5-Fluorouracil-Loaded PLGA Declined Expression of Pro-Inflammatory Genes IL-9, IL-17A, IL-23 and IFN- y; in the HT-29 Colon Cancer Cell Line.

Background: Pro-inflammatory cytokines play critical roles in cancer pathobiology and have been considered potential targets for cancer management and therapy. Understanding the impact of cancer therapeutics such as 5-fluorouracil (5-FU) on their expression might shed light on development of novel combinational therapies. This study aimed to encapsulate 5-FU into PLGA and evaluate their effects on the expression of pro-inflammatory genes IL-9, IL-17-A, IL-23, and IFN-y; in the HT-29 cells. Methods: PLGA-5-FU NPs were constructed and characterized by Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM). The cytotoxicity was evaluated by MTT test and, the IC50 was identified. HT-29 cells were treated with different concentrations of the PLGA-5-FU NPs for 48 hours and, gene expression levels were analyzed by qRT-PCR. Results: DLS and AFM analysis revealed that the prepared PLGA-5-FU NPs were negatively charged spherical-shaped particles with a mean size of 215.9 ± 43.3 nm. PLGA-5-FU NPs impacted the viability of HT-29 cells in a dose- and time-dependent manner. The qRT-PCR results revealed a dose-dependent decrease in the expression of IL-9, IL-17A, IL-23 and IFN-y; genes, and their expressions were significantly different in both 10 and 20 µg/mL treated groups compared to the control. However, although the treatment of HT-29 cells with 20 µg/mL free 5-FU resulted in decreased expression of the studied genes, the differences were not statistically significant compared to the control group. Conclusion: PLGA-5-FU NPs significantly suppressed expression of the IL-9, IL-17A, IL-23 and IFN-y; genes, and the encapsulation of 5-FU into PLGA improved considerably impact of the 5-FU on the HT-29 cells.

Nucleo(s)tide metabolism as basis for drug development; the Anne Simmonds award lecture.

Aberrant metabolism of purines and pyrimidines led to development of drugs for treatment of various diseases, such as inflammatory, neurological, cardiovascular, viral infections and cancer. Purine and Pyrimidine Symposia are characterized by close interactions, leading to extensive cross-fertilization on methodology and translating not only from bench-to-bedside, but also between various disciplines such as medicinal chemistry, pharmacology, oncology, virology, rheumatology, biochemistry, pediatrics, cardiology, surgery and immunology. This background was fundamental in our studies on how to optimize application of existing drugs (5-fluorouracil [5FU], thiopurines, antifolates such as methotrexate) but also to support development of novel drugs such as gemcitabine, novel antifolates, S-1, TAS-102 and fluorocyclopentenylcytosine. Knowledge of their metabolism helped to design rational combinations such as of gemcitabine with cisplatin, one of the most widely used drug combinations for various cancers. The combination of 5FU with uridine, led to the development of triacetyluridine registered for emergency treatment of patients with lethal 5FU toxicity. Mechanisms of action were studied by careful analysis of their metabolism, using classical enzyme assays with radioactive precursors and HPLC analysis. Drug metabolism moved from manually operated HPLC systems with UV-detection for peak identification and paper rolls for quantification, to computer-operated HPLC with automatic multi-wavelength and fluorometric peak detection and more recently to ultrasensitive, highly specific mass-spectrometry-based systems. Some aspects, however, never changed; careful analysis of the results and being prepared for the unexpected. The latter actually led to the most interesting results. Investigation of (nucleoside/nucleotide) metabolism remains an exciting field of research.

Efficacy of first-line combination therapies versus gemcitabine monotherapy for advanced pancreatic cancer: a systematic review and network meta-analysis.

