Drug Database
FL

fluorouracil (Carac, microsponge)

✓ Approved

Heron Therapeutics, Inc. · TYMS · Small Molecule

What is fluorouracil?

fluorouracil is a small molecule developed by Heron Therapeutics, Inc.. It is approved for therapeutic indications via transdermal.

Drug Profile

Brand NamesCarac, microsponge
CompanyHeron Therapeutics, Inc.
Drug ClassSmall Molecule
Molecular TargetTYMS
RouteTransdermal
StatusApproved
Sources: ClinicalTrials.gov, Heron Therapeutics, Inc.

Mechanism of Action

Molecular Targets

fluorouracil acts on 1 molecular target:

TYMSthymidylate synthetase (DKCD, TMS)
Want deeper analysis?Noah AI can explain complex mechanisms and compare to similar drugs.

Therapeutic Indications

fluorouracil is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Skin and subcutaneous tissue disordersActinic keratosis✓ Approved

Related Research Articles

PubMedAnnals of clinical and laboratory science2026-06-09

NFYA Activates REG1A Expression to Promote Malignant Progression and Chemosensitivity in Rectal Cancer.

Zhai Xiaolu X, Hua Mei M, Chen Ying Y, Yin Dian D

This study aimed to investigate the molecular mechanisms of rectal cancer (RC) progression and provide new insights for its treatment. The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER) databases, and the UALCAN platform were used to predict gene expression and correlations. The JASPAR database was used to predict transcription factors. Quantitative polymerase chain reaction (qPCR) and western blot (WB) were performed to detect gene and protein expression. Cell viability was measured using the cell counting kit-8 (CCK-8). Transcription factor-promoter interactions were examined through chromatin immunoprecipitation (ChIP) and the dual-luciferase reporter assay (DLR assay). Transcription factor-gene interactions were validated in vivo. The stats and ggplot2 packages in R were used for analysis and visualization. Regenerating islet-derived protein 1 alpha (REG1A) was significantly associated with RC malignant progression and was the most markedly upregulated. REG1A expression was elevated in RC patient tissues and cells. REG1A knockdown reduced RC cell survival and increased phosphorylated H2A histone family member X (γH2AX) levels under X-ray or 5-Fluorouracil (5FU). Nuclear transcription factor Y subunit alpha (NFYA) was correlated with REG1A, and NFYA knockdown decreased REG1A expression and cell survival while increasing γH2AX; REG1A reversed these effects. In vivo, NFYA knockdown reduced tumor volume, weight, and REG1A levels. NFYA promoted REG1A expression, and the NFYA-REG1A axis enhanced RC resistance to RT and CT and malignant progression.

PMID 42259544
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PubMedJournal for immunotherapy of cancer2026-06-09

Targeting ATF4 overcomes dual resistance to chemo-immunotherapy in gastric cancer by disrupting the DNA damage response.

Ye Huili H, Zhang Wentao W, Cao Hongtai H, Peng Zhiyi Z et al.

The efficacy of chemo-immunotherapy in gastric cancer (GC) is limited by heterogeneous resistance and the lack of predictive biomarkers. However, the molecular mechanisms underlying concurrent intrinsic chemoresistance and extrinsic immunosuppression remain poorly understood. We performed integrative analysis of single-cell RNA sequencing and bulk transcriptomic datasets from GC cohorts to identify key regulators of chemo-immunotherapy resistance. The functional role of activating transcription factor 4 (ATF4) was validated in GC cell lines, patient-derived organoids (PDOs), and patient-derived xenograft (PDX) models. Mechanistic investigations employed chromatin immunoprecipitation sequencing, RNA-seq, and multiplex immunofluorescence to elucidate the ATF4-HSPA9-DNA damage response (DDR) axis. Clinical relevance was assessed in GC patients treated with 5-fluorouracil (5-FU) monotherapy and those receiving combination 5-FU plus anti-PD-1 therapy. We identify integrated stress-response transcription factor ATF4 as a key regulator of dual resistance. Mechanistically, ATF4 transcriptionally upregulates HSPA9 to activate the DDR, which promotes both intrinsic chemoresistance and extrinsic immunosuppression. ATF4 overexpression reduces 5-FU sensitivity and induces CD8+ T cell exhaustion in PDOs and PDX models. Clinically, low ATF4 expression correlates with improved survival in GC patients receiving chemo-immunotherapy. These findings establish the ATF4-HSPA9 axis as a dual-function therapeutic target and predictive biomarker in GC chemo-immunotherapy. This axis bridges DNA damage repair-mediated chemoresistance and T cell exhaustion, providing a strategy to overcome resistance to 5-FU and PD-1 blockade.

PMID 42259601
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PubMedJCO precision oncology2026-06-08

Pharmacokinetics of 5-Fluorouracil in Patients Treated With Capecitabine Carrying the c.1236G>A DPYD Variant Allele.

Heersche Niels N, Knikman Jonathan E JE, Deenen Maarten J MJ, Rosing Hilde H et al.

