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Background: Cancer and diabetes mellitus are quite common diseases found together worldwide. A considerable amount of evidence is available for the rapid development and presentation of various types of cancer in the type 2 diabetes mellitus (DM2) population as compared with the population without diabetes. The objective of the study is to formulate and evaluate 5-fluorouracil (5-FU) and metformin (MET) nanoparticles (NPs) and to establish the characteristic features of the biodegradable NPs. 5-FU and MET NPs with chitosan as a biodegradable polymer were formulated by the ionotropic cross-linking method. 0.25 gm of MET and 0.25 gm of 5-FU were dissolved in 100 ml of distilled water, and stock solution was prepared. 5 ml of stock solution was slowly mixed into the chitosan solution to obtain the mixture of drugs and chitosan. The tripolyphosphate reserve liquid was dripped slowly into the chitosan solution with constant stirring until the opaline appearance was noticed in the mixture, then filtered, and dried. The NPs were evaluated for their physical properties and drug release kinetics. Cell proliferation assay was done using human colorectal carcinoma cell line (HCT 116). Results: The formulation composed of 1.5 w/v of chitosan, 0.25 w/v of MET, and 5-FU had an average particle diameter of 198.7 nm. The polydispersity index was 0.757. Thermal and infrared spectroscopy results indicated the drugs and polymers selected for the formulation were unique without any identifiable interaction. The NPs were spherical in appearance, with numerous pours on the surface, which was evident when microscopically examined. Uniformity in drug release was observed, and the formulation demonstrated excellent release kinetics. HTC 116 cell line confirmed that the maximum percentage of cell death and minimum viability of cells were observed while using the combination of MET and 5-FU-NPs as compared to the pure MET or 5-FU alone. Conclusion: MET and 5-FU-loaded chitosan NPs were found to have excellent physiochemical properties, particle size, and drug release from the polymer in a controlled manner. Half-maximal inhibitory concentration value (IC50) of MET and 5-FU-NPs was found to be significantly less as compared to MET and 5-FU alone or the combination. [ABSTRACT FROM AUTHOR]

A 74-year-old Chinese man underwent extracapsular cataract extraction in his right eye and developed a translucent iris membrane 4 months later. He was treated with two intracameral 5-FU injections and membranectomy at 2 weeks apart. At one year following the second membranectomy, the patient maintained a clear cornea without residual or recurrent membrane, an endothelial cell density of 1072 cell/mm2, a visual acuity of 20/50 and a normal intraocular pressure. Our technique of using dispersive and cohesive viscoelastics in protecting the corneal endothelium from intracameral 5-FU, helped preserve corneal endothelial cells and maintain corneal clarity at one year after surgery. [ABSTRACT FROM AUTHOR]

Zinc-phosphate/hydroxyapatite hybrid form (ZP/HP) in core-shell nanostructure was developed and functionalized with both chitosan (CS@ZP/HP) and β-cyclodextrin (CD@ZP/HP) as bio-composite of enhanced physicochemical and biological properties. These structures were assessed as potential deliveries of 5-fluorouracil, exhibiting enhanced loading, release, and anti-cancer behaviors. The functionalization strongly prompted the loading effectiveness to be 301.3 mg/g (CS@ZP/HP) and 342.8 mg/g (CD@ZP/HP) instead of 238.9 mg/g for ZP/HP. The loading activities were assessed based on the hypotheses of traditional kinetic and isotherm models, alongside the computational variables of the monolayer model with a single energetic site as an advanced isotherm model. The functionalized versions exhibit much greater loading efficacy compared to ZP/ HP as a result of the increment in the density of the existing loading sites [Nm(5-Fu) = 78.85 mg/g (ZP/HP), 93.87 mg/g (CS@ZP/HP), and 117.8 mg/g (CD@ZP/HP)]. Furthermore, the loading energies of approximately 40 kJ/mol, together with the loading potential of each receptor (n > 1) and Gaussian energies of approximately 8 kJ/mol, indicate the physical entrapment of 5-Fu molecules according to a vertical orientation. The materials mentioned verify long-term and continuous release characteristics. Following the modification processes, this behavior became faster as both CS@ZP/HP and CD@ZP/HP displayed complete release within 120 h at pH 1.2. The kinetic studies and diffusing exponent (>0.45) indicate that release characteristics are controlled by both diffusion and erosion processes. These carriers also markedly increase the cytotoxicity of 5-Fu against HCT-116 colorectal cancer cell lines: 5-Fu-ZP/HP (3.2% cell viability), 5-Fu-CS@ZP/HP (1.12% cell viability), and 5-Fu-CD@ZP/HP (0.63% cell viability). [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the top 10 most common cancers worldwide and caused approximately 10 million deaths in 2022. CRC mortality has increased by 10% since 2020 and 52.000 deaths will occur in 2024, highlighting the limitations of current treatments due to ineffectiveness, toxicity, or non-adherence. The widely used chemotherapeutic agent, 5-fluorouracil (5-FU), is associated with several adverse effects, including renal, cardiac, and hepatic toxicity; mucositis; and resistance. Taurine (TAU), an essential β-amino acid with potent antioxidant, antimutagenic, and anti-inflammatory properties, has demonstrated protective effects against tissue toxicity from chemotherapeutic agents like doxorubicin and cisplatin. Taurine deficiency is linked to aging and cancers such as breast and colon cancer. This study hypothesized that TAU may mitigate the adverse effects of 5-fluorouracil (5-FU). Carcinogenesis was chemically induced in rats using 1,2-dimethylhydrazine (DMH). Following five months of cancer progression, taurine (100 mg/kg) was administered orally for 8 days, and colon tissues were analyzed. The results showed 80% of adenocarcinoma (AC) in DMH-induced control animals. Notably, the efficacy of 5-FU showed 70% AC and TAU 50% while, in the 5-FU + TAU group, no adenocarcinoma was observed. No differences were observed in the inflammatory infiltrate or the expression of genes such as K-ras, p53, and Ki-67 among the cancer-induced groups whereas APC/β-catenin expression was increased in the 5FU + TAU-treated group. The mitotic index and dysplasia were increased in the induced 5-FU group and when associated with TAU, the levels returned to normal. These data suggest that 5-FU exhibits a synergic anticancer effect when combined with taurine. [ABSTRACT FROM AUTHOR]

Purpose: To report the demographic profile, clinical presentation, and management outcomes of ocular surface squamous neoplasia (OSSN) treated with primary topical chemotherapy in a limited resource secondary eye care facility in rural parts of South India. Methods: Retrospective interventional study of 38 eyes of 37 patients with OSSN treated with topical 1% 5-Fluorouracil (5FU), over a period of two years. Results: The median age at presentation with OSSN was 44 years (mean, 46 years; range 13 to 74 years). Majority (76%) were males. The most common morphological variant was placoid OSSN (18, 47%). Limbus was the most common epicenter (31, 82%). Corneal OSSN was the most initially misdiagnosed variant (n = 3). Of the 38 eyes receiving one week on and 3-weeks off cycles of 5FU regimen, complete tumor resolution was achieved in 36 (95%) eyes. The median number of topical 5FU cycles for tumor resolution was 2 (mean, 2; range, 1 to 4). Over a median follow-up period of 5 months (mean, 6 months; range, 1 to 27 months), tumor recurrence was noted in 3 eyes (8%), of which one case had xeroderma pigmentosum with bilateral multifocal recurrence. Complication rate was 5% (n = 2), which included transient conjunctival hyperemia (n = 1), and bacterial keratitis (n = 1) which resolved with fortified antibiotics. Conclusion: Primary chemotherapy with topical 1% 5FU is a safe and effective management modality for OSSN at limited resource settings in rural India. [ABSTRACT FROM AUTHOR]