Various first-line gemcitabine-based or fluorouracil-based combination regimens were approved in patients with advanced pancreatic cancer. Recent randomized clinical trials (RCTs) have investigated chemotherapy backbones in combination with novel investigational drugs, including chemotherapy agents or targeted drugs. However, the comparative efficacy of these different combination therapies remains limited. This systematic review and network meta-analysis aimed to assess the efficacy of first-line combination therapies for advanced pancreatic cancer. The study included 46 RCTs with 10,499 patients and 47 distinct regimens, using data sources from MEDLINE, EMBASE, Cochrane Clinical Trials, and ClinicalTrials.gov from January 1, 2010 to April 23, 2024. The primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included overall response rate (ORR) and disease control rate (DCR). The analysis revealed that gemcitabine+nab-paclitaxel (GA), GA with platinum and fluorouracil (GA+Plat+FU), gemcitabine with fluorouracil (G+FU), G+Plt+FU, and FOLFIRINOX were associated with superior OS and PFS compared to gemcitabine monotherapy. Triplet or quadruplet polychemotherapy combinations, such as GA+Plat+FU, G+Plt+FU, and FOLFIRINOX, demonstrated better OS benefit with hazard ratios of 0.42 (95% CI, 0.26-0.68), 0.41 (95% CI, 0.24-0.71), and 0.58 (95% CI, 0.48-0.71), respectively, compared to doublet regimens like GA and G+FU, which had hazard ratios of 0.70 (95% CI, 0.59-0.82) and 0.82 (95% CI, 0.72-0.95), respectively. Notably, no targeted drugs, monoclonal antibodies, or other medications showed improved survival when added to chemotherapy backbones. These findings support the use of gemcitabine-based or fluorouracil-based triplet or quadruplet regimens for better survival outcomes in patients with advanced pancreatic cancer. Further research is warranted to explore the potential benefits of adding chemotherapy agents, such as fluorouracil, to the GA doublet regimen.

Berberine attenuates 5-fluorouracil-induced intestinal mucosal injury by modulating the gut microbiota without compromising its anti-tumor efficacy.

Background: 5-Fluorouracil (5-Fu), a prominent chemotherapeutic agent for colorectal cancer (CRC) treatment, is often associated with gastrointestinal toxicities, particularly diarrhea. Our previous study demonstrated that berberine (BBR) ameliorates 5-Fu-induced intestinal mucosal injury by modulating the gut microbiota in rats. Nevertheless, the precise molecular mechanism underlying BBR's protective effect on intestinal mucosa remains elusive, and its impact on the anti-tumor efficacy of 5-Fu warrants further investigation. Methods: The effect of BBR on 5-Fu-induced intestinal mucosal injury was investigated using a tumor-bearing murine model, employing H&E staining, 16 S rDNA sequencing, transcriptome sequencing, Western blot analysis, cell experiments and constructing a pseudo-germ-free tumor xenograft model. Result: Our findings demonstrate that BBR alleviates intestinal mucosal damage, reduces the levels of inflammatory factors (IL-6, TNF-α, and IL-1ß), and inhibits epithelial cell apoptosis in 5-Fu-treated mice without compromising 5-Fu's anti-tumor efficacy. Moreover, 16 S rDNA sequencing indicated that BBR significantly increases the abundance of Akkermansia and decreases the abundance of pathogenic bacteria Escherichia/Shigella at the genus level. Mechanistically, transcriptome sequencing and Western blot analysis confirmed that BBR upregulates PI3K/AKT/mTOR expression in the intestinal mucosa. However, this effect was not observed in tumor tissues. Notably, BBR did not demonstrate a direct protective effect on 5-Fu-treated CCD841 and SW480 cells. Additionally, BBR had no effect on the PI3K/AKT/mTOR pathway in the intestinal tissue of the 5-Fu-treated mouse model with a depleted gut microbiota. Conclusion: This study indicates that BBR alleviates 5-Fu-induced intestinal mucosal injury by modulating the gut microbiota and regulating the PI3K/AKT/mTOR signaling pathway without compromising the anti-tumor efficacy of 5-Fu.

Identification of cancer-associated fibroblast-related Ectodysplasin-A as a novel indicator for prognosis and immune response in gastric cancer.

Studies have indicated cancer-associated fibroblasts (CAFs) could have a significant impact in gastric cancer (GC) progression and chemotherapy resistance. However, the gene related to cancer fibroblasts that can be used as biomarkers to judge the occurrence of gastric cancer has not been fully explored. Based on two Gene Expression Omnibus (GEO) datasets, we focus on differentially expressed genes which may act as CAFs markers related to GC. Through COX regression, LASSO regression and Kaplan-Meier survival analysis, we discovered three upregulated genes (GLT8D2, GNAS and EDA) associated with poor GC patients' survival. By single-cell analysis and nomogram, we found that EDA may affect fibroblast production and disease prognosis in GC patients. EDA expression showed a positive correlation with 5-Fluorouracil IC50 values. Immunohistochemistry (IHC) and real time PCR indicated elevated EDA levels in GC tissues and cells. Enrichment analysis revealed that EDA was closely linked to immune system regulation. IHC and single-cell analysis indicated that EDA gene was associated with cancer fibroblasts marker FGF12 and influence cell interferon-gamma response, which may play a role in regulating immune-related characteristics. In summary, we concluded that EDA may be used as a new therapeutic CAFs marker for GC.

