جستجوی مقالات مرتبط با کلیدواژه "fluorouracil" در نشریات گروه "پزشکی"

 Myeloid Derived Suppressor Cells (MDSCs) are capable of inhibiting both innate and adaptive immune responses and accumulate in the microenvironment of breast tumors. Hence, MDSC depletion by chemotherapeutic agents can improve clinical efficacy of cancer immunotherapy. The effects of 5-FU and doxorubicin agents on MDSC reduction in 4T1 breast cancer murine model were evaluated.

 5×105 of 4T1 tumor cells were injected into mammary fat pad of BALB/c female mice. Tumor bearing mice were randomly divided into 4 groups: PBS receiving control group, doxorubicin receiving groups at doses of 2.5 and 5 mg/kg, and 5-FU receiving group at dose of 50 mg/kg. Doxorubicin and 5-FU agents were intraperitoneally administrated at three doses with 5-day intervals and five doses for three times a week, respectively. Then, on day 20 post tumor cells injection, spleens and tumors were isolated to determine frequency of CD11b+ Gr1+ MDSCs by flow cytometry analysis.

 5-FU was able to reduce significantly both splenic and interatumoral MDSCs comparing to control group (p=0.0276 and p=0.0067, respectively). Also, Doxorubicin treatment at dose of 50 mg/kg was associated to a significant reduction of splenic MDSCs in comparison to untreated group (p=0.0382). However, only 5-FU injection led to inhibit notably tumor growth in comparison to control group (p=0.0139).

 Findings show that 5-FU has inhibitory effects on MDSCs and tumor growth in 4T1 tumor model. So, more investigations are needed to study combination of 5-FU with immune based approaches to enhance the efficacy of cancer therapies.

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-γ in the HT-29 cells.

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.

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-γ 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.

PLGA-5-FU NPs significantly suppressed expression of the IL-9, IL-17A, IL-23 and IFN-γ genes, and the encapsulation of 5-FU into PLGA improved considerably impact of the 5-FU on the HT-29 cells.

5-Fluorouracil (5-FU) is currently the main drug used in chemotherapy for gastric cancer (GC). The main clinical problems of 5-FU therapy are insensitivity and acquired resistance to 5-FU. The mechanism of GC cell resistance to 5-FU is currently unknown.

This study employed next-generation sequencing (NGS) to analyze the differentially expressed genes (DEGs) in chemotherapy-sensitive and non-sensitive GC tissues. In addition, a bioinformatics analysis was conducted using the GC dataset of GEO, and further validated and explored through in vitro experiments.

Thyroid adenoma-associated gene (THADA) was highly expressed in GC tissues from chemotherapy-sensitive patients and was an independent prognostic factor in GC patients receiving postoperative 5-FU adjuvant chemotherapy. Notably, heightened THADA expression in GC cells was associated with the down-regulation of autophagy-related proteins (LC-3, ATG13, ULK1, and TFEB). Furthermore, the PI3K/AKT/mTOR signaling pathway and mTORC1 signaling pathway were remarkably increased in patients with elevated THADA expression. THADA expression was associated with mTOR, the core protein of the mTOR signaling pathway, and related proteins involved in regulating the mTORC1 signaling pathway (mLST8, RHEB, and TSC2). THADA exhibited inhibitory effects on autophagy and augmented the sensitivity of GC cells to 5-FU through the PI3K/AKT/mTOR signaling pathway.

The findings suggest that THADA may be involved in the regulatory mechanism of GC cell sensitivity to 5-FU. Consequently, the detection of THADA in tumor tissues may bring clinical benefits, specifically for 5-FU-related chemotherapy administered to GC patients with elevated THADA expression.

5-Fluorouracil (5FU) and Fe3O4 nanoparticles were encapsulated in core-shellpolycaprolactone (PCL)/chitosan (CS) nanofibers as a multi-mode anticancer system to studydrug release sustainability. The structure of the core-shell drug delivery system was alsooptimized according to drug release behavior by artificial intelligence.