Background: L-Leucovorin (l-LV; 5-formyltetrahydrofolate, folinic acid) is a precursor for 5,10-methylenetetrahydrofolate (5,10-CH2-THF), which is important for the potentiation of the antitumor activity of 5-fluorouracil (5FU). LV is also used to rescue antifolate toxicity. LV is commonly administered as a Racemic mixture of its l-LV and d-LV stereoisomers. We compared dl-LV with l-LV and investigated whether d-LV would interfere with the activity of l-LV. Methods: Using radioactive substrates, we characterized the transport properties of l-LV and d-LV, and compared the efficacy of l-LV with d-LV to potentiate 5FU- mediated thymidylate synthase (TS) inhibition. Using proliferation assays, we investigated their potential to protect cancer cells from cytotoxicity of the antifolates methotrexate, pemetrexed (Alimta), raltitrexed (Tomudex) and pralatrexate (Folotyn). Results: l-LV displayed an 8-fold and 3.5-fold higher substrate affinity than d-LV for the reduced folate carrier (RFC/SLC19A1) and proton coupled folate transporter (PCFT/SLC46A1), respectively. In selected colon cancer cell lines, the greatest enhanced efficacy of 5FU was observed for l-LV (2-fold) followed by the racemic mixture, whereas d-LV was ineffective. The cytotoxicity of antifolates in lymphoma and various solid tumor cell lines could be protected very efficiently by l-LV but not by d-LV. This protective effect of l-LV was dependent on cellular RFC expression as corroborated in RFC/PCFT-knockout and RFC/PCFT- transfected cells. Assessment of TS activity in situ showed that TS inhibition by 5FU could be enhanced by l-LV and dl-LV and only partially by d-LV. However, protection from inhibition by various antifolates was solely achieved by l-LV and dl-LV. Conclusion: In general l-LV acts similar to the dl-LV formulations, however disparate effects were observed when d-LV and l-LV were used in combination, conceivably by d-LV affecting (anti)folate transport and intracellular metabolism. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is one of the most common causes of death worldwide. Today, this disease does not have an effective treatment, leading to the exploration of novel pharmacological molecules. In this paper, we design and synthesize with a new synthetic route the lipophilic cation derived from gallic acid (TPP+C10) and gentisic acid (GA-TPP+C10), both able to reach mitochondria and uncouple the electron transport chain. Our results show that combining 5-fluorouracil with GA-TPP+C10 has a synergistic cytotoxic effect on CRC cells. Both compounds show antimigratory effects, decreasing signaling pathways and biomarkers. Our results show that mitochondrial agents could be an alternative to standard CRC drugs against this disease. Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC—such as 5-fluorouracil (5FU)—remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10 with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10 and TPP+C10 using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10 and GA-TPP+C10 increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity. [ABSTRACT FROM AUTHOR]

5-Fluorouracil has demonstrated certain efficiency in patients with colorectal cancer. However, significant side effects of use by injection are common. To address this issue defects, a reengineered 5′-deoxy-5-fluorocytidine (DFCR) based drug delivery system (POACa) is developed as a prominent tumor-selective nano-activator. Investigations demonstrate that the constructed nano-activator exhibits good biocompatibility and high therapeutic efficiency in mice with subcutaneous and orthotopic SW-480 colorectal tumors, as its activity is strictly dependent on the tumor-associated acid environment and thymidine phosphorylase. These strategies diminish the off-target toxicity and improve the specificity and sensitivity of human colorectal cancer cells to 5-Fu, obtaining potent efficiency by the combination of H 2 O 2 mediated oxidative stress, calcium overload and 5-Fu-induced chemotherapy (the combination index is 0.11). Overall, the engineered nano-activator exhibits a high therapeutic index in vitro and in vivo. In this study, we designed and prepared a pH-responsive polymer to synchronously deliver DFCR (5′-deoxy-5-fluorocytidine, a prodrug of 5-Fu), Ca2+ and H 2 O 2. The constructed nano-activator was denoted as POACa. (1) To address the problem of premature leakage of cargo by physical embedding, our research modified the inactive prodrug DFCR through chemical bonding. (2) The activation of the prepared nano-activator was strictly dependent on the tumor-associated acid environment and thymidine phosphorylase, providing the drug delivery system with inherent safety. (3) A distinctly low combination index value (0.11) of CaO 2 and DFCR indicated that POACa has a prominent tumor suppression effect by tumor calcium overload sensitized chemotherapy and H 2 O 2 mediated cytotoxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

The increasing use of hyaluronic acid (HA) implants has made adverse effects more apparent. Here, we present a rare case of massive allergic dermatitis due to HA injections. We performed dermoscopy and color ultrasound, which clarified that this was an allergic dermatitis caused by fillers, and analyzed the possible causes of the allergy. Common treatments were compared, and the advantages of 5-FU-based treatment regimens and their associated mechanisms were noted. A low dose of 5-fluorouracil and triamcinolone acetonide was administered to the patient's entire face and neck, and significant efficacy was achieved. We aimed to gather evidence on extensive dermatitis caused by HA injection, provide new perspectives and solutions for subsequent HA injections, and promote further research on the potential mechanisms of extensive skin inflammation and allergies caused by local HA injections. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU) is widely used in chemotherapy but poses serious risks of cardiotoxicity, which can significantly affect treatment outcomes. Identifying interventions that can prevent these adverse effects without undermining anticancer efficacy is crucial. This study investigates the efficacy of Thymoquinone (TQ) and Hesperidin (HESP) in preventing cardiotoxicity induced by 5-FU in Wistar rats and elucidates the molecular interactions through docking studies. We employed an experimental design involving multiple groups of Wistar rats exposed to 5-FU, with and without the concurrent administration of TQ and HESP. Cardiac function markers, oxidative stress indicators, and inflammatory markers were assessed. Additionally, molecular docking was used to analyze the interaction of TQ and HESP with key inflammatory proteins. Treatment with TQ and HESP not only lowered levels of cardiac enzymes but also improved antioxidant capacity and reduced inflammation in cardiac tissues. Notably, the combination of TQ and HESP provided more significant protective effects than either agent alone. Molecular docking supported these findings, showing effective binding of TQ and HESP to inflammatory targets. TQ and HESP demonstrate potential as protective agents against cardiotoxicity in 5-FU-treated rats, with their combined use offering enhanced protection. These findings suggest a viable strategy for reducing cardiac risks associated with 5-FU chemotherapy. [ABSTRACT FROM AUTHOR]

Colon cancer is the third most common cancer worldwide, with high mortality. Adverse side effects and chemoresistance of the first-line chemotherapy 5-fluorouracil (5-FU) have promoted the widespread use of combination therapies. Thymoquinone (TQ) is a natural compound with potent antioxidant activity. Loading antioxidants into nano delivery systems has been a major advance in enhancing their bioavailability to improve clinical application. Hence, this study aimed to prepare the optimal TQ-loaded calcium carbonate nanoparticles (TQ-CaCO3 NPs) and investigate their therapeutic potential and underlying molecular mechanisms of TQ-CaCO3 NPs in combination with 5-FU against colon cancer. Firstly, we developed purely aragonite CaCO3 NPs with a facile mechanical ball-milling method. The pH-sensitive and biocompatible TQ-CaCO3 NPs with sustained release properties were prepared using the optimal synthesized method (a high-speed homogenizer). The in vitro study revealed that the combination of TQ-CaCO3 NPs (15 μM) and 5-FU (7.5 μM) inhibited CT26 cell proliferation and migration, induced cell apoptosis and cell cycle arrest in the G0/G1 phase, and suppressed the CT26 spheroid growth, exhibiting a synergistic effect. Finally, network pharmacology and molecular docking results indicated the potential targets and crucial signaling pathways of TQ-CaCO3 NPs in combination with 5-FU against colon cancer. Therefore, TQ-CaCO3 NPs combined with 5-FU could enhance the anti-colon cancer effects of 5-FU with broader therapeutic targets, warranting further application for colon cancer treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Cancer and diabetes mellitus are quite common diseases found together worldwide. A considerable amount of evidence is available for the rapid development and presentation of various types of cancer in the type 2 diabetes mellitus (DM2) population as compared with the population without diabetes. The objective of the study is to formulate and evaluate 5-fluorouracil (5-FU) and metformin (MET) nanoparticles (NPs) and to establish the characteristic features of the biodegradable NPs. 5-FU and MET NPs with chitosan as a biodegradable polymer were formulated by the ionotropic cross-linking method. 0.25 gm of MET and 0.25 gm of 5-FU were dissolved in 100 ml of distilled water, and stock solution was prepared. 5 ml of stock solution was slowly mixed into the chitosan solution to obtain the mixture of drugs and chitosan. The tripolyphosphate reserve liquid was dripped slowly into the chitosan solution with constant stirring until the opaline appearance was noticed in the mixture, then filtered, and dried. The NPs were evaluated for their physical properties and drug release kinetics. Cell proliferation assay was done using human colorectal carcinoma cell line (HCT 116). Results The formulation composed of 1.5 w/v of chitosan, 0.25 w/v of MET, and 5-FU had an average particle diameter of 198.7 nm. The polydispersity index was 0.757. Thermal and infrared spectroscopy results indicated the drugs and polymers selected for the formulation were unique without any identifiable interaction. The NPs were spherical in appearance, with numerous pours on the surface, which was evident when microscopically examined. Uniformity in drug release was observed, and the formulation demonstrated excellent release kinetics. HTC 116 cell line confirmed that the maximum percentage of cell death and minimum viability of cells were observed while using the combination of MET and 5-FU-NPs as compared to the pure MET or 5-FU alone. Conclusion MET and 5-FU-loaded chitosan NPs were found to have excellent physiochemical properties, particle size, and drug release from the polymer in a controlled manner. Half-maximal inhibitory concentration value (IC50) of MET and 5-FU-NPs was found to be significantly less as compared to MET and 5-FU alone or the combination.