5-Fluorouracil resistance due to sphingosine kinase 2 overexpression in colorectal cancer is associated with myeloid-derived suppressor cell-mediated immunosuppressive effects.

PURPOSE: Colorectal cancer (CRC) is one of the top five cancer-related causes of mortality globally. Acquired resistance has hindered the effectiveness of 5-fluorouracil (5-FU), the main chemotherapeutic drug used to treat CRC. Sphingosine kinase 2 (SphK2) may be a cancer treatment target and involved in 5-FU resistance. METHODS: Cell growth was examined using MTT and clone formation assays for SphK2 expression. To identify immune cells in mice, flow cytometry was performed. West blotting demonstrated alterations in cell division and inflammation-related proteins. SphK2 levels and inflammation-related variables were studied using Elisa. RESULTS: Due to SphK2 overexpression, immunosuppression, and 5-FU resistance are caused by the development of myeloid-derived suppressor cells (MDSCs) subsequent to IL-6/STAT3 activation and alterations in the arginase (ARG-1) protein. After therapy, the combination of SphK2 inhibitors and 5-FU can effectively suppress MDSCs while increasing CD4+ and CD8+ T cell infiltration into the tumor microenvironment, lowering tumor burden, and exhibiting a therapeutic impact on CRC. CONCLUSIONS: Our findings suggest that 5-FU treatment combined with simultaneous Spkh2 inhibition by ABC294640 has anti-tumor synergistic effects by influencing multiple effects on tumor cells, T cells, and MDSCs, potentially improving the poor prognosis of colorectal cancer patients.

Carrier-free nanoparticles based on self-assembly of 5-FU and copper-genistein complexes for the combined treatment of hepatocellular carcinoma.

5-Fluorouracil (5-FU) is commonly used as a chemotherapeutic drug for advanced HCC. However, the effectiveness of 5-FU is limited by the emergence of resistance and poor targeting efficiency. Combining 5-FU with natural compounds has shown promise in HCC treatment. In this study, we prepared carrier-free nanoparticles (GEN-Cu-GEN@FUA) containing 5-FU and genistein (GEN) in a synergistic ratio via a green synthesis procedure. The resulting GEN-Cu-GEN@FUA nanoparticles had a spherical or near spherical shape, a dynamic size of 129.3 ± 40.1 nm, and a high drug loading content of approximately 21.40% (5-FU) and 61.48% (GEN). These nanoparticles exhibited approximately 3.6-fold lower IC50 value than 5-FU alone in Bel-7402 cells and resulted in a 3.7-fold greater reduction in tumor weight compared to 5-FU alone in Bel-7402 tumor-bearing BALB/c mice. Importantly, the nanoparticles showed negligible systemic toxicity due to their synergistic effect on cancer cell dysfunction and significant amplification of intracellular glutathione consumption. Our findings suggest that the developed carrier-free nanomedicines offer a highly promising platform for the co-delivery of genistein (GEN) copper(II) complexes and 5-FU, with easy fabrication and great potential for clinical translation in HCC synergistic therapy.

A Comprehensive Multi-drug Strategy for the Management of Foreign Body Granuloma Following Mesotherapy.

