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Prediction and regulation of 5-FU blood concentration

ABSTRACT: Primary objectives: To determine the percentage of the patients that achieve optimal 5-FU exposure within two dose cycles of 5-FU, which is defined by an AUC target of 5-FU between 20 and 30 mg*h/L or dose limiting toxicity. Primary endpoints: The percentage of the patients that achieve optimal 5-FU exposure within two dose cycles of 5-FU, which is defined by an AUC target of 5-FU between 20 and 30 mg*h/L or dose limiting toxicity.

DISEASE(S): The Clinical Trial Is Conducted In Patients Undergoing Folfox, Folfiri And Folfirinox Chemotherapy. Most Of These Patients Have Colorectal Or Pancreatic Cancer.

PROVIDER: 2539584 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Gene expression patterns induced by 5-Fluorouracil in breast cancer cell lines

Project description:We have compared the changes in cell cycle and cell death parameters induced by 2 different concentrations of 5-FU (IC50 and IC80) in the breast adenocarcinoma cell line MCF7. G1/S cell cycle arrest was associated with both concentrations, whereas cell death was mainly induced after IC80 5-FU. These changes were correlated with gene expression assessed by cDNA microarray analysis. Main findings included an overexpression of p53 target genes involved in cell cycle and apoptosis (CDKN1A/p21, TP53INP, TNFRSF6/FAS and BBC3/PUMA), and significant repression of Myc. High dose 5-FU also induced a higher regulation of the mitochondrial death genes APAF1, BAK1 and BCL2, and induction of genes of the ID family. Keywords: Dose Response

2006-04-07 | GSE2584 | GEO

Gene expression patterns induced by 5-Fluorouracil in breast cancer cell lines

2010-07-01 | E-GEOD-2584 | biostudies-arrayexpress

Analysis of mid-colon and mid-jejunum segments from C57BL/6J wild-type mice exposed to 5-fluorouracil (5-FU). Intravenous exposure to 5-FU was performed with two doses (20 and 50 mg/kg), over a period of 4 days. Mucosal scrapes samples were collected for RNA isolation at 6, 24 and 96h since initial exposure. A recovery period of 2 days (sampled at 144h) followed up the 96h of repeated exposure. Samples from time-matched controls (saline 10 mM Tris/NaOH buffer pH 8.5) were also quantified.

Project description:ADRs (adverse drug reactions) are one of the main reasons for treatment discontinuation or alterations in dose regimens in clinical settings. Chemotherapy-induced ADRs are common, especially gastrointestinal-induced ones. Within TransQST (transqst.org), one of the main goal is to improve the in vitro-in vivo translation in toxicological studies, as well as translation between non-clinical species (such as rat and mouse) and humans. This experimental setup aimed to investigate the injury dynamics underlying repeated exposure to two doses of 5-FU (20 and 50 mg/kg), sampled at multiple time points (6, 24, 96 and 144h). The 144h time point comprises of recovery samples (i.e., 48h following the last dosing with 5-FU). This dataset is part of the TransQST collection.

2023-09-29 | E-MTAB-9120 | biostudies-arrayexpress

INDIVIDUAL 5-FLUOROURACIL DOSE INDIVIDUALIZATION IN PATIENTS WITH COLORECTAL CANCER

Project description:Primary objectives: 5-fluorouracil (5-FU) is the drug most commonly used in the treatment of patients with colorectal cancer. Its efficacy and toxicity can also be evaluated and predicted according to individual pharmacogenetic (PG), pharmacokinetic (PK) and dynamic data (PD). Individual PK is estimated according to drug plasma concentrations –Cpl and kinetic parameters of 5-FU, mainly the AUC as the measure of exposure to drugs. Clinical outcome which is evaluated according to PD parameters, is more depedent on pharmacokinetics than on the dose. This study is devoted to kinetally guided therapy with 5-FU. Primary endpoints: interindividual variability in pharmacokinetics and dynamics (toxicity)

| 2527156 | ecrin-mdr-crc

small RNA-Seq of rat kidney in a model of ischemic preconditioning/ischemia-reperfusion injury

Project description:Ischemic preconditioning is effective in limiting subsequent ischemic acute kidney injury in experimental models. microRNAs are an important class of post-transcriptional regulator and show promise as biomarkers of kidney injury. An evaluation was performed of the time- and dose-dependent effects of ischemic preconditioning in a rat model of functional (bilateral) ischemia-reperfusion injury. A short, repetitive sequence of ischemic preconditioning resulted in optimal protection from subsequent ischemia-reperfusion injury. A detailed characterization of microRNA expression in ischemic preconditioning/ischemia-reperfusion injury was performed by small RNA-Seq.