Abstract A 74-year-old Chinese man underwent extracapsular cataract extraction in his right eye and developed a translucent iris membrane 4 months later. He was treated with two intracameral 5-FU injections and membranectomy at 2 weeks apart. At one year following the second membranectomy, the patient maintained a clear cornea without residual or recurrent membrane, an endothelial cell density of 1072 cell/mm2, a visual acuity of 20/50 and a normal intraocular pressure. Our technique of using dispersive and cohesive viscoelastics in protecting the corneal endothelium from intracameral 5-FU, helped preserve corneal endothelial cells and maintain corneal clarity at one year after surgery.

Introduction: The use of antineoplastic drugs in cancer treatment, while essential, poses risks due to their non-selective action on both cancerous and healthy cells. Assessing and controlling environmental contamination with these drugs in workplaces is crucial. This study aimed to evaluate the efficacy of various commercial wipes in sampling the antineoplastic drug 5-fluorouracil from surfaces to develop standardized sampling methods. Material and Methods: This study assessed the efficiency of commonly used commercial wipes (Whatman cellulose filter, cotton swab, Millipore™ filter, sterile gauze pad, and alcohol pad) for sampling 5-fluorouracil from different surfaces (stainless steel, vinyl, and ceramic). The sampling area was defined using disposable cardboard frames, and 1000 microliters of a 1 µg/mL 5-fluorouracil solution were applied to each surface. Sampling and extraction were conducted following NIOSH guidelines. The frame dimensions were 10 × 10 cm, limiting the sampling area to 100 square centimeters. Analysis was performed using high-performance liquid chromatography (HPLC), and results were analyzed using Prism GraphPad software, version 8. Results: The sampling efficiency varied across wipes and surfaces, ranging from 11.2% to 86.2%. Alcohol pads showed the highest efficiency on stainless steel surfaces, while the Millipore™ filter had the lowest efficiency across all surfaces. Extraction efficiency ranged from 43.8% to 98.8%, with alcohol pads providing the highest recovery. Sample stability was maintained over 15 days. Conclusion: Alcohol pads were most effective in collecting and extracting 5-fluorouracil, particularly from hard, smooth surfaces such as stainless steel and ceramic. These findings may improve sampling methods, thereby reducing occupational exposure to antineoplastic drugs. Further research on different wipes and extraction parameters could refine drug analysis techniques.

Abstract 5-Fluorouracil (5-FU) is the leading chemotherapeutic drug used to treat hepatocellular carcinoma, one of the major cancer diseases after atherosclerosis. Because of chemo-resistance, the success rate of treatment declines with time due to continuous drug exposure. Though autophagy induction is majorly responsible for acquired resistance, the exact role of this evolutionary conserved mechanism is unknown in cancer cell survival and suppression. The usual practice involves the combinatorial use of chemotherapeutic drugs with autophagy inhibitors like Chloroquine and Bafilomycin A, while neglecting the side effects caused by autophagy impairment in healthy cells. Starvation is a well-known physiological inducer of autophagy. In this study, by caloric modulation, we tried to circumvent the resistance imposed by prolonged drug exposure and investigated the effect of 5-FU in nutrient-sufficient and deficient conditions. Our findings show a substantial correlation between autophagy and increased cancer cell death in the presence of 5-FU, with negligible effects on normal cells. Experimental data revealed that nutritional deprivation augmented cell death in the presence of 5-FU through mitochondrial membrane damage and excessive reactive oxygen species (ROS) production, initiating apoptosis. Lipidation study also unveiled that under such combinatorial treatment cellular metabolism shifts from glucose to lipid biosynthesis. Overall, our experimental findings suggest that nutritional deprivation in combination with chemotherapeutic medication can be a new effective strategy to control hepatocellular carcinoma.

Abstract 5-Fluorouracil (5-FU) is used as a standard first-line drug for colorectal cancer malignancy (CRC), but it brings a series of side effects such as severe diarrhea and intestinal damage. Our previous study found that a large number of senescent cells increased while 5-Fu induced intestinal damage, and anti-senescence drugs can alleviate its side effects of inflammatory damage. Oleanolic acid (OA) is a common pentacyclic triterpenoid mainly derived from food fungi and medicinal plants, and studies have shown that it mainly possesses hepatoprotective, enzyme-lowering, anti-inflammatory, and anti-tumor effects. But its role in senescence is still unclear. In the present study, we demonstrated for the first time that OA ameliorated 5-Fu-induced human umbilical vein endothelial cells (HUVECs) and human normal intestinal epithelial cells (NCM460) in a 5-Fu-induced cellular senescence model by decreasing the activity of SA-β-gal-positive cells, and the expression of senescence-associated proteins (p16), senescence-associated genes (p53 and p21), and senescence-associated secretory phenotypes (SASPs: IL-1β, IL-6, IL-8, IFN-γ and TNF-α). Meanwhile, in this study, in a BALB/c mouse model, we demonstrated that 5-FU induced intestinal inflammatory response and injury, which was also found to be closely related to the increase of senescent cells, and that OA treatment was effective in ameliorating these adverse phenomena. Furthermore, our in vivo and in vitro studies showed that OA could alleviate senescence by inhibiting mTOR. In colon cancer cell models, OA also enhanced the ability of 5-FU to kill HCT116 cells and SW480 cells. Overall, this study demonstrates for the first time the potential role of OA in counteracting the side effects of 5-FU chemotherapy, providing a new option for the treatment of colorectal cancer to progressively achieve the goal of high efficacy and low toxicity of chemotherapy.

Abstract Background Fluoropyrimidines are chemotherapy drugs utilized to treat a variety of solid tumors. These drugs predominantly rely on the enzyme dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene, for their metabolism. Genetic mutations affecting this gene can cause DPYD deficiency, disrupting pyrimidine metabolism and increasing the risk of toxicity in cancer patients treated with 5-fluorouracil. The severity and type of toxic reactions are influenced by genetic and demographic factors and, in certain instances, can result in patient mortality. Among the more than 50 identified variants of DPYD, only a subset has clinical significance, leading to the production of enzymes that are either non-functional or impaired. The study aims to examine treatment-related mortality in cancer patients undergoing fluoropyrimidine chemotherapy, comparing those with and without DPD deficiency. Methods The meta-analysis selected and evaluated 9685 studies from Pubmed, Cochrane, Embase and Web of Science databases. Only studies examining the main DPYD variants (DPYD*2A, DPYD p.D949V, DPYD*13 and DPYD HapB3) were included. Statistical Analysis was performed using R, version 4.2.3. Data were examined using the Mantel-Haenszel method and 95% CIs. Heterogeneity was assessed with I2 statistics. Results There were 36 prospective and retrospective studies included, accounting for 16,005 patients. Most studies assessed colorectal cancer, representing 86.49% of patients. Other gastrointestinal cancers were evaluated by 11 studies, breast cancer by nine studies and head and neck cancers by five studies. Four DPYD variants were identified as predictors of severe fluoropyrimidines toxicity in literature review: DPYD*2A (rs3918290), DPYD p.D949V (rs67376798), DPYD*13 (rs55886062) and DPYD Hap23 (rs56038477). All 36 studies assessed the DPYD*2A variant, while 20 assessed DPYD p.D949V, 7 assessed DPYD*13, and 9 assessed DPYDHap23. Among the 587 patients who tested positive for at least one DPYD variant, 13 died from fluoropyrimidine toxicity. Conversely, in the non-carrier group there were 14 treatment-related deaths. Carriers of DPYD variants was found to be significantly correlated with treatment-related mortality (OR = 34.86, 95% CI 13.96–87.05; p