BACKGROUND: Mesotherapy is a medical technique that administers cosmetic nutrients directly to the dermis through microdrop injections for aesthetic purposes. Its application has become increasingly widespread. However, there have also been a growing number of reported cases of multiple foreign body granulomas following mesotherapy. It is crucial to find an effective and safe treatment. METHODS: In this study, 31 patients with facial foreign body granuloma after mesotherapy were included. A mixture of 5-fluorouracil, lidocaine injection , and normal saline was prepared in a ratio of 1:1:4 and injected subcutaneously. Triamcinolone acetonide, 5-fluorouracil, lidocaine injection, and normal saline were prepared in a ratio of 2:5:3:10. Subcutaneous injections were administered to each papule using a 34G needle. The treatments were scheduled at intervals of 10-14 days. Color Doppler ultrasound was used to evaluate the condition before the initial treatment and after the final treatment. RESULTS: The preoperative ultrasonography revealed diffuse hypoechoic areas in the dermis of the facial skin. After an average of 2-4 treatment sessions, a significant improvement was observed in all patients' appearance, with reduced redness and swelling, softened nodules, absence of pain and itching symptoms, and no evident abnormal echo on ultrasound examination. During a follow-up period ranging from 1 to 8 months, no recurrence or adverse reactions were reported. CONCLUSION: This technique demonstrates clear efficacy. And this formulation effectively reduces the dosage of triamcinolone acetonide and minimizes the risk of adverse reactions such as skin atrophy. Therefore, it can be considered an effective treatment for multiple foreign body granulomas following mesotherapy. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Establishment of patient-derived organoids and a characterization based drug discovery platform for treatment of gastric cancer.

BACKGROUND: Gastric cancer (GC) encompasses many different histological and molecular subtypes. It is a major driver of cancer mortality because of poor survival and limited treatment options. Personalised medicine in the form of patient-derived organoids (PDOs) represents a promising approach for improving therapeutic outcomes. The goal of this study was to overcome the limitations of current models by ameliorating organoid cultivation. METHODS: Organoids derived from cancer tissue were evaluated by haematoxylin and eosin staining, immunohistochemistry, mRNA, and whole-exome sequencing. Three representative chemotherapy drugs, 5-fluorouracil, docetaxel, and oxaliplatin, were compared for their efficacy against different subtypes of gastric organoids by ATP assay and apoptosis staining. In addition, drug sensitivity screening results from two publicly available databases, the Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopaedia, were pooled and applied to organoid lines. Once key targeting genes were confirmed, chemotherapy was used in combination with poly (ADP ribose) polymerase (PARP)-targeted therapy. RESULTS: We successfully constructed GC PDOs surgically resected from GC patient tissue. PDOs closely reflected the histopathological and genomic features of the corresponding primary tumours. Whole-exosome sequencing and mRNA analysis revealed that changes to the original tumour genome were maintained during long-term culture. The drugs caused divergent responses in intestinal, poorly differentiated intestinal, and diffuse gastric cancer organoids, which were confirmed in organoid lines. Poorly differentiated intestinal GC patients benefited from a combination of 5-fluorouracil and veliparib. CONCLUSION: The present study demonstrates that combining chemotherapy with PARP targeting may improve the treatment of chemotherapy-resistant tumours.

Efficacy and safety of 0.5% colchicine cream versus 5% 5-fluorouracil cream in the treatment of cutaneous field cancerization: a randomized clinical trial

Abstract Background 5-Fluorouracil (5-FU) is a first-line drug to treat cutaneous field cancerization (CFC). There are few clinical trials with topical colchicine (COL). Objective To evaluate the effectiveness of 0.5% COL cream versus 5% 5-FU cream in the treatment of CFC. Method This was a randomized, open, self-controlled clinical trial. Forty-five patients (90 forearms), with three to ten actinic keratoses (AK) on each forearm, used 0.5% COL cream 2×/day for seven days on one forearm, and 5% 5-FU cream 2× /day, for 21 days, on the other forearm. The dosages were defined based on previous clinical trials for each drug. Adverse effects were evaluated after 14 days and outcomes after 90 days of inclusion. The primary outcome was complete AK clearance and the secondary outcomes were: partial clearance (≥50%), reduction in AK count, assessment of the Forearm Photoaging Scale (FPS), AK Severity Score (AKSS), and adverse effects. Results After 90 days, there was complete clearance of AK in 37% (95% CI 24%-49%) and partial clearance in 85% (95% CI 76%-93%) of the forearms treated with 5-FU,versus 17% (95% CI 7%-27%) and 78% (95% CI 66%-88%) for COL (p > 0.07). There was a percentage reduction of 75% in the AK count of the forearms treated with 5-FU (95% CI 66%-83%) and 64% in those treated with COL (95% CI 55%-72%). Regarding FPS and AKSS, there was improvement in both groups, with no difference regarding FPS (p = 0.654), and 5-FU superiority for AKSS (p = 0.012). Study limitations Single-center study. Conclusions 5-FU and COL are effective for treating CFC, with neither showing superiority regarding the reduction in AK counts.

