fluorouracil

Overview

Fluorouracil (5-FU) is a pyrimidine analog and an antimetabolite used primarily in the treatment of various cancers, particularly colorectal cancer (CRC). It functions by inhibiting thymidylate synthase, an enzyme critical for DNA synthesis and repair, thereby disrupting the proliferation of cancer cells. As a cornerstone of chemotherapy regimens, 5-FU is often combined with other agents such as leucovorin and oxaliplatin to enhance its efficacy. Despite its widespread use, the clinical effectiveness of 5-FU is often limited by systemic toxicity and severe side effects, prompting ongoing research into novel delivery methods and combination therapies to improve patient outcomes.

Focus of Latest Publications

Recent publications demonstrate that fluorouracil (5-FU) remains a foundational chemotherapeutic agent across multiple cancer types, with ongoing investigation of optimized combination regimens and patient populations. Clinical trials and preclinical studies have evaluated 5-FU paired with novel cytotoxic agents and targeted therapies: liposomal irinotecan (nal-IRI) combined with 5-FU/leucovorin for pancreatic ductal adenocarcinoma and rare pancreatic cancer subtypes; aflibercept plus 5-FU as first-line treatment for elderly patients with metastatic colorectal cancer; modified FOLFIRINOX-based adjuvant regimens for resected ampullary adenocarcinoma; and hepatic arterial infusion of oxaliplatin combined with intravenous 5-FU/leucovorin for colorectal liver metastases. Immunomodulatory approaches have also emerged, with mannose-functionalized liposomes co-encapsulating levamisole and lipopolysaccharide demonstrating enhanced efficacy when combined with 5-FU through remodeling of the tumor microenvironment and suppression of M2 macrophage markers.

A major focus of recent research addresses fluorouracil resistance, a significant limitation in gastric, colorectal, and pancreatic cancers. Mechanistic studies have identified key resistance pathways: PTPRE upregulation suppresses ferroptosis in gastric cancer cells via the Src/FAK/TRIB3 axis, promoting 5-FU resistance; conversely, SLC44A4 expression is negatively correlated with 5-FU sensitivity while conferring increased sensitivity to DNA-damaging agents. To circumvent resistance, multiple natural compounds and derivatives have demonstrated synergistic activity with 5-FU: celacarfurine and celafurine showed synergistic effects in 5-FU-resistant colorectal cancer cells; heteronemin exhibited greater cytotoxicity than 5-FU in chemoresistant oral squamous cell carcinoma; mycosubtilin significantly outperformed 5-FU in colon cancer cell proliferation suppression; apigeninidin derivatives enhanced 5-FU potency in cervical cancer; subcellular redistribution of GPR15 boosted 5-FU chemosensitivity in colorectal cancer through NAD+-mediated metabolic reprogramming; and disulfiram/copper complexes overcame 5-FU resistance in pancreatic cancer through reactive oxygen species modulation and NRF2 suppression.

Substantial innovation has focused on advanced delivery systems designed to improve 5-FU bioavailability, reduce systemic toxicity, and enable targeted or sustained release. Nanoparticulate platforms have emerged as promising carriers: gold-cerium oxide nanohybrids and glutathione-responsive gold nanoclusters demonstrated favorable binding to cancer-associated molecular targets with controlled intracellular drug release; silver-selenium and silver-gold bimetallic nanoparticles achieved efficient 5-FU encapsulation with enhanced antioxidant properties; hierarchically structured calcium carbonate-gelatin microparticles enabled pH-responsive and sustained-release delivery in combined colorectal cancer therapy; and in situ gelling hydrogels based on oxidized gellan gum and gelatin, incorporating graphene quantum dots, provided localized 5-FU delivery with imaging capability for breast cancer. curcumin-conjugated nanomicelles featuring pH-, enzyme-, and redox-responsive linkages demonstrated complete drug release under simulated tumor microenvironment conditions and enhanced potency against hepatocellular and breast carcinoma cells. Bacterial nanocellulose encapsulation systems achieved colon-targeted 5-FU delivery with markedly improved bioavailability and therapeutic performance in azoxymethane/dextran sulfate sodium-induced colorectal cancer models.