DPYD-guided fluoropyrimidine dosing effectively limits the risk of severe toxicity while maintaining clinical efficacy. However, recent data suggest that c.1236G>A variant carriers, starting with a 25% reduced dose, have shorter progression-free survival than wild-type patients receiving a full dose. Although overall survival was unaffected, further investigation is warranted. To address this, we retrospectively compared 5-fluorouracil (5-FU) exposure between c.1236G>A variant carriers and DPYD wild-type patients. Pharmacokinetic data from nine clinical trials involving capecitabine-treated patients were pooled. Blood samples were collected before and after administration of capecitabine to assess systemic levels of its metabolites, including 5-FU. Capecitabine dosages were reduced for c.1236G>A variant carriers in accordance with the clinical guidelines at the time of study execution and varied from no reduction (n = 11) to a 25% (n = 16) or 50% (n = 8) reduction. Pharmacokinetic exposure, expressed as area under the plasma concentration-time curve (AUC0-∞), was determined using noncompartmental analysis and dose-normalized to 850 mg/m2. In total, 35 heterozygous c.1236G>A patients and 66 DPYD wild-type patients were evaluable. Patients carrying c.1236G>A who received a 50% dose reduction had a lower dose-normalized geometric mean 5-FU exposure (234 ng·h/mL coefficient of variation [CV = 43%]) compared with fully dosed c.1236G>A carriers (553 ng·h/mL [CV = 51%]) and fully dosed DPYD wild-type patients (582 ng·h/mL [CV = 48%]; P < .001). All c.1236G>A carriers who received a 50% dose reduction had AUC0-∞ values below the AUC0-∞ range observed in the wild-type group. Our findings indicate that an upfront 25% dose reduction for capecitabine in c.1236G>A carriers is likely more appropriate than the currently recommended 50% dose reduction. We stress the importance of individual dose titration in c.1236G>A carriers to avoid both over- and undertreatment.

PMID 42258784
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PubMedEClinicalMedicine2026-06-08

Sequential alternation of nal-IRI/5-FU and gemcitabine/nab-paclitaxel versus nal-IRI/5-FU versus gemcitabine/nab-paclitaxel in first-line metastatic pancreatic cancer: results of the randomized phase II PRODIGE 61-FUNGEMAX trial (France).

Taieb Julien J, Pernot Simon S, Thuillier Frédéric F, Delattre Alexis A et al.

New chemotherapeutic approaches are still needed to improve survival and quality of life in metastatic pancreatic ductal adenocarcinoma (mPDAC). In the absence of validated predictive biomarkers, first-line sequential treatment strategies may allow to delay chemoresistance and reduce cumulative side effects. PRODIGE 61-FUNGEMAX was an open-label, multicentre, randomised phase II trial conducted in 31 centres in France. Between November 2018 and January 2024, chemotherapy-naive patients aged 18-75 years with histologically confirmed metastatic pancreatic ductal adenocarcinoma (mPDAC) and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 were randomly assigned (1:1:1) to receive either nal-IRI (nanoliposomal irinotecan; 70 mg/m2 intravenously [IV] over 90 min) plus leucovorin (400 mg/m2 IV over 30 min) and 5-fluorouracil (5-FU; 2400 mg/m2 IV over 46 h) every 2 weeks (NAPOLI regimen), gemcitabine (1000 mg/m2 IV over 30 min) plus nab-paclitaxel (125 mg/m2 IV over 30 min) on days 1, 8, and 15 of a 28-day cycle (MPACT regimen), or both regimens alternating every 2 months (sequential arm). The primary endpoint was the 6-month progression-free survival (PFS) rate, assessed in the modified intention-to-treat (mITT)/safety population (patients who received at least one dose of study treatment). Secondary efficacy analyses were performed in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov (NCT03693677) and EudraCT (2017-004309-41). Between 16 November 2018 and 25 January 2024, 288 patients were enrolled in 31 French centres. Baseline characteristics were well balanced between the three arms. With a median follow-up of 39.2 months, median treatment durations were 6.3/3.3/5.3 months, for sequential, NAPOLI and MPACT arms, respectively. The 6-month PFS rates were 51.6%, 32.3% and 45.3% in the sequential, NAPOLI and MPACT arms, respectively. Neither sequential (HR = 0.76, p = 0.072) nor NAPOLI regimens (HR = 1.20, p = 0.22) lead to a statistically significant improvement of PFS over the MPACT regimen. The 12-month PFS rates were 20·3%, 12·7%, and 11·9%, and the 24-month OS rates were 23·8%, 9·5%, and 12·5% in the sequential, NAPOLI, and MPACT arms, respectively; these differences were not statistically significant. Safety profiles were consistent with previous publications for each regimen and QoL (QLQ-C30 and EQ5D) was preserved in the sequential arm. The sequential NAPOLI/MPACT regimen seems feasible and tolerable, with higher rates of 12-month PFS and 24-month OS compared with standard MPACT, despite no improvement in median PFS or OS. Future trials should be adequately powered, integrate predictive biomarkers, and include contemporary first-line standards as comparators. This trial was sponsored by the Fédération Francophone de Cancérologie Digestive (FFCD) and supported by a grant from Servier, France.