Capecitabine-loaded NLC for Breast Cancer Treatment: Preparation, Characterization, and In vitro Evaluation.

BACKGROUND: Cancer treatment often involves the use of potent antineoplastic drugs like Capecitabine [CAP], which can lead to serious toxicities. There is a need for dosage forms to manage these toxicities that can deliver the medication effectively to the target site while maintaining therapeutic efficacy at lower doses. To achieve the aforesaid objective, NLC containing capecitabine [NANOBIN] was prepared and evaluated. Different formulations of NANOBIN, denoted as CaTS, CaT1S, CaT2S, CaTS1, and CaTS2, were designed and evaluated to improve drug delivery and therapeutic outcomes. METHODS: The NANOBIN formulations were prepared using the hot homogenization method. The characterization of these formulations was conducted based on various parameters such as particle size, Polydispersity Index [PDI], Zeta Potential [ZP], Transmission Electron Microscopy [TEM] imaging, and Encapsulation Efficiency [EE]. In vitro evaluations included stability testing, release studies to assess drug release kinetics, and a cytotoxicity assay [MTT assay] to evaluate the efficacy of these formulations against human breast cancer cells [MCF-7]. RESULTS: The characterization results revealed that all NANOBIN formulations exhibited particle sizes ranging from 65 to 193 nm, PDI values within the range of 0.26-0.37, ZP values between 46.47 to 61.87 mV [-ve], and high EE percentages ranging from 94.121% to 96.64%. Furthermore, all NANOBIN formulations demonstrated sustained and slow-release profiles of CAP. The MTT assay showed that the NANOBINs exhibited significantly enhanced cytotoxic efficacy, approximately 10 times greater than free CAP when tested on MCF-7 cells. These findings indicate the potential of NANOBINs to deliver CAP effectively to the target site, enabling prolonged drug availability and enhanced therapeutic effects at lower doses. CONCLUSION: The study demonstrates that NANOBINs can effectively deliver CAP to target sites, prolonging drug exposure and enhancing therapeutic efficacy while reducing the required dose. Further studies are necessary to validate these findings and establish NANOBINs as a preferred treatment option for cancer therapy.

Delivery of 5-fluorouracil for cancer therapy using aptamer-based nonlinear hybridization chain reaction.

5-Fluorouracil (5-FU) is a conventional nucleotide analogue used for cancer treatment. However, its clinical application faces challenges such as low stability and non-specific toxicity. With the remarkable advancements in DNA nanotechnology, DNA-based self-assembled nanocarriers have emerged as powerful tools for delivering nucleotide drugs. In this study, we have designed a non-linear hybrid chain reaction involving a fuel strand with AS1411 aptamer sequence to construct a dendritic structure capable of carrying 5-FU. This structure specifically targets cancer cells with overexpressed nucleolin on their surface, allowing the 5-FU to exert its anticancer effects and achieve therapeutic outcomes. Furthermore, we have also investigated the mechanistic action of this drug delivery system, aiming to establish a novel therapeutic platform for 5-FU treatment.

Thymoquinone Increases the Sensitivity of SW-480 Colon Cancer Cells to 5-Fluorouracil.

Background: Studies have concentrated on the therapeutic potential of thymoquinone (TQ), a natural polyphenol, in diverse malignancies, such as colorectal cancer. Nevertheless, the precise mechanisms of TQ-mediated anticancer properties are not yet fully elucidated. Objective: The present study has been designed to scrutinize the impact of TQ on 5-fluorouracil (5-FU)-mediated apoptosis in SW-480 cells. Materials and Methods: SW-480 cells were treated with TQ, 5-FU, and a combination of TQ + 5-FU. MTT assay was employed to assess cell viability. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to evaluate apoptotic markers comprising Bcl-2, Bax, and caspase-9 expression levels. The γ-H2AX protein expression was assessed by western blotting, and Annexin V flow cytometry was implemented to determine the apoptosis rate. Results: 5-FU significantly reversed the cell proliferation in a dose-dependent circumstance. The concurrent administration of TQ and 5-FU led to a substantial inhibition of cell growth in comparison to single treatments (p < 0.05). TQ also facilitated apoptosis via upregulating Bax and caspase-9 proapoptotic markers and suppressing antiapoptotic mediators, like Bcl-2. In addition, TQ augmented 5-FU-induced apoptosis in SW-480 cells. 5-FU, combined with TQ, increased the protein expression of γ-H2AX in SW-480 cells compared with groups treated with TQ and 5-FU alone. Conclusion: The present study's findings unveil the significance of TQ as a potential therapeutic substance in colorectal cancer, particularly through enhancing 5-FU-induced apoptosis.

