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Combination of Brivanib With 5-Fluorouracil/Leucovorin (5FU/LV) and 5-Fluorouracil/Leucovorin/Irinotecan (FOLFIRI)

ABSTRACT: The purpose of this study is to determine a safe and maximum tolerable dose of Brivanib when combined with standard dose 5FU/LV and FOLFIRI.

DISEASE(S): Gastrointestinal Neoplasms,Gastro-intestinal Cancer,Intestinal Neoplasms

PROVIDER: 2083265 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Transcriptional response of Schizosaccharomyces pombe to 5-Fluorouracil (5FU)

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Analysis of mouse enteroids and colonoids exposed to chemotherapy agent 5-fluorouracil (5FU)

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 therefore aimed to investigate the effects of 5FU on 3D mouse organoid cultures derived from small intestine and colon segments. Experiments were conducted in a dose-repeated (daily media refreshing with 10, 100 or 1000 uM of 5FU) and time series regimen (24, 48 and 72h). Time-matched controls (DMSO 0.1% and medium only) were measured, as well as a baseline exposure prior to the beginning of the exposures (medium only, 0h).

2023-09-29 | E-MTAB-9119 | biostudies-arrayexpress

Transcriptional response of Schizosaccharomyces pombe to 5-Fluorouracil (5FU)

Project description:We use high-density tiling DNA microarray technology to obtain the specific transcriptome-wide response induced by 5-Fluorouracil (5FU) in the eukaryotic model Schizosaccharomyces pombe. Schizosaccharomyces pombe cultures with 5FU added to a final concentration of 500 M-NM-<M. Incubation was allowed to proceed for 0, 15, 60 and 240 minutes.Two biological replicates each.

2013-11-14 | E-GEOD-46919 | biostudies-arrayexpress

VEGF receptor inhibitor brivanib sensitizes chemotherapy by targeting cGAS to boost antitumor immunity

Project description:Chemoresistance challenges the clinical application of most widely used platinum-based cancer chemotherapeutics which canonically function through inducing DNA damage. The DNA sensor cyclic GMP–AMP synthase (cGAS) connects genome instability to type I IFN response which confers vulnerability to platinum treatment. Here, by using a high throughput small-molecule-microarray-based screening of cGAS interacting compounds, we identified brivanib, known as an inhibitor of the vascular endothelial growth factor receptor (VEGFR), as a novel cGAS agonist. Brivanib markedly enhanced platinum-induced STING-TBK1-type I IFN response in tumor cells indispensable of cGAS. Importantly, brivanib synergizes the effect of cisplatin in restricting the growth of xenografted Lewis Lung Cancer (LLC) cells by boosting CD8+ T cell response in a cGAS-dependent manner. Mechanistically, brivanib enhances the DNA binding affinity of cGAS by directly targeting leucine 495 of cGAS. Moreover, leucine 495 of cGAS is essential for brivanib-mediated promoting effect on cisplatin-mediated type I IFN response and inhibition of tumor growth. Clinically, higher expression of cGAS in tumor renders a more favorable response to platinum-based chemotherapeutic regimens and better prognosis in lung cancer patient. Taken together, our findings discover cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.

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The Effects of 5-Fluorouracil/Leucovorin Chemotherapy on Cognitive Function in Mice

Project description:5-Fluorouracil (5-Fu) and leucovorin (LV) are often given in combination to treat colorectal cancer. 5-Fu/LV prevents cell proliferation by inhibiting thymidylate synthase, which catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. While 5-Fu has been shown to cause cognitive impairment, the synergistic effect of 5-Fu with LV has not been fully explored. The present investigation was designed to assess how the combination of 5-Fu and LV affect cognition in a murine model. Six-month-old male mice were used in this study; 15 mice received saline injections and 15 mice received 5-Fu/LV injections. One month after treatment, the elevated plus maze, Y-maze, and Morris water maze behavioral tasks were performed. Brains were then extracted, cryosectioned, and stained for CD68 to assay microglial activation and with tomato lectin to assay the vasculature. All animals were able to locate the visible and hidden platform locations in the water maze. However, a significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden-platform training (first probe trial) in animals that received 5-Fu/LV, but these animals showed spatial memory retention by day 5. There were no significant increases in inflammation as measured by CD68, but 5-Fu/LV treatment did modulate blood vessel morphology. Tandem mass tag proteomics analysis identified 6,049 proteins, 7 of which were differentially expressed with a P-value of < 0.05 and a fold change of >1.5. The present data demonstrate that 5-Fu/LV increases anxiety and significantly impairs spatial memory retention.