Abstract Purpose To report the demographic profile, clinical presentation, and management outcomes of ocular surface squamous neoplasia (OSSN) treated with primary topical chemotherapy in a limited resource secondary eye care facility in rural parts of South India. Methods Retrospective interventional study of 38 eyes of 37 patients with OSSN treated with topical 1% 5-Fluorouracil (5FU), over a period of two years. Results The median age at presentation with OSSN was 44 years (mean, 46 years; range 13 to 74 years). Majority (76%) were males. The most common morphological variant was placoid OSSN (18, 47%). Limbus was the most common epicenter (31, 82%). Corneal OSSN was the most initially misdiagnosed variant (n = 3). Of the 38 eyes receiving one week on and 3-weeks off cycles of 5FU regimen, complete tumor resolution was achieved in 36 (95%) eyes. The median number of topical 5FU cycles for tumor resolution was 2 (mean, 2; range, 1 to 4). Over a median follow-up period of 5 months (mean, 6 months; range, 1 to 27 months), tumor recurrence was noted in 3 eyes (8%), of which one case had xeroderma pigmentosum with bilateral multifocal recurrence. Complication rate was 5% (n = 2), which included transient conjunctival hyperemia (n = 1), and bacterial keratitis (n = 1) which resolved with fortified antibiotics. Conclusion Primary chemotherapy with topical 1% 5FU is a safe and effective management modality for OSSN at limited resource settings in rural India.

Fluorouracil (5-Fu, 1) is an antimetabolite cancer drug and the first-line drug of anticancer administration by WHO that has been widely used worldwide for more than 50 years. The development of 5-fluorouracil is an effort to obtain higher activity, decrease side effects, and create a specific target receptor compared to 5-fluorouracil. In this research, a series of novel 5-Fluorouracil (5-Fu) derivatives has been synthesized based on a benzoylation reaction (Schotten-Baumann reaction) of N1-hydroxylated 5-Fu called compound 2, 5-fluoro-1-(hydroxymethyl)-uracil. The benzoyl chloride substituents used in this research, including 3-chlorobenzoyl (4a), 2-chlorobenzoyl (4b), 3-nitrobenzoyl (4c), 4-methoxy benzoyl (4d), 4-trifluoromethylbenzoyl (4e), 3,4-dichlorobenzoyl (4f), and 4-nitrobenzoyl (4g) chloride become (4a-4f)-5Fu. This research meticulously examined the conditions (time and reaction temperature) at the second step of the synthesis reaction (esterification), ensuring the reliability of the results. The best synthesis conditions for 4a, 4b, 4c, 4d, and 4g compounds were found to be reflux at 40°C for 6 hours, whereas 4e and 4f compounds reactions were performed in an ice bath for 11 and 17 hours, respectively. All product syntheses, 4a-4g compound, were purified using column chromatography and eluted using eluent hexane: acetone (6:4), and the yields of 4a-4g compounds were around 61-79%. The pure compounds were characterized using FTIR and 1HNMR spectrometer, further validating the research. Based on these findings, it can be concluded that all 5-Fu derivatives can be synthesized using the Schotten-Baumann reaction method.

Abstract 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.

Objective: Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme that degrades uracil, thymine, and 5-fluorouracil, which are important for treating gastric, colorectal, and breast cancers. In this study, we aimed to determine the association between chemotherapy-related toxicities and DPD gene variants; evaluate the consequences of these genetic differences; and integrate DPYD genetic screening into conventional cancer treatment regimens. Methods: Sixty-two patient files from 2015 to 2018 were retrospectively reviewed to investigate whether the DPYD gene causes toxicity before or during treatment. A total of 50 patients were enrolled after receiving informed consent and ethical clearance for the comprehensive examinations. The aim of this study was to reveal the genetic causes of adverse effects and better understand treatment responses. Results: Our analysis of 50 patients with cancer revealed that the severity of response to fluoropyrimidine compounds used in chemotherapy varied depending on DPYD gene polymorphisms. These mutations increased susceptibility to severe neutropenia -which can weaken immune systems- among other negative effects. It also found that IVS14 + 1G>A had a significant effect on treatment outcome, indicating that genetic screening should be included in planning therapy as it can prevent major side effects. Conclusion: Dihydropyrimidine connected to dehydrogenase gene polymorphism occurred in patients with gastrointestinal cancer who developed diarrhea, nausea, anemia, thrombostitopenia, and grade 3-4 neutropenia side effects while receiving 5-FU.

Yixin Li,1– 6,&ast; Qi Sun,2,3,7,&ast; Lingjia Hao,1,8 Han Shan,2,3,7 Zixi Jiang,1– 6 Ying Wang,1– 6 Zeyu Chen,2,3,7 Wu Zhu,1– 6 Shuang Zhao1– 6 1Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 2Furong Laboratory (Precision Medicine), Changsha, 410008, People’s Republic of China; 3National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 4Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 5Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 6National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 7School of Mechanical and Electrical Engineering, Central South University, Changsha, 410083, People’s Republic of China; 8Xiangya School of Medicine, Central South University, Changsha, 410083, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuang Zhao; Wu Zhu, Department of Dermatology, Xiangya Hospital of Central South University, 87 Xiangya Road, Kaifu District, Changsha, Hunan Province, People’s Republic of China, Email shuangxy@csu.edu.cn; zhuwuxy@csu.edu.cnIntroduction: Pathological scars, such as hypertrophic scars and keloids, are characterized by the proliferation of fibroblasts and the deposition of collagen that often cause pruritus, pain, and disfigurement. Due to their high incidence and deformity, pathological scars have resulted in severe physical and psychological trauma for patients. Intralesional injection of 5-fluorouracil (5-Fu) is a recommended option for treating pathological scars. However, the efficacy of 5-Fu injection was limited and unstable due to limited drug penetration and short retention time.Methods: Liposomes are promising carriers that have advantages, such as high biocompatibility, controlled release property, and enhanced clinical efficacy. Here, we constructed a transdermal 5-Fu-loaded liposome (5-Fu-Lip) to provide a more effective and safer modality to scar treatment.Results: Compared to 5-Fu, 5-Fu-Lip showed superior ability in inhibiting primary keloid fibroblasts proliferation, migration, and collagen deposition, and also significantly inhibited human umbilical vein endothelial cells (HUVECs) proliferation and microvessel construction. In vivo experiments demonstrated that 5-Fu-Lip can significantly reduce the severity of hypertrophic scars in a rabbit ear wounding model.Discussion: 5-Fu-Lip provides a promising strategy to improve drug efficacy, which has great potential in the treatment of pathological scars.Keywords: liposome, pathological scar, 5-fluorouracil, fibroblast

Background: Keloids and hypertrophic scars are a commonly encountered problem in dermatology. There are many treatment modalities available with variable efficacy and recurrences. This study highlights the use of hyaluronidase with triamcinolone acetonide (TAC) and 5-fluorouracil (5-FU). Purpose: To assess the utility of hyaluronidase in combination with TAC and 5-FU in treatment of hypertrophic scars and keloids. Methods: In this study a combination of hyaluronidase along with TAC and 5-FU was given in one part and a combination of TAC and 5-FU was given in another half of same hypertrophic scar/keloid keeping 1cm gap in between the two untreated at 4 weekly interval for 24 weeks. Results were assessed by measuring height, volume of lesion and their percentage decrease. Also, pliability, vascularity, pigmentation of lesion and Vancouver scar assessment scale score were assessed. Side effects like ulceration, surrounding skin atrophy and telangiectasias were noted. Results: There was a reduction in all the parameters in both the treatment segments. Faster improvement in height, volume, pliability, vascularity, pigmentation, and Vancouver scar assessment scale score was noted with combination of hyaluronidase, TAC, and 5-FU compared to TAC and 5-FU alone. Side effect profile of ulceration, surrounding skin atrophy and telangiectasias was comparable in both the segments. Conclusion: Combination of hyaluronidase along with TAC and 5-FU offered a better outcome and faster response when compared to combination of TAC and 5-FU.