PMID 42256682
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PubMedAnnals of surgical oncology2026-06-07

Survival Outcomes in Early Onset Appendiceal Adenocarcinoma (EOAA).

Gujarathi Rushabh R, Belmont Erika E, Rodman Christopher C, Bansal Varun Vivek VV et al.

The incidence of early onset (age < 50 years at diagnosis) appendiceal adenocarcinoma (EOAA) is rising alarmingly. Reported data on etiology, treatment, and outcomes is scarce. In this study, we report clinical outcomes for patients with EOAA. Patients diagnosed with appendiceal adenocarcinoma between 2013 and 24 were stratified on the basis of age at diagnosis as having either EOAA (< 50 years) or average-age onset appendiceal adenocarcinoma (AOAA; ≥ 50 years). Clinicopathological and genomic data were abstracted from electronic medical records. Baseline clinicopathologic features and survival outcomes were compared between patients with EOAA and AOAA. Of 181 eligible patients, 49 (27.1%) had EOAA. Median age at diagnosis for patients with EOAA was 42.1 years (interquartile range [IQR], 35.7-46). Of the 76 patients (EOAA = 23 [30.3%] + AOAA = 53 (69.7%)] who had locoregional disease at presentation, 44 (57.9%) remained disease-free for at least 2 years. Within these 44 (conditional survival), the EOAA group showed numerically shorter recurrence-free survival (RFS) and higher risk of recurrence (median RFS, EOAA = 49.5 months versus AOAA = 83.3 months; hazard ratio [HR], 4.07; 95% confidence interval [CI], 1.49-11.18; p = 0.06). Long-term recurrences (≥ 5 years) were seen in 9/15 (60%) patients during the 5-year follow-up period. Of 139 evaluable patients (EOAA = 36 [25.9%] + AOAA = 103 [74.1%]) with metastatic/recurrent disease, patients with EOAA received more non-fluorouracil (FU)-based systemic treatments, including experimental agents, in any line of treatment (8/36, 22.2% versus 6/103, 5.8%; p = 0.009). A higher proportion of patients in the EOAA group received bevacizumab in any line of treatment (24/36, 66.7% versus 49/103, 47.6%; p = 0.055) and three or more lines of systemic therapy (10/36, 27.8% versus 14/103, 13.6%; p = 0.07). There was no significant difference in OS between the EOAA and AOAA groups despite more aggressive therapy in EOAA (median OS, EOAA = 35.2 months versus AOAA = 40.6 months; HR, 0.90; 95% CI, 0.57-1.44; p = 0.66). Among patients who remained disease-free after initial surgical resection for locoregional disease for at least 2 years, recurrence was more frequent in patients with EOAA. Aggressive systemic therapy, including trials and non-FU based therapies were more frequent in patients with EOAA but were not associated with improved survival. EOAA may represent a unique entity within this rare disease, which warrants further exploration.

PMID 42251206
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PubMedPhotodiagnosis and photodynamic therapy2026-06-06

Sequential 5-Fluorouracil-Photodynamic Therapy: A Mechanism-Based Approach to Actinic Keratosis.

Nizam Rabia R, Jalal Amna Amir AA, Adnan Zahabia Z, Mehmood Zainab Z et al.

Actinic keratosis (AK) is a common premalignant condition arising from chronic ultraviolet exposure and frequently occurs within fields of sun-damaged skin that harbour subclinical dysplasia. To summarize the mechanistic rationale, clinical evidence, safety profile, and practical considerations for a sequential regimen of short-course topical 5-fluorouracil (5-FU) pretreatment followed by daylight-mediated photodynamic therapy (dPDT) for field-directed management of AK. We performed a narrative synthesis of randomized controlled trials, split-site studies, mechanistic investigations and cohort reports identified through comprehensive searches of major biomedical databases. An intra-individual randomized trial demonstrated that pretreatment with 4% 5-FU cream prior to daylight-PDT achieved superior overall clearance 87% versus 74% especially in thicker (grade II) lesions. Across the reviewed studies, the sequential use of 5-fluorouracil followed by daylight photodynamic therapy achieved higher rates of complete lesion clearance, particularly in grade II cases. These benefits were sustained in 12 months, with lower recurrence rates and strong patient satisfaction. While the combination approach was linked to temporary redness and scaling, these side effects were mild and did not result in treatment discontinuation in the reported trials. Short-course topical 5-FU pretreatment before dPDT is a biologically plausible and clinically promising strategy to improve lesion and field clearance in AK, particularly for moderately thick lesions. Larger multicentre randomized trials with standardized protocols and longer follow-up are required to define optimal dosing, timing, and applicability to hyperkeratotic high-grade lesions.

PMID 42248280
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