ArticleCancer chemotherapy and pharmacology2023
The novel anti-cancer fluoropyrimidine NUC-3373 is a potent inhibitor of thymidylate synthase and an effective DNA-damaging agent.
Article in Cancer chemotherapy and pharmacology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 19 citations in OpenAlex.
- Repurposing antifolates as G9a methyltransferase inhibitors for potential Alzheimer's disease therapeutics via 3D QSAR/pharmacophore mapping and experimental validations.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.Nature metabolism · 2026Article
- The Inflammation-Mediated Bidirectional Relationship Between Cardiovascular Disease and Cancer.Diseases (Basel, Switzerland) · 2026Review
- Expanding the payload scope in antibody-drug conjugates by delivery of hydroxy-containing drugs through self-immolative phosphoramidates.Nature communications · 2026Article
- Bridging mechanism and design: modern medicinal chemistry approaches to thymidylate synthase inhibitors.RSC advances · 2026Review
- Recent Advances and Future Directions in 5-Fluorouracil Drug Delivery: A Comprehensive Review.Current topics in medicinal chemistry · 2026Review
- What is in a name? Rethinking SMUG1 in genome maintenance.NAR cancer · 2025Review
- Activation of sphingosine-1-phosphate receptor 2 (S1PR2) upregulates dihydropyrimidine dehydrogenase (DPD) expression in colon cancer cells.Journal of advanced research · 2025Article
- Article
- Dihydropyrimidine Dehydrogenase Polymorphism c.2194G>A Screening Is a Useful Tool for Decreasing Gastrointestinal and Hematological Adverse Drug Reaction Risk in Fluoropyrimidine-Treated Patients.Current issues in molecular biology · 2024Article
- An insight into thymidylate synthase inhibitor as anticancer agents: an explicative review.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Secondary metabolite profiling using HR-LCMS, antioxidant and anticancer activity ofBiotechnology reports (Amsterdam, Netherlands) · 2024Article
- Review of Prodrug and Nanodelivery Strategies to Improve the Treatment of Colorectal Cancer with Fluoropyrimidine Drugs.Pharmaceutics · 2024Review
- Advances and key focus areas in gastric cancer immunotherapy: A comprehensive scientometric and clinical trial review (1999-2023).World journal of gastroenterology · 2023Review
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10 authors at 2 institutions in 1 country.
Funding
Abstract
introductionFluoropyrimidines, principally 5-fluorouracil (5-FU), remain a key component of chemotherapy regimens for multiple cancer types, in particular colorectal and other gastrointestinal malignancies. To overcome key limitations and pharmacologic challenges that hinder the clinical utility of 5-FU, NUC-3373, a phosphoramidate transformation of 5-fluorodeoxyuridine, was designed to improve the efficacy and safety profile as well as the administration challenges associated with 5-FU.
methodsHuman colorectal cancer cell lines HCT116 and SW480 were treated with sub-IC
resultsWe demonstrated that NUC-3373 generates more FdUMP than 5-FU, resulting in a more potent inhibition of TS, DNA misincorporation and subsequent cell cycle arrest and DNA damage in vitro. Unlike 5-FU, the thymineless death induced by NUC-3373 was rescued by the concurrent addition of exogenous thymidine. 5-FU cytotoxicity, however, was only reversed by supplementation with uridine, a treatment used to reduce 5-FU-induced toxicities in the clinic. This is in line with our findings that 5-FU generates FUTP which is incorporated into RNA, a mechanism known to underlie the myelosuppression and gastrointestinal inflammation associated with 5-FU.
conclusionTaken together, these results highlight key differences between NUC-3373 and 5-FU that are driven by the anti-cancer metabolites generated. NUC-3373 is a potent inhibitor of TS that also causes DNA-directed damage. These data support the preliminary clinical evidence that suggest NUC-3373 has a favorable safety profile in patients.
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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.