Abstract Background and aims The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for the development of cardiovascular illnesses in individuals without pre-existing health conditions. However, it remains unclear whether the levels of SII are linked to cardiotoxicity related to 5-FU. This retrospective study aims to fill this knowledge gap by examining the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort. Methods The study comprised colorectal cancer patients who received 5-FU-based chemotherapy at the affiliated cancer hospital of Guizhou Medical University between January 1, 2018 and December 31, 2020. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were conducted. Results Of the 754 patients included final analysis, approximately 21% (n = 156) of them ultimately experienced cardiotoxicity related to 5-FU. Monocytes (M) was found as an influential element in the interaction between SII and cardiotoxicity related to 5-FU. In the low tertile of M (T1: M ≤ 0.38 × 109/L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a curvilinear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38 0.52 × 109/L), there was a tendency towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98). Conclusion Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1). Conversely, in the middle monocytes levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect.

Abstract Background 5-Fluorouracil (5-FU) is used as an antineoplastic agent in distinct cancer types. Increasing evidence suggests that the gut microbiota might modulate 5-FU efficacy and toxicity, potentially affecting the patient’s prognosis. The current experimental study investigated 5-FU-induced microbiota alterations, as well as the potential of prebiotic fibre mixtures (M1-M4) to counteract these shifts. Methods A pooled microbial consortium was derived from ten healthy donors, inoculated in an in vitro model of the colon, and treated with 5-FU, with or without prebiotic fibre mixtures for 72 h. Four different prebiotic fibre mixtures were tested: M1 containing short-chain galacto-oligosaccharides (sc GOS), long-chain fructo-oligosaccharides (lcFOS), and low viscosity pectin (lvPect), M2 consisting of arabinoxylan, beta-glucan, pectin, and resistant starch, M3 which was a mixture of scGOS and lcFOS, and M4 containing arabinoxylan, beta-glucan, pectin, resistant starch, and inulin. Results We identified 5-FU-induced changes in gut microbiota composition, but not in microbial diversity. Administration of prebiotic fibre mixtures during 5-FU influenced gut microbiota composition and taxa abundance. Amongst others, prebiotic fibre mixtures successfully stimulated potentially beneficial bacteria (Bifidobacterium, Lactobacillus, Anaerostipes, Weissella, Olsenella, Senegalimassilia) and suppressed the growth of potentially pathogenic bacteria (Klebsiella, Enterobacter) in the presence of 5-FU. The short-chain fatty acid (SCFA) acetate increased slightly during 5-FU, but even more during 5-FU with prebiotic fibre mixtures, while propionate was lower due to 5-FU with or without prebiotic fibre mixtures, compared to control. The SCFA butyrate and valerate did not show differences among all conditions. The branched-chain fatty acids (BCFA) iso-butyrate and iso-valerate were higher in 5-FU, but lower in 5-FU + prebiotics, compared to control. Conclusions These data suggest that prebiotic fibre mixtures represent a promising strategy to modulate 5-FU-induced microbial dysbiosis towards a more favourable microbiota, thereby possibly improving 5-FU efficacy and reducing toxicity, which should be evaluated further in clinical studies.

Prostate and bladder cancer treatments have several challenges, including intense side effects and mechanisms of resistance. Thus, it is urgent to find drugs that can fill these gaps. For this purpose, Entecavir (ETV) was tested alone and in combination with 5-Fluorouracil (5-FU). Prior to this, a preliminary computational analysis was conducted to evaluate the combination of these two drugs. After exposing PC-3 and UM-UC-5 cells to the drugs, cell morphology was assessed using a microscope, while cell viability, proliferation, and cytotoxicity were evaluated using the MTT assay, and finally, the statistical analysis was performed. It was concluded that ETV showed significant cytotoxic effects in the PC-3 cells, and 5-FU, although not as effective as in other tumor types, it managed to inhibit the viability of the PC-3 cells. The combination of 5-FU with ETV after 72 h of exposure is an advantageous association, surpassing the results of each drug alone. In the UM-UC-5 cells, ETV alone did not produce the expected effect, neither did the combination. Nevertheless, repurposing ETV has proven to be an effective strategy in PC, especially through its combination with 5-FU.

Background: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5‐fluorouracil (5‐FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5‐FU with Lut in PDACs. Methods and Results: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5‐FU. The xenograft tumors of DPYD‐overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA‐seq analysis of the DPYD‐overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity—MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5‐FU on DPYD‐overexpressing xenograft tumors and PDAC of Pdx1‐Cre; LSL‐KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5‐FU nor Lut showed significant inhibitory effects; however, the combined administration of 5‐FU and Lut exhibited a significant tumor‐suppressive effect in both the xenograft tumors and KPPC models. Conclusion: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5‐FU resistance, in PDACs. The combination therapy of Lut and 5‐FU holds the potential for enhanced efficacy against PDACs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Drug resistance is a major challenge in the treatment of advanced cholangiocarcinoma (CCA). Understanding the mechanisms of drug resistance can aid in identifying novel prognostic biomarkers and therapeutic targets to improve treatment efficacy. This study established 5-fluorouracil- (5-FU) and gemcitabine-resistant CCA cell lines, KKU-213FR and KKU-213GR, and utilized comparative proteomics to identify differentially expressed proteins in drug-resistant cells compared to parental cells. Additionally, bioinformatics analyses were conducted to explore the biological and clinical significance of key proteins. The drug-resistant phenotypes of KKU-213FR and KKU-213GR cell lines were confirmed. In addition, these cells demonstrated increased migration and invasion abilities. Proteomics analysis identified 81 differentially expressed proteins in drug-resistant cells, primarily related to binding functions, biological regulation, and metabolic processes. Protein–protein interaction analysis revealed a highly interconnected network involving MET, LAMB1, ITGA3, NOTCH2, CDH2, and NDRG1. siRNA-mediated knockdown of these genes in drug-resistant cell lines attenuated cell migration and cell invasion abilities and increased sensitivity to 5-FU and gemcitabine. The mRNA expression of these genes is upregulated in CCA patient samples and is associated with poor prognosis in gastrointestinal cancers. Furthermore, the functions of these proteins are closely related to the epithelial–mesenchymal transition (EMT) pathway. These findings elucidate the potential molecular mechanisms underlying drug resistance and tumor progression in CCA, providing insights into potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to compare the clinical outcomes of deep sclerectomy and trabeculectomy surgeries, both utilizing 5-fluorouracil. Methods: In this study, 11 eyes of 10 patients (14.3%) in the deep sclerectomy group and 66 eyes of 61 patients (85.7%) in the trabeculectomy group were retrospectively examined. Success in intraocular pressure (IOP) was defined as being below 21 mmHg without medication, partially successful if achieved below 21 mmHg with a single molecule, considered less successful with two to four molecules for maintaining IOP below 21 mmHg, and deemed unsuccessful if IOP exceeded 21 mmHg. Results: The deep sclerectomy group showed a success rate of 81.8% on post-operative day 1, with 18.2% considered unsuccessful; at post-operative 6 months, the success rate was 12.5%, with 50% partially successful and 37.5% less successful. In the trabeculectomy group, the success rate was 97% on post-operative day 1, with 3% considered unsuccessful; at post-operative 6 months, the success rate was 60.8%, with 15.7% partially successful, 13.7% less successful, and 9.8% unsuccessful. Trabeculectomy patients experienced complications such as choroidal detachment (6.1%), shallow anterior chamber (4.5%), tight suturing (3%), internal ostium occlusion (3%), posterior synechia (3%), bleb failure (1.5%), cyclodialysis/iridodialysis (1.5%), and hyphema (1.5%). In the deep sclerectomy group, tight suturing (36.3%), and dellen (9.09%) were observed, with no other complications reported. Conclusion: Trabeculectomy surgery has been observed to be superior to deep sclerectomy in follow-ups up to 48 months postoperatively. However, it is noted that there is a higher risk of post-operative complications. [ABSTRACT FROM AUTHOR]

