Phase II Study of Simvastatin Plus Irinotecan, Fluorouracil, and Leucovorin(FOLFIRI) for Metastatic CRC
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ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms,Metastasis
PROVIDER: 2028019 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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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.
2022-02-17 | PXD028899 | Pride
Project description:In patients with advanced colorectal cancer, leucovorin, fluorouracil, and irinotecan (FOLFIRI) is considered as one of the reference first-line treatments. However, only about half of treated patients respond to this regimen, and there is no clinically useful marker that predicts response. A major clinical challenge is to identify the subset of patients who could benefit from this chemotherapy. We aimed to identify a gene expression profile in primary colon cancer tissue that could predict chemotherapy response. Patients and Methods:- Tumor colon samples from 21 patients with advanced colorectal cancer were analyzed for gene expression profiling using Human Genome GeneChip arrays U133. At the end of the first-line treatment, the best observed response, according to WHO criteria, was used to define the responders and nonresponders. Discriminatory genes were first selected by the significance analysis of microarrays algorithm and the area under the receiver operating characteristic curve. A predictor classifier was then constructed using support vector machines. Finally, leave-one-out cross validation was used to estimate the performance and the accuracy of the output class prediction rule. Results:- We determined a set of 14 predictor genes of response to FOLFIRI. Nine of nine responders (100% specificity) and 11 of 12 nonresponders (92% sensitivity) were classified correctly, for an overall accuracy of 95%. Conclusion:- After validation in an independent cohort of patients, our gene signature could be used as a decision tool to assist oncologists in selecting colorectal cancer patients who could benefit from FOLFIRI chemotherapy, both in the adjuvant and the first-line metastatic setting.
2014-10-06 | GSE62080 | GEO
Project description:In patients with advanced colorectal cancer, leucovorin, fluorouracil, and irinotecan (FOLFIRI) is considered as one of the reference first-line treatments. However, only about half of treated patients respond to this regimen, and there is no clinically useful marker that predicts response. A major clinical challenge is to identify the subset of patients who could benefit from this chemotherapy. We aimed to identify a gene expression profile in primary colon cancer tissue that could predict chemotherapy response. Patients and Methods:- Tumor colon samples from 21 patients with advanced colorectal cancer were analyzed for gene expression profiling using Human Genome GeneChip arrays U133. At the end of the first-line treatment, the best observed response, according to WHO criteria, was used to define the responders and nonresponders. Discriminatory genes were first selected by the significance analysis of microarrays algorithm and the area under the receiver operating characteristic curve. A predictor classifier was then constructed using support vector machines. Finally, leave-one-out cross validation was used to estimate the performance and the accuracy of the output class prediction rule. Results:- We determined a set of 14 predictor genes of response to FOLFIRI. Nine of nine responders (100% specificity) and 11 of 12 nonresponders (92% sensitivity) were classified correctly, for an overall accuracy of 95%. Conclusion:- After validation in an independent cohort of patients, our gene signature could be used as a decision tool to assist oncologists in selecting colorectal cancer patients who could benefit from FOLFIRI chemotherapy, both in the adjuvant and the first-line metastatic setting. All tissue samples were maintained at −180°C (liquid nitrogen) until RNA extraction and were weighed before homogenization. Tissue samples were then disrupted directly into a lysis buffer using Mixer Mill MM 300 (Qiagen, Valencia, CA). Total RNA was isolated from tissue lysates using the RNeasy Mini Kit (Qiagen), and additional DNAse digestion was performed on all samples during the extraction process (RNase-Free DNase Set Protocol for DNase treatment on RNeasy Mini Spin Columns; Qiagen). After each extraction, a small fraction of the total RNA preparation was taken to determine the quality of the sample and the yield of total RNA. Controls analyses were performed by UV spectroscopy and analysis of total RNA profile using the Agilent RNA 6000 Nano LabChip Kit with the Agilent 2100 Bioanalyser (Agilent Technologies, Palo Alto, CA) to determine RNA purity, quantity, and integrity.
2014-10-06 | E-GEOD-62080 | biostudies-arrayexpress
Project description:The purpose of this study is to compare 2nd line XELIRI/FOLFIRI + simvastatin vs XELIRI/FOLFIRI + placebo.