Advanced in vitro models have improved predictive capability for 5-FU efficacy and resistance. Multicellular three-dimensional colorectal cancer models based on gelatin methacrylate hydrogels, incorporating endothelial cells, cancer-associated fibroblasts, and macrophages, demonstrated that three-dimensional microenvironments attenuate cytotoxicity and apoptotic responses compared to two-dimensional monolayers through multicellular interactions and diffusion-mediated effects. Mechanistic studies examining reactive oxygen species production and genotoxic damage in isogenic colorectal cancer cell lines exposed to 5-FU revealed marginal effects on genomic damage and ROS generation relative to other chemotherapeutic agents, indicating that 5-FU operates through distinct cytotoxic mechanisms independent of p53 status under non-cytotoxic conditions.

Key Publications

• NEWJun Downregulation of SLC44A4 in nasopharyngeal carcinoma is associated with malignant progression, B-cell/TLS-related immune features, and sensitivity to DNA-damaging agents. (PloS one, 2026, PMID 42361082): "SLC44A4 overexpression also increased sensitivity to DNA-damaging agents, including temozolomide, doxorubicin, cisplatin, olaparib, and etoposide, while decreasing sensitivity to 5-fluorouracil."
• NEWJun Economic evaluation of the second-line regimen of liposome irinotecan (II) combined with 5-FU/LV versus placebo combined with 5-FU/LV for locally advanced or metastatic pancreatic ductal adenocarcinoma in China. (PloS one, 2026, PMID 42329888): "The cost-effectiveness of liposome irinotecan (II) in combination with 5-fluorouracil and leucovorin as a treatment for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma offering a potential new standard of care has not been established."
• NEWJun Hierarchically Structured CaCO3-Gelatin Carriers for Oral Gastro-Protective Delivery of Broccoli Seed-Derived Isothiocyanates in Combined Chemotherapy of Colorectal Cancer. (ACS applied materials & interfaces, 2026, PMID 42319756): "Oral administration of encapsulated ITC in combination with clinically relevant 5-fluorouracil (5-FU) produces strong synergistic effect against CRC."
• NEWJun PTPRE promotes gastric cancer cell resistance to 5-fluorouracil by inhibiting ferroptosis via the Src/FAK/TRIB3 axis. (PloS one, 2026, PMID 42313735): "In vitro experiments were then conducted to investigate the effects of PTPRE on the resistance of cancer cells to 5-fluorouracil (5-FU) and its potential mechanisms."
• NEWJun Heteronemin suppresses chemoresistant oral squamous cell carcinoma cells through ROS-mediated apoptosis and cuproptosis-associated mitochondrial stress. (Apoptosis : an international journal on programmed cell death, 2026, PMID 42315805): "HET dose- and time-dependently reduced SAS-CR viability, inhibited clonogenic growth, and exhibited stronger cytotoxicity than cisplatin or 5-fluorouracil."
• NEWJun Nitrogen-containing dihydro-β-agarofuran derivatives and macrocyclic spermidine alkaloids with anti-tumor activity from the stems of Tripterygium wilfordii. (Fitoterapia, 2026, PMID 42297080): "...celacarfurine and celafurine exhibited synergistic effects on 5-fluorouracil-resistant HCT116 cell model."
• NEWJun The β-lactam adjuvant guanosine potentiates anti-folate antibiotics and pyrimidine synthesis inhibitors by depleting thymidine in methicillin-resistant Staphylococcus aureus. (Antimicrobial agents and chemotherapy, 2026, PMID 42268235): "Here, we show that guanosine significantly reduces intracellular thymidine levels in MRSA and potentiates the activity of antifolate antibiotics (TMP-SMX), as well as the pyrimidine antimetabolites 5-fluorouracil and 5-fluorouridine."
• Jun Biomedical publication details. (PubMed Database, 2026, PMID 42240071)
• May Comparative DFT investigation of glutathione-mediated drug release from Au 13 , A g 13 , and P t 13 nanoclusters: implications for metal-selective anticancer drug delivery. (Journal of molecular modeling, 2026, PMID 42165898): "By computing the thermodynamic feasibility of glutathione (GSH)-mediated competitive displacement of four anticancer drugs-5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), hydroxyurea (HU), and cytarabine (Ara-C)-from icosahedral Au 13 , Ag 13 , and Pt 13 nanoclusters, we predict whether elevated intracellular GSH concentrations in tumor cells can trigger drug release."
• May Inhibitory effects of mycosubtilin on proliferation of colon cancer SW480 cells. (PloS one, 2026, PMID 42160403): "Findings revealed that Myco significantly outperformed 5-Fluorouracil (5-FU) in inhibiting SW480 cell proliferation."