Research press release





今回、David Sabatiniたちの研究グループは、CRISPR-Cas9系を用いたスクリーニング法によって、メトトレキサートを投与された白血病細胞のスクリーニングを行い、メトトレキサートに対する感受性を亢進させる遺伝子の検出を試みた。その結果、ヒスチジン(タンパク質合成に用いられるアミノ酸)の異化を助ける酵素のコード化過程が同定された。この過程は、これまでメトトレキサートに対する感受性とは結び付けられていなかった。ヒスチジンの異化過程では、メトトレキサートの場合と同様に細胞内のTHF濃度が低下し(THFの産生が阻害されたためではなく、THFが枯渇したため)、それによってメトトレキサートががん細胞に及ぼす負の影響が増強された。


A common chemotherapy agent might be made more effective through supplements of histidine, suggests a mouse study published online this week in Nature.

Methotrexate is a chemotherapy agent used to treat various solid tumours and blood cancers. An antimetabolite, it works by stopping cancer cells from both making and repairing DNA, as well as producing proteins, both of which are extensively required for cancer growth. Methotrexate works by inhibiting the production of tetrahydrofolate (THF), which is essential to nucleotide synthesis. Methotrexate’s drawback, however, is its high toxicity, which limits its use in patients. Means of enhancing methotrexate’s effect on cancer cells are therefore highly sought after.

David Sabatini and colleagues used a CRISPR-Cas9-based screen of methotrexate-treated leukaemia cells to pick out genes that increase sensitivity to the chemotherapy agent. Through this, they identified a process that had not previously been linked to methotrexate sensitivity: the encoding of an enzyme that helps catabolize histidine, an amino acid used to synthesize proteins. As with methotrexate, the process of catabolizing histidine also reduces THF levels in cells - albeit by draining them, rather than by inhibiting THF production - thereby enhancing the negative impact of the chemotherapy agent.

In mice, chemotherapy treatments with low doses of methotrexate were seen to be more effective at reducing tumour size and killing tumour cells when also administered with histidine. If these findings translate to clinical trials, the authors conclude, the effectiveness of methotrexate-based treatments could be improved with simple and inexpensive dietary interventions, allowing doctors to prescribe lower doses of the toxic agent.

doi: 10.1038/s41586-018-0316-7

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