fluorouracil
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.
Recent Publications Focus
Below is a summary of the newest research publications targeting fluorouracil (sorted by publication date).
Recent research has focused extensively on developing advanced drug delivery systems to enhance 5-fluorouracil (5-FU) efficacy and overcome bioavailability limitations. chitosan/β-cyclodextrin nanocarriers demonstrated improved activity against colorectal cancer cells with an IC50 of 16.5 µM compared to 42.5 µM for free 5-FU, through pH-responsive release and modulation of apoptotic pathways involving P53 and caspase-3 upregulation [42414363]. Hierarchically structured calcium carbonate-gelatin carriers enabled oral gastro-protective delivery of broccoli seed-derived isothiocyanates, producing strong synergistic effects when combined with 5-FU in colorectal cancer models [42319756]. Gelatin methacrylate (GelMA) hydrogels incorporating graphene quantum dots achieved sustained 5-FU release with pronounced cytotoxicity against MCF-7 breast cancer cells [42097427]. Multi-stimuli-responsive curcumin-integrated nanomicellar carriers with pH-, enzyme-, and redox-responsive linkages enhanced anticancer potency, reducing IC50 values to 49.5 µg/mL in MCF-7 cells and 46.3 µg/mL in HepG2 cells compared to free drug [41996327]. Bacterial nanocellulose-based 5-FU encapsulation demonstrated enhanced bioavailability in an azoxymethane/dextran sulfate sodium-induced colorectal cancer model through diffusion-controlled release at colonic pH [41740349]. Bimetallic nanosystems synthesized with silver-selenium and silver-gold showed efficient 5-FU encapsulation (55.07% and 36.23%, respectively) while maintaining drug conjugate integrity [41779332].
Clinical and preclinical investigations have evaluated 5-FU-based combination regimens across multiple cancer types and patient populations. Liposomal irinotecan combined with 5-FU and leucovorin was assessed as a second-line therapy for locally advanced or metastatic pancreatic ductal adenocarcinoma [42329888]. A randomized phase II trial compared liposomal irinotecan plus S-1 versus liposomal irinotecan plus 5-FU in metastatic pancreatic cancer patients [41921365]. aflibercept combined with 5-FU was assessed as first-line treatment for older adults and frail elderly patients with metastatic colorectal cancer [41905242]. Adjuvant hepatic arterial infusion of oxaliplatin combined with intravenous 5-FU and leucovorin was evaluated following surgery for four or more colorectal liver metastases [42018958]. Nanoliposomal irinotecan plus 5-FU and l-leucovorin was tested in rare pancreatic cancer subtypes including acinar cell carcinoma and neuroendocrine carcinoma [41860175]. Modified FOLFIRINOX was compared to capecitabine or gemcitabine as adjuvant chemotherapy in resected ampullary adenocarcinoma [41622055].
Multiple studies have identified mechanisms underlying 5-FU resistance and demonstrated strategies to enhance chemosensitivity. PTPRE upregulation in gastric cancer promoted 5-FU resistance by suppressing ferroptosis through the Src/FAK/TRIB3 signaling pathway [42313735]. In nasopharyngeal carcinoma, reduced SLC44A4 expression was associated with decreased sensitivity to 5-FU alongside increased vulnerability to DNA-damaging agents [42361082]. Mannose-functionalized liposomes co-encapsulating levamisole and lipopolysaccharide enhanced 5-FU efficacy in colon cancer by modulating tumor-associated macrophages and downregulating M2 markers (CD206 and Arg1) [42069203]. Natural compounds demonstrated promise in overcoming resistance: celacarfurine and celafurine from Tripterygium wilfordii showed synergistic effects with 5-FU in resistant HCT116 cells with combination indices of 0.50 and 0.66 [42297080]. Heteronemin, a marine-derived sesterterpenoid, exhibited stronger cytotoxicity than both cisplatin and 5-FU in chemoresistant oral squamous cell carcinoma through ROS-mediated apoptosis and cuproptosis-associated mitochondrial stress [42315805]. The combination of guanosine with 5-FU potentiated activity against methicillin-resistant Staphylococcus aureus through thymidine depletion and increased intracellular reactive oxygen species [42268235].
Advances in understanding subcellular signaling mechanisms and physiologically relevant model systems have revealed additional therapeutic opportunities. Golgi-localized GPR15 underwent spatiotemporal trafficking to enhance 5-FU chemosensitivity in colorectal cancer through NAD+-mediated metabolic reprogramming, with the PARP inhibitor rucaparib showing potent synergy with 5-FU in patient-derived organoids and xenograft models [41661673]. Site-specific propynylation of apigeninidin enhanced cell membrane permeability and synergistically potentiated 5-FU efficacy in cervical cancer by targeting PARP-1 and DNA replication pathways [41653678]. Three-dimensional GelMA-based colorectal cancer models revealed that multicellular tumor microenvironment interactions attenuate 5-FU cytotoxicity compared to conventional 2D monolayers, providing improved physiological relevance for drug screening [42066109]. Mycosubtilin, a cyclic lipopeptide from Bacillus subtilis, significantly outperformed 5-FU in inhibiting SW480 colorectal cancer cell proliferation through downregulation of the anti-apoptotic protein B-cell lymphoma 2 [42160403]. Gold nanoparticles demonstrated favorable computational binding alongside 5-FU to cancer-associated targets including p53 and NF-κB in triple-negative breast cancer models [42240071]. Computational investigations predicted that Au13 nanoclusters emerged as optimal GSH-responsive 5-FU carriers with favorable displacement energies, while Pt13 was unsuitable due to overly strong drug binding [42165898]. Evaluation of genotoxic damage in isogenic HCT116 colorectal cancer cell lines revealed that 5-FU exhibited marginal effects on micronucleus formation and reactive oxygen species production compared to oxaliplatin and irinotecan [41870588].