ArticleCell death & disease2012
Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair.
Article in Cell death & disease, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 93 citations in OpenAlex.
- Engineered Allosteric Biosensor for In Situ DNA Glycosylase Detection in Neuroblastoma Risk Stratification and Drug Resistance Monitoring.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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- Ablating UNG activity in a mouse model inhibits colorectal cancer growth by increasing tumor immunogenicity.JCI insight · 2025Article
- Repair pathway coordination from gap filling by polβ and subsequent nick sealing by LIG1 or LIG3α governs BER efficiency at the downstream steps.DNA repair · 2025Article
- Cytotoxic mechanisms of pemetrexed and HDAC inhibition in non-small cell lung cancer cells involving ribonucleotides in DNA.Scientific reports · 2025Article
- Bypass of Methoxyamine-Adducted Abasic Sites by Eukaryotic Translesion DNA Polymerases.International journal of molecular sciences · 2025Article
- Impact of DNA ligase inhibition on the nick sealing of polβ nucleotide insertion products at the downstream steps of base excision repair pathway.Mutagenesis · 2024Article
- Connecting dots between nucleotide biosynthesis and DNA lesion repair/bypass in cancer.Bioscience reports · 2024Review
- Detection of Uracil-Excising DNA Glycosylases in Cancer Cell Samples Using a Three-Dimensional DNAzyme Walker.ACS measurement science au · 2024Article
- Unprocessed genomic uracil as a source of DNA replication stress in cancer cells.Molecular cell · 2024Article
- Enhanced anticancer effect of thymidylate synthase dimer disrupters by promoting intracellular accumulation.Frontiers in pharmacology · 2024Article
- Adding Base-Excision Repair Inhibitor TRC102 to Standard Pemetrexed-Platinum-Radiation in Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer: Results of a Phase I Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- A New Class of Uracil-DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme.Molecules (Basel, Switzerland) · 2021Article
- Anchored linear oligonucleotides: the effective tool for the real-time measurement of uracil DNA glycosylase activity.Open biology · 2021Article
- An effective human uracil-DNA glycosylase inhibitor targets the open pre-catalytic active site conformation.Progress in biophysics and molecular biology · 2021Article
- Inhibition of Human Uracil DNA Glycosylase Sensitizes a Large Fraction of Colorectal Cancer Cells to 5-Fluorodeoxyuridine and Raltitrexed but Not Fluorouracil.Molecular pharmacology · 2021Article
- Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors.Investigational new drugs · 2021Article
- Base excision repair and its implications to cancer therapy.Essays in biochemistry · 2020Review
- A possible link to uracil DNA glycosylase in the synergistic action of HDAC inhibitors and thymidylate synthase inhibitors.Journal of translational medicine · 2020Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Uracil DNA glycosylase (UDG) specifically removes uracil bases from DNA, and its repair activity determines the sensitivity of the cell to anticancer agents that are capable of introducing uracil into DNA. In the present study, the participation of UDG in the response to pemetrexed-induced incorporation of uracil into DNA was studied using isogenic human tumor cell lines with or without UDG (UDG(+/+)/UDG(-/-)). UDG(-/-) cells were very sensitive to pemetrexed. Cell killing by pemetrexed was associated with genomic uracil accumulation, stalled DNA replication, and catastrophic DNA strand breaks. By contrast, UDG(+/+) cells were >10 times more resistant to pemetrexed due to the rapid removal of uracil from DNA by UDG and subsequent repair of the resultant AP sites (abasic sites) via the base excision repair (BER). The resistance to pemetrexed in UDG(+/+) cells could be reversed by the addition of methoxyamine (MX), which binds to AP sites and interrupts BER pathway. Furthermore, MX-bound AP sites induced cell death was related to their cytotoxic effect of dual inactivation of UDG and topoisomerase IIα, two genes that are highly expressed in lung cancer cells in comparison with normal cells. Thus, targeting BER-based therapy exhibits more selective cytotoxicity on cancer cells through a synthetic lethal mechanism.
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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.