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Project description:BackgroundChemotherapy may improve survival in patients undergoing resection of colorectal liver metastases (CLM). Neoadjuvant chemotherapy may help identify patients with occult extrahepatic disease (averting unnecessary metastasectomy), and it provides in vivo chemosensitivity data.MethodsA phase II trial was initiated in which patients with resectable CLM received CPT-11, 5-FU and LV for 12 weeks. Metastasectomy was performed unless extrahepatic disease appeared. Postoperatively, patients with stable or responsive disease received the same regimen for 12 weeks. Patients with progressive disease received either second-line chemotherapy or best supportive care. The primary endpoint was disease-free survival (DFS); secondary endpoints included overall survival (OS) and safety.Results35 patients were accrued. During preoperative chemotherapy, 16 patients (46%) had grade 3/4 toxicities. Resection was not possible in 5 patients. One patient died of arrhythmia following surgery, and 1 patient had transient liver failure. During the postoperative treatment phase, 12 patients (55%) had grade 3/4 toxicities. Deep venous thrombosis (DVT) occurred in 11 patients (34%) at various times during treatment. Of those who underwent resection, median DFS was 23.0 mo. and median OS has not been reached. The overall survival from time of diagnosis of liver metastases was 51.6 mo for the entire cohort.ConclusionA short course of chemotherapy prior to hepatic metastasectomy may serve to select candidates best suited for resection and it may also direct postoperative systemic treatment. Given the significant incidence of DVT, alternative systemic neoadjuvant regimens should be investigated, particularly those that avoid the use of a central venous line.Trial registrationClinicalTrials.gov NCT00168155.

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Analysis of human enteroids and colonoids (3D organoid models from small intestine and colon) exposed to chemotherapy agent 5-fluorouracil (5FU) in a dose-repeated exposure across three doses (10,100 and 1000uM) and sampled at three points (24, 48 and 72h) since initial exposure. Organoids were obtained from healthy human tissues.

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 therefore aimed to investigate the effects of 5FU on 3D human organoid cultures derived from small intestine and colon segments. Experiments were conducted in a dose-repeated (daily media refreshing with 10, 100 or 1000 uM of 5FU) and time series regimen (24, 48 and 72h). Time-matched controls (DMSO 0.1% and medium only) were measured, as well as a baseline exposure prior to the beginning of the exposures (medium only, 0h). This dataset is part of the TransQST collection.

2021-09-09 | E-MTAB-9134 | biostudies-arrayexpress

5-fluorouracil (5-Fu) resistant Bel/5Fu cell line and its parent Bel7402 cell line

Project description:The extensive drug resistance of hepatocellular carcinoma (HCC) has become the main cause of chemotherapy failure. The mechanisms leading to drug resistance in tumor cells are not well understood. Previous studies demonstrated that plasma membrane proteins play important roles in mediating drug disposal or pharmacokinetics. Therefore, we performed proteomic studies on the composition of 5-fluorouracil (5-Fu) resistant Bel/5Fu cell line and its parent Bel7402 cell line by using an ionic liquid-assisted proteins extraction method with the advantage of extracting plasma membrane proteins to a greater extent. In total, 4,532 unique proteins were quantified and 103 proteins (>2-fold change, p-value <0.05) including 25 plasma membrane proteins showed to be differentially expressed in Bel/5Fu compared with Bel7402. Western blot analysis results were further confirmed that the plasma membrane proteins EPHX1 PLIN2 RAB27B SLC4A2 were up-regulated in Bel/5Fu cells in accordance with the proteomics data. Moreover, cell viability assay and clonogenic survival assay results demonstrated that EPHX1 are closely related to the chemoresistance of Bel/5Fu to 5Fu.

2019-10-19 | PXD015917 |

Mouse HSC proteomics in basal or 5FU activated conditions

Project description:Proteomics of hemaopoietic stem cells under basal or 5FU activated conditions

2022-02-16 | PXD021340 | Pride