Probiotics and prebiotics have gained attention for their potential health benefits. However, their efficacy hinges on probiotic survival through the harsh gastrointestinal environment. Microencapsulation techniques provide a solution, with resistant starch (RS)-based techniques showing promise in maintaining probiotic viability. Specifically, RS-encapsulated probiotics significantly improved probiotic survival in gastric acid, bile salts, and simulated intestinal conditions. This study investigated the effects of a resistant-starch-encapsulated probiotic cocktail (RS-Pro) in the context of 5-fluorouracil (5-FU) chemotherapy, which frequently induces microbiota dysbiosis and intestinal mucositis. Female BALB/c mice were divided into three groups: a 5-FU group, a 5-FU+Pro group receiving free probiotics, and a 5-FU+RS-Pro group receiving RS-encapsulated probiotics. After 28 days of treatment, analyses were conducted on fecal microbiota, intestinal histology, peripheral blood cell counts, and body and organ weights. It was revealed by 16S rRNA MiSeq sequencing that 5-FU treatment disrupted gut microbiota composition, reduced microbial diversity, and caused dysbiosis. RS-Pro treatment restored microbial diversity and increased the population of beneficial bacteria, such as Muribaculaceae, which play roles in carbohydrate and polyphenol metabolism. Furthermore, 5-FU administration induced moderate intestinal mucositis, characterized by reduced cellularity and shortened villi. However, RS-Pro treatment attenuated 5-FU-induced intestinal damage, preserving villus length. Mild leukopenia observed in the 5-FU-treated mice was partially alleviated in 5-FU+Pro and 5-FU+RS-Pro groups. These findings suggest that RS-Pro may serve as an adjunct to chemotherapy, potentially reducing adverse effects and improving therapeutic outcomes in future clinical applications. [ABSTRACT FROM AUTHOR]

Fluorouracil (5-Fu, 1) is an antimetabolite cancer drug and the first-line drug of anticancer administration by WHO that has been widely used worldwide for more than 50 years. The development of 5-fluorouracil is an effort to obtain higher activity, decrease side effects, and create a specific target receptor compared to 5-fluorouracil. In this research, a series of novel 5-Fluorouracil (5-Fu) derivatives has been synthesized based on a benzoylation reaction (Schotten-Baumann reaction) of N1-hydroxylated 5-Fu called compound 2, 5-fluoro-1- (hydroxymethyl)-uracil. The benzoyl chloride substituents used in this research, including 3-chlorobenzoyl (4a), 2-chlorobenzoyl (4b), 3-nitrobenzoyl (4c), 4-methoxy benzoyl (4d), 4-trifluoromethylbenzoyl (4e), 3,4-dichlorobenzoyl (4f), and 4-nitrobenzoyl (4g) chloride become (4a-4f)-5Fu. This research meticulously examined the conditions (time and reaction temperature) at the second step of the synthesis reaction (esterification), ensuring the reliability of the results. The best synthesis conditions for 4a, 4b, 4c, 4d, and 4g compounds were found to be reflux at 40°C for 6 hours, whereas 4e and 4f compounds reactions were performed in an ice bath for 11 and 17 hours, respectively. All product syntheses, 4a-4g compound, were purified using column chromatography and eluted using eluent hexane: acetone (6:4), and the yields of 4a-4g compounds were around 61-79%. The pure compounds were characterized using FTIR and 1HNMR spectrometer, further validating the research. Based on these findings, it can be concluded that all 5-Fu derivatives can be synthesized using the Schotten-Baumann reaction method. [ABSTRACT FROM AUTHOR]

Our current study reports the successful synthesis of thiolated chitosan-based nanoparticles for targeted drug delivery of 5-Fluorouracil. This process was achieved through the ionic gelation technique, aiming to improve the efficacy of the chemotherapeutic moiety by modifying the surface of the nanoparticles (NPs) with a ligand. We coated these NPs with hyaluronic acid (HA) to actively target the CD44 receptor, which is frequently overexpressed in various solid malignancies, including breast cancer. XRD, FTIR, SEM, and TEM were used for the physicochemical analysis of the NPs. These 5-Fluorouracil (5-FU) loaded NPs were evaluated on MDA-MB-231 (a triple-negative breast cell line) and MCF-10A (normal epithelial breast cells) to determine their in vitro efficacy. The developed 5-FU-loaded NPs exhibited a particle size within a favorable range (< 300 nm). The positive zeta potential of these nanoparticles facilitated their uptake by negatively charged cancer cells. Moreover, they demonstrated robust stability and achieved high encapsulation efficiency. These nanoparticles exhibited significant cytotoxicity compared to the crude drug (p < 0.05) and displayed a promising release pattern consistent with the basic diffusion model. These traits improve the pharmacokinetic profile, efficacy, and ability to precisely target these nanoparticles, offering a potentially successful anticancer treatment for breast cancer. However, additional in vivo assessments of these formulations are obligatory to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: 5-Fluorouracil (5-FU) is a chemotherapy drug commonly used in the treatment of colon cancer. There is a significant drive to mitigate the limitations of 5-fluorouracil while maintaining its therapeutic potency by exploring the potential of using natural products such as curcumin in conjunction with 5-FU. Thus, the present study investigates the in vitro pharmacodynamic interaction between 5-FU and curcumin using the Chou-Talalay method in HT29 cell lines. Materials and Methods: Initially, the estimation of half-maximal concentration of the medications against HCT116 and HT29 cell lines was performed by 3-4,5-dimethylthiazol-2-yl-2,5 diphenyl tetrazolium bromide assay. Later, the combination effect was studied in HT29 cell lines by constant ratio experiment design. Results and Discussion: The research findings revealed that the 5-FU and curcumin exhibit dose-dependent anti-proliferative activity in HCT116 and HT29 cells. Moreover, it was observed that HT29 cell lines are less sensitive to 5-FU than HCT116 cell lines, rather than curcumin was found to inhibit cell proliferation in both cell lines with no significant statistical difference (p<0.05). The Combination Index (CI) values of less than 1 for all the combined experimental ratios indicated the synergistic effect of the two compounds. The generated Dose Reduction Index (DRI) values for the combination imply for the favourable dose reduction in the treatment of colorectal cancer. Conclusion: Significantly, the study indicates that 40:1 ratio of 5-FU to curcumin might represent an ideal proportion for co-administration using an appropriate delivery system. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The microbiome is capable of modulating the bioavailability of chemotherapy drugs, mainly due to metabolizing these agents. Multiple cytostatic bacterial metabolites were recently identified that have cytostatic effects on cancer cells. In this study, we addressed the question of whether a set of cytostatic bacterial metabolites (cadaverine, indolepropionic acid and indoxylsulfate) can interfere with the cytostatic effects of the chemotherapy agents used in the management of breast cancer (doxorubicin, gemcitabine, irinotecan, methotrexate, rucaparib, 5-fluorouracil and paclitaxel). The chemotherapy drugs were applied in a wide concentration range to which a bacterial metabolite was added in a concentration within its serum reference range, and the effects on cell proliferation were assessed. There was no interference between gemcitabine, irinotecan, methotrexate or rucaparib and the bacterial metabolites. Nevertheless, cadaverine and indolepropionic acid modulated the Hill coefficient of the inhibitory curve of doxorubicin and 5-fluorouracil. Changes to the Hill coefficient implicate alterations to the kinetics of the binding of the chemotherapy agents to their targets. These effects have an unpredictable significance from the clinical or pharmacological perspective. Importantly, indolepropionic acid decreased the IC50 value of paclitaxel, which is a potentially advantageous combination. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU) is a chemotherapeutic agent used in therapies for both systematically and topical treatment of different types of cancers. Depending on the period of application, its administration may lead to different side effects such as nausea, headache, pain or even photosensitivity. To avoid them, the drug may be encapsulated into polymeric particles. In the present study, bio polymeric spheres based on chitosan, a linear polysaccharide, are presented. The spheres are formulated by an emulsion technique with solvent evaporation. Three types of particles are synthesized: without crosslinker, with sodium tripolyphosphate and glutaraldehyde crosslinker. The resultant structures are evaluated regarding their size, morphology, and encapsulation efficiency. The crosslinking process and the drug presence in the particles is confirmed by FT-IR. A drug release study is conducted to examine the release kinetics and understand the release behaviour depending on the presence and the type of the crosslinker. [ABSTRACT FROM AUTHOR]

