
DNAの損傷に対する細胞の反応は,これらの段階の間に大きく変化した.
第"段階ではMDMXの減少が DNAの損傷と連携して細胞死を誘発します
第2段階では,MDMXの減少により,DNA損傷による細胞死が抑制されました.

結論:

DNA損傷に対するMDMX抑制のタイミングは,治療結果にとって極めて重要です.
組み合わせ治療の最適化には,p53信号のダイナミクスと細胞状態を理解することが不可欠です.
この研究は,MDMX阻害剤とDNAダメージを与える物質を含む二重薬剤投与のスケジュールを定めるための定量的な基礎を提供します.

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