ArticleEMBO molecular medicine2009
Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2.
Article in EMBO molecular medicine, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers, 2 of them syntheses that pooled it.
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Who cites it
79 citing papers in PubMed, 2 syntheses or guidelines pooled it, 157 citations in OpenAlex.
- Synthetic lethal gene pairs: Experimental approaches and predictive models.Frontiers in genetics · 2022Pooled it
- Rethinking ovarian cancer: recommendations for improving outcomes.Nature reviews. Cancer · 2011Guideline
- Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours.British journal of cancer · 2020Trial
- A phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA defective tumours: a study protocol.BMC cancer · 2014Trial
- Variable cellular and radiobiological effects of [Journal of experimental & clinical cancer research : CR · 2026Article
- Mismatch repair protein imbalance in head and neck squamous cell carcinoma: associations with clinical features and survival.Therapeutic advances in medical oncology · 2026Article
- Combinatorial QM and MD in silico design of natural product-based DHFR inhibitors.Scientific reports · 2025Article
- De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression.Cancer research communications · 2024Article
- Loss of mismatch repair promotes a direct selective advantage in human stem cells.Stem cell reports · 2022Article
- Article
- A Drug Screening Revealed Novel Potential Agents against Malignant Pleural Mesothelioma.Cancers · 2022Article
- Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy.Communications biology · 2022Article
- Targeting mitochondrial DNA polymerase gamma for selective inhibition of MLH1 deficient colon cancer growth.PloS one · 2022Article
- Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro.Biomedicines · 2021Article
- Ameliorative effect of metformin on methotrexate-induced genotoxicity: AnBiomedical reports · 2021Article
- The emerging relationship between metabolism and DNA repair.Cell cycle (Georgetown, Tex.) · 2021Review
- Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer.Cell death & disease · 2021Article
- Inhibition by Tetrahydroquinoline Sulfonamide Derivatives of the Activity of Human 8-Oxoguanine DNA Glycosylase (OGG1) for Several Products of Oxidatively induced DNA Base Lesions.ACS chemical biology · 2021Article
- Alterations of DNA damage repair in cancer: from mechanisms to applications.Annals of translational medicine · 2020Review
- AnChemical science · 2020Article
19 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Mutations in the MSH2 gene predispose to a number of tumourigenic conditions, including hereditary non-polyposis colon cancer (HNPCC). MSH2 encodes a protein in the mismatch repair (MMR) pathway which is involved in the removal of mispairs originating during replication or from damaged DNA. To identify new therapeutic strategies for the treatment of cancer arising from MMR deficiency, we screened a small molecule library encompassing previously utilized drugs and drug-like molecules to identify agents selectively lethal to cells lacking functional MSH2. This approach identified the drug methotrexate as being highly selective for cells with MSH2 deficiency. Methotrexate treatment caused the accumulation of potentially lethal 8-hydroxy-2'-deoxyguanosine (8-OHdG) oxidative DNA lesions in both MSH2 deficient and proficient cells. In MSH2 proficient cells, these lesions were rapidly cleared, while in MSH2 deficient cells 8-OHdG lesions persisted, potentially explaining the selectivity of methotrexate. Short interfering (si)RNA mediated silencing of the target of methotrexate, dihydrofolate reductase (DHFR), was also selective for MSH2 deficiency and also caused an accumulation of 8-OHdG. This suggested that the ability of methotrexate to modulate folate synthesis via inhibition of DHFR, may explain MSH2 selectivity. Consistent with this hypothesis, addition of folic acid to culture media substantially rescued the lethal phenotype caused by methotrexate. While methotrexate has been used for many years as a cancer therapy, our observations suggest that this drug may have particular utility for the treatment of a subset of patients with tumours characterized by MSH2 mutations.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.