The core-shell nanofibers were electrospun by a coaxial syringe. Artificial neuralnetwork (ANN) was used for function approximation to estimate release parameters. A geneticalgorithm was then used for optimizing the structure. Chemical assay of the optimized samplewas performed by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD),and energy-dispersive X-ray spectroscopy (EDX). vibration sample magnetometer (VSM) testwas conducted to measure the real amount of loaded magnetic nanoparticles. HepG2 cellcytotoxicity was studied and the results for the optimized samples with and without Fe3O4 after72 hours were reported.

Feeding ratio of sheath to core and the amount of CS, Fe3O4, and 5FU had a statisticaleffect on nanofibers diameters, which were 300-450 nm. The drug loading efficiency of thesenanofibers was 65-86%. ANN estimated the release parameters with an error of 10%. Thetemperature increased about 5.6°C in the alternative magnetic field (AMF) of 216 kA.m-1~300kHz and 4.8°C in the AMF of 154 kA.m-1~400 kHz after 20 minutes. HepG2 cell cytotoxicityfor the optimized samples with and without Fe3O4 after 72 hours were 39.7% and 38.8%,respectively.

Since this core-shell drug release system was more sustainable compared to theblend structure despite the low half-life of 5FU, it is suggested to utilize it as post-surgicalimplants for various cancer treatments such as liver or colorectal cancer in the future. Thissystem is capable of providing chemotherapy and hyperthermia simultaneously.

Drugs are mainly delivered to the target tissues by plasma proteins, such as human serum albumin, in the human body. Practical information about the thermodynamic parameters of drugs and their stability can be obtained using simulation methods, such as molecular docking.

This study, investigated the molecular docking of human serum albumin with fluorouracil anticancer drug. Moreover, partial charges on serum albumin protein atoms and fluorouracil atoms were calculated in this study. The best configuration was also searched using the Lamarckian genetic algorithm. The dimensions of the grid maps were selected to be about 40 * 40 * 40 angstroms with a distance of 0.375 angstroms. The number of genetic algorithms and the number of studies were adjusted to about 100 and 2.5 million, respectively. In the end, the best performed interaction configurations with the least amount of free energy were selected. Ligplot and VMD graphic software were used to view the performed docking.

In the best model, fluorouracil is able to bind to the human serum albumin protein HSA four hydrogen bonds via nitrogen and oxygen atoms with two amino acids tyrosine, one amino acid histidine and one amino acid arginine. The estimation of the free bond energies (kcal/mol) for the best model was -5.1. Negative Gibbs free energy values (ΔG °) indicated a spontaneous process, and a constant binding value (Ka ≈ 109 L • mol-1) demonstrated the optimal biological distribution of the drug in the blood plasma.

The docking study of the proposed models shows that fluorouracil has an aliphatic ring and hydrophobic fractions and therefore it has a high ability to form hydrophobic interactions with major amino acids at the active site of serum albumin protein.

This study is designed to present an agent-based model (ABM) to simulate the interactions between tumor cells and the immune system in the melanoma model. The Myeloid-derived Suppressor Cells (MDSCs) and dendritic cells (DCs) are considered in this model as immunosuppressive and antigen-presenting agents respectively. The animal experiment was performed on 68 B16F10 melanoma tumor-bearing C57BL/6 female mice to collect dynamic data for ABM implementation and validation. Animals were divided into 4 groups; group 1 was control (no treatment) while groups 2 and 3 were treated with DC vaccine and low-dose 5- fluorouracil (5-FU) respectively and group 4 was treated with both DC Vaccine and low-dose of 5-FU. The tumor growth rate, number of MDSC, and presence of CD8+/CD107a+ T cells in the tumor microenvironment were evaluated in each group. Firstly, the tumor cells, the effector immune cells, DCs, and the MDSCs have been considered as the agents of the ABM model and their interaction methods have been extracted from the literature and implemented in the model. Then, the model parameters were estimated by the dynamic data collected from animal experiments.  To validate the ABM model, the simulation results were compared with the real data. The results show that the dynamics of the model agents can mimic the relations among considered immune system components to an emergent outcome compatible with real data. The simplicity of the proposed model can help to understand the results of the combinational therapy and make this model a useful tool for studying different scenarios and assessing the combinational results. Determining the role of each component helps to find critical times during tumor progression and change the tumor and immune system balance in favor of the immune system.