The molecular mechanisms governing the response of hematopoietic stem cells (HSCs) to stress insults remain poorly defined. Here, we investigated effects of conditional knock-out or overexpression of Hmga2 (High mobility group AT-hook 2), a transcriptional activator of stem cell genes in fetal HSCs. While Hmga2 overexpression did not affect adult hematopoiesis under homeostasis, it accelerated HSC expansion in response to injection with 5-fluorouracil (5-FU) or in vitro treatment with TNF-α. In contrast, HSC and megakaryocyte progenitor cell numbers were decreased in Hmga2 KO animals. Transcription of inflammatory genes was repressed in Hmga2 -overexpressing mice injected with 5-FU, and Hmga2 bound to distinct regions and chromatin accessibility was decreased in HSCs upon stress. Mechanistically, we found that casein kinase 2 (CK2) phosphorylates the Hmga2 acidic domain, promoting its access and binding to chromatin, transcription of anti-inflammatory target genes, and the expansion of HSCs under stress conditions. Notably, the identified stress-regulated Hmga2 gene signature is activated in hematopoietic stem progenitor cells of human myelodysplastic syndrome patients. In sum, these results reveal a TNF-α/CK2/phospho-Hmga2 axis controlling adult stress hematopoiesis. Synopsis: The molecular mechanisms controlling the response of hematopoietic stem cells (HSCs) to insults remain poorly defined. Here, genetic data support a critical role of chromatin modifier Hmga2 in stress-induced regeneration of the adult murine blood system. Conditional depletion of Hmga2 does not affect steady-state hematopoiesis but impairs HSC response to 5-fluorouracil (5-FU) in adult mice. Under stress, CK2 kinase phosphorylates Hmga2 in TNF-α-dependent manner, promoting its chromatin binding and repression of inflammatory genes by transcription factor Rfx5. The identified stress-induced Hmga2 gene signature is activated in hematopoietic stem and progenitor cells of human myelodysplastic syndrome patients. A TNF-a/CK2/phospho-HMGA2 axis controls chromatin accessibility, transcription, and expansion of blood stem cells in response to stress. [ABSTRACT FROM AUTHOR]

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Colorectal cancer is one of the most common causes of cancer mortality worldwide, and innovative drugs for the treatment of colorectal cancer are continually being developed. 5-Fluorouracil (5-FU) is a common clinical chemotherapeutic drug. Acquired resistance to 5-FU is a clinical challenge in colorectal cancer treatment. Parecoxib is a selective COX-2-specific inhibitor that was demonstrated to inhibit metastasis in colorectal cancers in our previous study. This study aimed to investigate the synergistic antimetastatic activities of parecoxib to 5-FU in human colorectal cancer cells and determine the underlying mechanisms. Parecoxib and 5-FU synergistically suppressed metastasis in colorectal cancer cells. Treatment with the parecoxib/5-FU combination induced an increase in E-cadherin and decrease in β-catenin expression. The parecoxib/5-FU combination inhibited MMP-9 activity, and the NF-κB pathway was suppressed as well. Mechanistic analysis denoted that the parecoxib/5-FU combination hindered the essential molecules of the PI3K/Akt route to obstruct metastatic colorectal cancer. Furthermore, the parecoxib/5-FU combination could inhibit reactive oxygen species. Our work showed the antimetastatic capacity of the parecoxib/5-FU combination for treating colorectal cancers via the targeting of the PI3K/Akt/NF-κB pathway. [ABSTRACT FROM AUTHOR]

According to our preliminary study, melatonin and its N-amide derivatives (N-(2-(1-4-bromobenzoyl-5-methoxy-1H-indol-3-yl)ethyl)acetamide (BBM) and 4-bromo-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)benzamide (EBM)) inhibited the marker of acute inflammation in tests in vitro and in vivo. The anti-inflammatory agent is intended for the prevention and treatment of chemotherapy-induced toxicity. In this study aimed to evaluate the effect of melatonin and its derivatives on mechanisms related to chemotherapy-induced oral mucositis by in vitro ROS and 5-FU-induced human keratinocyte cells as well as in vivo oral mucositis model. In in vitro H2O2-induced HaCaT cells, BBM had the highest level of protection (34.57%) at a concentration 50 µM, followed by EBM (26.41%), and melatonin (7.9%). BBM also protected cells against 5-FU-induced to 37.69–27.25% at 12.5–100 µM while EBM was 36.93–29.33% and melatonin was 22.5–11.39%. In in vivo 5-FU-induced oral mucositis in mice, melatonin, BBM, and EBM gel formulations protected tissue damage from 5-FU similar to the standard compound, benzydamine. Moreover, the weight of mice and food consumption recovered more quickly in the BBM group. These findings suggested that it was possible to develop BBM and EBM as new therapeutic agents for the treatment of oral mucositis. [ABSTRACT FROM AUTHOR]

Background and aims: The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for the development of cardiovascular illnesses in individuals without pre-existing health conditions. However, it remains unclear whether the levels of SII are linked to cardiotoxicity related to 5-FU. This retrospective study aims to fill this knowledge gap by examining the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort. Methods: The study comprised colorectal cancer patients who received 5-FU-based chemotherapy at the affiliated cancer hospital of Guizhou Medical University between January 1, 2018 and December 31, 2020. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were conducted. Results: Of the 754 patients included final analysis, approximately 21% (n = 156) of them ultimately experienced cardiotoxicity related to 5-FU. Monocytes (M) was found as an influential element in the interaction between SII and cardiotoxicity related to 5-FU. In the low tertile of M (T1: M ≤ 0.38 × 109/L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a curvilinear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38 < M ≤ 0.52 × 109/L). An increase in log SII above 1.37 was shown to be associated with a decreased risk of cardiotoxicity (OR, 0.14; 95%CI, 0.02 to 0.88), indicating a threshold effect. In the high tertile of M (T3: M > 0.52 × 109/L), there was a tendency towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98). Conclusion: Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1). Conversely, in the middle monocytes levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect. [ABSTRACT FROM AUTHOR]