Clinical outcomes of second-line chemotherapy in patients with advanced pancreatic adenocarcinoma: a real-world study.

OBJECTIVE: Little progress has been made in recent years using first-line chemotherapy, including gemcitabine combined with nab-paclitaxel, FOLFIRINOX, and NALIRIFOX, for advanced pancreatic adenocarcinoma (APC). In addition, the optimal second-line chemotherapy regimen has not been determined. This study aimed to compare the effectiveness of different types of second-line chemotherapy for APC. METHODS: Patients with APC who received first-line treatment from January 2008 to January 2021 were considered eligible for this retrospective analysis. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS), respectively. RESULTS: Four hundred and thirty-seven and 617 patients were treated with 5-fluorouracil- and gemcitabine-based chemotherapy as first-line treatment, respectively. Demographic and clinical features, except age and liver metastasis, were comparable between the two groups (P < 0.05). The median OS was 8.8 and 7.8 months in patients who received a 5-fluorouracil- and gemcitabine-based combined regimen for first-line therapy, respectively (HR = 1.244, 95% CI = 1.090-1.419; P < 0.001). The median OS was 5.6 and 1.9 months in patients who received second-line chemotherapy and supportive care, respectively (HR = 0.766, 95% CI = 0.677-0.867; P < 0.001). The median PFS was not significantly differently between gemcitabine or 5-fluorouracil monotherapy and combination therapy. CONCLUSIONS: A 5-fluorouracil- or gemcitabine-based combined regimen was shown to be as effective as a single 5-fluorouracil or gemcitabine regimen as second-line therapy for patients with APC.

Stimuli-Responsive Liposomes of 5-Fluorouracil: Progressive Steps for Safe and Effective Treatment of Colorectal Cancer.

5-Fluorouracil (5-FU) has become one of the most widely employed antimetabolite chemotherapeutic agents in recent decades to treat various types of cancer. It is considered the standard first-line treatment for patients with metastatic colorectal cancer. Unfortunately, traditional chemotherapy with 5-FU presents many limitations, such as a short half-life, a low bioavailability, and a high cytotoxicity, affecting both tumor tissue and healthy tissue. In order to overcome the drawbacks of 5-FU and enhance its therapeutic effectiveness against colorectal cancer, many studies have focused on designing new delivery systems to successfully deliver 5-FU to tumor sites. Liposomes have gained attention as a well-accepted nanocarrier for several chemotherapeutic agents. These amphipathic spherical vesicles consist of one or more phospholipid bilayers, showing promise for the drug delivery of both hydrophobic and hydrophilic components in addition to distinctive properties, such as biodegradability, biocompatibility, a low toxicity, and non-immunogenicity. Recent progress in liposomes has mainly focused on chemical and structural modifications to specifically target and activate therapeutic actions against cancer within the proximity of tumors. This review provides a comprehensive overview of both internal-stimuli-responsive liposomes, such as those activated by enzymes or pH, and external-stimuli-responsive liposomes, such as those activated by the application of a magnetic field, light, or temperature variations, for the site-specific delivery of 5-FU in colorectal cancer therapy, along with the future perspectives of these smart-delivery liposomes in colorectal cancer. In addition, this review critically highlights recent innovations in the literature on various types of stimuli-responsive liposomal formulations designed to be applied either exogenously or endogenously and that have great potential in delivering 5-FU to colorectal cancer sites.

Unraveling the Potential of Saccharum officinarum and Chlorella vulgaris towards 5-Fluorouracil-Induced Nephrotoxicity in Rats.