2021-12-31 | E-MTAB-9896 | biostudies-arrayexpress

Exiqon miRCURY microRNA array of rat kidney in a model of ischemic preconditioning/ischemia-reperfusion injury

2021-12-31 | E-MTAB-9900 | biostudies-arrayexpress

Data independent acquisition mass spectrometry (DIA-MS) analysis of FFPE rectal cancer samples offers in depth proteomics characterization of response to neoadjuvant chemoradiotherapy

Project description:A total of 97 LARC patients treated at the Institute for Oncology and Radiology of Serbia in the period of 2018-2019 were included in the study. Patients were treated with long-course chemoradiotherapy (CRT): Radiotherapy (RT) was delivered with a total dose of 50.4 Gy in 28 fractions; concomitant chemotherapy (5-FU, 350 mg/m2 daily) and Leucovorin (25 mg/m2 daily) was administered during the first and the fifth week of RT. Patients were evaluated in week 6-8 after treatment completion with pelvic MRI scan and rigid proctoscopy. Pathohistological response after surgery was assessed according to tumor regression grading (TRG) categories by Mandard. Twenty biopsy samples taken at diagnosis were used for proteomic analysis, 9 responders (R, TRG 1-2), and 11 non-responders (NR, TRG 3-5), in order to achieve the maximum range of different molecular features potentially associated with response.

2023-11-21 | PXD040451 | Pride

β-Globin Lentiviral Vectors Have Reduced Titers Due to Incomplete Vector RNA Genomes and Lowered Virion Production

Project description:Lentiviral vectors (LV) commonly used for the treatment of hemoglobinopathies often have low titers and sub-optimal gene transfer efficiency for human hematopoietic stem and progenitor cells (HSPC), hindering clinical translation and commercialization for ex vivo gene therapy. We observed that a high percentage of β-globin LV viral genomic RNAs were incomplete towards the 3’ end in packaging cells and in released vector particles. The incomplete vector genomes impeded reverse transcription in target cells, limiting stable gene transfer to HSPC. By combining three modifications to vector design and production (shortening the vector length to 5.3-kb; expressing TAT protein during packaging; and packaging in PKR-/- cells) there was a 30-fold increase in vector titer and a 3-fold increase in vector infectivity in HSPC. These approaches may improve the manufacturing of β-globin and other complex LVs for enhanced gene delivery and may facilitate clinical applications.

2020-09-21 | GSE158252 | GEO

5-Fluorouracil Treatment Represses Pseudouridine-Containing miRNA Export into Extracellular Vesicles (smallRNA seq)

Project description:5-Fluorouracil (5-FU) has been used for chemotherapy for colorectal and other cancers for over 50 years. The prevailing view of its mechanism of action is inhibition of thymidine synthase leading to defects in DNA replication and repair. However, 5-FU is also incorporated into RNA causing defects in RNA metabolism, inhibition of pseudouridine modification, and altered ribosome function. We examined the impact of 5-FU on the expression and export of small RNAs into small extracellular vesicles (sEVs) and regulation of post-transcriptional small RNA modifications (PTxMs). EVs are secreted by all cells and contain a variety of proteins and RNAs that can function in cell-cell communication. PTxMs on cellular and extracellular small RNAs provide yet another layer of gene regulation. We found that treatment of colorectal cancer (CRC) cells with 5-FU represses sEV export of miRNA and snRNA-derived RNAs, but promotes export of snoRNA-derived RNAs. Strikingly, 5-FU treatment significantly decreased the levels of pseudouridine on both cellular and sEV small RNA profiles. In contrast, 5-FU exposure led to increased levels of cellular small RNAs containing a variety of methyl-modified bases. Our results suggest that 5-FU exposure leads to altered expression, base modification, and mislocalization of sEV small RNAs.

2024-09-18 | GSE255876 | GEO

5-Fluorouracil Treatment Represses Pseudouridine-Containing miRNA Export into Extracellular Vesicles (RNA-seq)

2024-09-18 | GSE255875 | GEO

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