Background: 5-Fluorouracil (5-FU) is used as an antineoplastic agent in distinct cancer types. Increasing evidence suggests that the gut microbiota might modulate 5-FU efficacy and toxicity, potentially affecting the patient's prognosis. The current experimental study investigated 5-FU-induced microbiota alterations, as well as the potential of prebiotic fibre mixtures (M1-M4) to counteract these shifts. Methods: A pooled microbial consortium was derived from ten healthy donors, inoculated in an in vitro model of the colon, and treated with 5-FU, with or without prebiotic fibre mixtures for 72 h. Four different prebiotic fibre mixtures were tested: M1 containing short-chain galacto-oligosaccharides (sc GOS), long-chain fructo-oligosaccharides (lcFOS), and low viscosity pectin (lvPect), M2 consisting of arabinoxylan, beta-glucan, pectin, and resistant starch, M3 which was a mixture of scGOS and lcFOS, and M4 containing arabinoxylan, beta-glucan, pectin, resistant starch, and inulin. Results: We identified 5-FU-induced changes in gut microbiota composition, but not in microbial diversity. Administration of prebiotic fibre mixtures during 5-FU influenced gut microbiota composition and taxa abundance. Amongst others, prebiotic fibre mixtures successfully stimulated potentially beneficial bacteria (Bifidobacterium, Lactobacillus, Anaerostipes, Weissella, Olsenella, Senegalimassilia) and suppressed the growth of potentially pathogenic bacteria (Klebsiella, Enterobacter) in the presence of 5-FU. The short-chain fatty acid (SCFA) acetate increased slightly during 5-FU, but even more during 5-FU with prebiotic fibre mixtures, while propionate was lower due to 5-FU with or without prebiotic fibre mixtures, compared to control. The SCFA butyrate and valerate did not show differences among all conditions. The branched-chain fatty acids (BCFA) iso-butyrate and iso-valerate were higher in 5-FU, but lower in 5-FU + prebiotics, compared to control. Conclusions: These data suggest that prebiotic fibre mixtures represent a promising strategy to modulate 5-FU-induced microbial dysbiosis towards a more favourable microbiota, thereby possibly improving 5-FU efficacy and reducing toxicity, which should be evaluated further in clinical studies. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a global health concern, necessitating adjuvant chemotherapy post-curative surgery to mitigate recurrence and enhance survival, particularly in intermediate-stage patients. However, existing therapeutic disparities highlight the need for biomarker-guided adjuvant chemotherapy to achieve better CRC inhibition. This study explores the molecular mechanisms underlying the inhibition of CRC through a genome-wide association study (GWAS) focused on 5-fluorouracil (5-FU)-based adjuvant therapy in intermediate-stage CRC patients, a domain previously unexplored. We retrospectively included 226 intermediate-stage CRC patients undergoing surgical resection followed by 5-FU-based adjuvant chemotherapy. The exploration cohort comprised 31 patients, and the validation cohort included 195 individuals. Genotyping was carried out using either Axiom Genome-Wide TWB 2.0 Array Plate-based or polymerase chain reaction-based methods on genomic DNA derived from collected tissue samples. Statistical analyses involved descriptive statistics, Kaplan–Meier analyses, and Cox proportional hazard analyses. From the GWAS, potential genetic predictors, GALNT14-rs62139523 and DNMBP-rs10786578 genotypes, of 5-FU-based adjuvant therapy following surgery in intermediate-stage CRC patients were identified. Validation in a larger cohort of 195 patients emphasized the predictive significance of GALNT14-rs62139523 genotypes, especially the "A/G" genotype, for improved overall and progression-free survival. This predictive association remained robust across various subgroups, with exceptions for specific demographic and clinical parameters such as age < 58 years old, CEA ≤ 2.5 ng/mL, tumor diameter > 44.0 mm, and tumor-free margin ≥ 50 mm. This study identifies that the GALNT14-rs62139523 "A/G" genotype modulates therapeutic outcomes, establishing it as a promising biomarker for predicting favorable responses to 5-FU-based adjuvant chemotherapy in intermediate-stage CRC patients, although further investigations are needed to detail these mechanisms. [ABSTRACT FROM AUTHOR]

L-arginine can produce nitric oxide (NO) under the action of inducible nitric oxide synthase (iNOS), while 5-fluorouracil (5-FU) can induce the increase of iNOS expression. The present study was to investigate the mechanism of L-arginine combined with 5-FU regulating glucose metabolism of hepatocellular carcinoma (HCC) through iNOS/NO/AKT pathway. The combination of L-arginine and 5-FU resulted in decreased cell survival and exhibited synergistic cytotoxic effects in HepG2 and SMMC7721 cells. Meanwhile, L-arginine increased 5-FU inhibitory effect on HepG2 and SMMC7721 cells by increasing NO production. Cotreatment with L-arginine and 5-FU resulted in a significant decrease in both G6PDH and LDH enzymatic activities, as well as reduced levels of ATP and LD compared to treatment with L-arginine or 5-FU alone. Moreover, the combination of L-arginine and 5-FU resulted in a decrease in the expression of GLUT1, PKM2, LDHA, p-PI3K and p-AKT. Furthermore, the combination demonstrated a synergistic effect in downregulating the expression of HIF-1a and ß-catenin, which were further diminished upon the addition of shikonin, a specific inhibitor of PKM2. LY294002 treatment further reduced the expression of GLUT1, PKM2, and LDHA proteins induced by combined L-arginine and 5-FU treatment compared to the combined group. However, the reduction in p-PI3K, p-AKT, and GLUT1 expression caused by L-arginine and 5-FU combination was also reversed in HepG2 and SMMC7721 cells with iNOS knockdown, respectively. Additionally, the combination of L-arginine and 5-FU led to a greater reduction in the enzymatic activity of ALT, AST, G6PDH and LDH, as well as a significant reduction in hepatic index, AFP, AFP-L3, ATP and LD levels in a rat model of HCC. Moreover, the simultaneous administration of L-arginine and 5-FU significantly improved the gross morphology of the liver, reduced nuclear atypia, inhibited the proliferation of cancer cells, and decreased the expression levels of p-PI3K, p-AKT, GLUT1, PKM2, and LDHA, while iNOS expression was increased in the combination group. Taking together, L-arginine and 5-FU combination resulted in the inhibition of enzymes in aerobic glycolysis via the iNOS/NO/AKT pathway, which led to the suppression of glucose metabolism and downregulation of nuclear transcription factors, thereby impeding the proliferation of hepatocellular carcinoma cells. [ABSTRACT FROM AUTHOR]

Prostate and bladder cancer treatments have several challenges, including intense side effects and mechanisms of resistance. Thus, it is urgent to find drugs that can fill these gaps. For this purpose, Entecavir (ETV) was tested alone and in combination with 5-Fluorouracil (5-FU). Prior to this, a preliminary computational analysis was conducted to evaluate the combination of these two drugs. After exposing PC-3 and UM-UC-5 cells to the drugs, cell morphology was assessed using a microscope, while cell viability, proliferation, and cytotoxicity were evaluated using the MTT assay, and finally, the statistical analysis was performed. It was concluded that ETV showed significant cytotoxic effects in the PC-3 cells, and 5-FU, although not as effective as in other tumor types, it managed to inhibit the viability of the PC-3 cells. The combination of 5-FU with ETV after 72 h of exposure is an advantageous association, surpassing the results of each drug alone. In the UM-UC-5 cells, ETV alone did not produce the expected effect, neither did the combination. Nevertheless, repurposing ETV has proven to be an effective strategy in PC, especially through its combination with 5-FU. [ABSTRACT FROM AUTHOR]

Cyclodextrins (CDs) are cyclic oligosaccharides able to form noncovalent water-soluble complexes useful in many different applications for the solubilization, delivery, and greater bioavailability of hydrophobic drugs. The complexation of 5-fluorouracil (5-FU) with natural or synthetic cyclodextrins permits the solubilization of this poorly soluble anticancer drug. In this theoretical work, the complexes between β-CD and 5-FU are investigated using molecular mechanics (MM) and molecular dynamics (MD) simulations in water. The inclusion complexes are formed thanks to the favorable intermolecular interactions between β-CD and 5-FU. Both 1:1 and 1:2 β-CD/5-FU stoichiometries are investigated, providing insight into their interaction geometries and stability over time in water. In the 1:2 β-CD/5-FU complexes, the intermolecular interactions affect the drug's mobility, suggesting a two-step release mechanism: a fast release for the more exposed and hydrated drug molecule, with greater freedom of movement near the β-CD rims, and a slow one for the less-hydrated and well-encapsulated and confined drug. MD simulations study the intermolecular interactions between drugs and specific carriers at the atomistic level, suggesting a possible release mechanism and highlighting the role of the impact of the drug concentration on the kinetics process in water. A comparison with experimental data in the literature provides further insights. [ABSTRACT FROM AUTHOR]

4-O-Methyl-ascochlorin (MAC), a derivative of the prenyl–phenol antibiotic ascochlorin extracted from the fungus Ascochyta viciae, shows anticarcinogenic effects on various cancer cells. 5-Fluorouracil (5-FU) is used to treat colorectal cancer (CRC); however, its efficacy must be enhanced. In this study, we investigated the molecular mechanisms by which MAC acts synergistically with 5-FU to inhibit cell proliferation and induce apoptosis in CRC cells. MAC enhanced the cytotoxic effects of 5-FU by suppressing the Akt/mTOR/p70S6K and Wnt/β-catenin signaling pathways. It also reduced the viability of 5-FU-resistant (5-FU-R) cells. Furthermore, expression of anti-apoptosis-related proteins and cancer stem-like cell (CSC) markers by 5-FU-R cells decreased in response to MAC. Similar to MAC, the knockdown of CTNNB1 induced apoptosis and reduced expression of mRNA encoding CRC markers in 5-FU-R cells. In summary, these results suggest that MAC and other β-catenin modulators may be useful in overcoming the 5-FU resistance of CRC cells. [ABSTRACT FROM AUTHOR]