5-Fluorouracil (5-FU) is often used as a chemotherapeutic agent in treating tumors and is said to have adverse effects, including nephrotoxicity. Therefore, the present study aimed to evaluate the protective effects of Chlorella vulgaris (VL) and Saccharum officinarum L. (SOL) against 5-FU-induced nephrotoxicity in rats through the measurement of renal histology, kidney damage indicators, and antioxidant measures. A total of forty-eight male rats were allotted into six groups: group 1 acted as a control negative group (control), group 2 received 5-FU and worked as a control positive group (FU), group 3 received SOL 15 mL/kg (SOL), group 4 received VL 400 mg/kg (VL), group 5 received 5-FU+SOL (5-FU+SOL), and group 6 received 5-FU+VL (5-FU+VL). After fifteen days, blood and renal tissue specimens were collected for hematological, biochemical, molecular, and histopathological examinations. Findings of the current investigation showed that 5-FU leads to hematological alterations and kidney injury evinced by elevated serum concentrations of uric acid, creatinine, and urea (p < 0.01), and a marked increase in kidney MDA and NO levels with a reduction in kidney CAT, SOD and GSH activities (p < 0.05). Alterations of the histopathological structure of kidney tissue in the FU group were noticed compared to the other groups. 5-FU administration elevated expression levels of TNF-α, lipocalin 2, and KIM1 (p < 0.01) compared to the control ones. 5-FU-induced nephrotoxicity was ameliorated after treatment with SOL and VL via their free radical scavenging, potent antioxidant, and anti-inflammatory effects. In conclusion, our findings demonstrate that the treatment with SOL and VL significantly improved nephrotoxicity induced by 5-FU in rats.

The function and mechanism of circRNAs in 5-fluorouracil resistance in tumors: Biological mechanisms and future potential.

5-Fluorouracil (5-FU) is a well-known chemotherapy drug extensively used in the treatment of breast cancer. It works by inhibiting cancer cell proliferation and inducing cell death through direct incorporation into DNA and RNA via thymidylate synthase (TS). Circular RNAs (circRNAs), a novel family of endogenous non-coding RNAs (ncRNAs) with limited protein-coding potential, contribute to 5-FU resistance. Their identification and targeting are crucial for enhancing chemosensitivity. CircRNAs can regulate tumor formation and invasion by adhering to microRNAs (miRNAs) and interacting with RNA-binding proteins, regulating transcription and translation. MiRNAs can influence enzymes responsible for 5-FU metabolism in cancer cells, affecting their sensitivity or resistance to the drug. In the context of 5-FU resistance, circRNAs can target miRNAs and regulate biological processes such as cell proliferation, cell death, glucose metabolism, hypoxia, epithelial-to-mesenchymal transition (EMT), and drug efflux. This review focuses on the function of circRNAs in 5-FU resistance, discussing the underlying molecular pathways and biological mechanisms. It also presents recent circRNA/miRNA-targeted cancer therapeutic strategies for future clinical application.

Advancing targeted combination chemotherapy in triple negative breast cancer: nucleolin aptamer-mediated controlled drug release.

BACKGROUND: Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil. METHODS: We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo. RESULTS: Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo. CONCLUSIONS: This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.

Rapid determination of uracil in biological fluids at mercury thin film electrode for early detection of potential 5-fluorouracil toxicity due to dihydropyrimidine dehydrogenase deficiency.

Determination of plasma uracil was reported as a method for evaluation of Dihydropyrimidine dehydrogenase (DPD) activity that is highly demanded to ensure the safe administration of 5-fluorouracil (5-FU)-based therapies to cancer patients. This work reports the development of a simple electroanalytical method based on adsorptive stripping square wave voltammetry (AdSWV) at mercury film-coated glassy carbon electrode (MF/GCE) for the highly sensitive determination of uracil in biological fluids that can be used for diagnosis of decreased DPD activity. Due to the formation of the HgII-Uracil complex at the electrode surface, the accuracy of the measurement was not affected by the complicated matrices in biological fluids including human serum, plasma, and urine. The high sensitivity of the developed method results in a low limit of detection (≈1.3 nM) in human plasma samples, falling below the practical cut-off level of 15 ng mL-1 (≈0.14 µM). This threshold concentration is crucial for predicting 5-FU toxicity, as reported in buffer, and ≤1.15% in biological samples), and accuracy (recovery percentage close to 100%).