| 2097860 | ecrin-mdr-crc
Project description:Identificaiton of novel single-nucleotide polymorphism (SNP) candidates associated with chemo-responsiveness in colorectal cancers using microarray Response rates of 104 colorectal cancer patients to established regiments (FL, CAPE, FLOX, FLIRI) were evaluated by histoculture drug response assay. Affymetrix SNP 5.0 chips were used to determine genotypes of the same colorectal cancer patients. SNPs associated with chemosensitivity to standard regimens were identified by genome-wide association study. FL: 5-FU + Leucovorin; CA: Capecitabine, FLOX: 5-FU + Leucovorin + Oxaliplatin, FLIRI: 5-FU + Leucovorin + Irinotecan
2010-06-01 | GSE16718 | GEO
Project description:Purpose of the study: the goal of this study was to use Next-generation sequencing to investigate the gene expression profile of skeletal muscle from mice exposed to chemotherapy (Folfiri) for up to 5 weeks. Methods: Standard methods were used for polyA mRNA-seq library construction, EZBead preparation and Next-Gen sequencing, based on Life Technologies SOLiD5000xl system. Briefly, one microgram total RNA per sample was applied for library preparation. PolyA mRNA was first captured using the standard protocol of Dynabeads® mRNA DIRECT⢠Micro Kit (Life Technologies, #61021). Following the enrichment of polyA mRNA, the cDNA library was prepared and barcoded per sample using the standard protocol of SOLiD Total RNA-seq Kit (Life Technologies, #4445374). Each barcoded library was quantified by Bioanalyzer High Sensitivity DNA chip (Agilent, #5067-4626) and pooled in equal molarity. EZBead preparation, bead library amplification, and bead enrichment were then conducted using Life Technologies EZ Bead⢠E80 System (Life technologies, #4453095). Approximately four hundred forty million library-enriched beads per lane were deposited onto a SOLiD5500xl FlowChip (6 lanes/chip). Finally sequencing by ligation was carried out using standard single-read, 5â-3â strand-specific sequencing procedure (75b-read) on SOLiD5500xl Sequencer. The resulting 75 bp solid reads were mapped to Mus musculus mm9 reference genome using in-house mapping pipelines that utilizes bfast-0.7.0a [67]. In brief, using our RNA-seq pipeline, low quality reads and reads mapped to rRNA/tRNAs were first discarded. The remaining reads were mapped to reference genome mm9 and a splice-junction library, respectively; the genomic and splice-junction library mapping were merged at the end. The gene based expression levels were calculated using bamutils from NGSUtils based on the RefSeq gene annotation of mm9. Differential expression of genes across different treatments was determined with edgeR Results: Gene expression profiling, performed by means of RNA-Sequencing analysis, identified a limited number of genes that were significantly modulated (False Discovery Rate < 0.05) following Folfiri administration. Interestingly, the pathway analysis showed marked down-regulation of the regulators of mitochondrial metabolism Ucp1, Cidea1 and Acot2, as well as the marker of muscle cell proliferation/pluripotency Fhl3 . Further, we found increased expression of regulators of lipid metabolism and transport (such as Fabp1, Apoa1, Apob, Apoa2, Alb, Prkcz and Scd2) as well as acute phase response proteins (such as Alb, Fga and Fgb), and members of the PPAR signaling and markers of the Energy metabolism (such as Dnah5) were reported . Conclusions: Our study represents the first gene expression profiling of muscle from mice exposed to chemotherapy. The findings from our study identified several signaling pathways that were modulated following chemotherapy administration. These results will contribute to identify new modulators of muscle wasting associated with Folfiri administration, that might also represent putative new targets of interventions. Next-generation sequencing of RNA extracted from quadriceps muscle of CD2F1 male mice exposed to either Folfiri (a combination of 5-FU, Leucovorin and CPT-11) or vehicle alone (n=4) for up to 5 weeks.
2016-05-18 | E-GEOD-80473 | biostudies-arrayexpress
Project description:Based on the results from preclinical study, the investigators suggest that the addition of simvastatin at a dose of cardiovascular use (40 ~ 80 mg qd daily) may overcome cetuximab resistance in KRAS mutant colorectal cancer via B-Raf protein degradation and inducing Bim and Bad. Given the result of a phase II FOLFIRI plus cardiovascular dose of simvastatin (80mg qd daily) and this study, phase II study of conventional cetuximab treatment with 40 mg simvastatin is planned in metastatic colorectal cancer patients with KRAS mutation.
| 2101200 | ecrin-mdr-crc
Project description:To determine the effects of chemotherapy on cell state dyanmics, VAKPS tumroids were treated with FOLFIRI or DMSO for 72hrs before analyzing their transcriptome. We then performed gene expression profiling analysis using data obtained from mRNA-seq of the indicated tumoroid lines.
2024-10-17 | GSE237837 | GEO
Project description:The aim of our study was to assess the impact of simvastatin on the amount of cytosolic lipid droplets (LDs), which are implicated in many biological processes including proliferation, inflammation, carcinogenesis, apoptosis, necrosis or growth arrest. Human pancreatic cancer cells MiaPaCa-2 were treated with simvastatin (6 and 12 _M) for 24 hours. Changes in expression of genes related to lipid metabolism in the simvastatin-treated cells were examined by DNA microarray analysis. The treatment of the cells with simvastatin increased their intracellular content of LDs, partially due to the uptake of cholesterol and triacylglycerides from medium; but in particular, due to enhanced synthesis of triacylglycerides as proved by detection of significant overexpression of genes related to de novo synthesis of triacylglycerides and phospholipids. Further, simvastatin markedly influenced expression of genes directly affecting cell proliferation and signaling.
2013-11-21 | E-MTAB-1501 | biostudies-arrayexpress
Project description:Sadanandam et al. (2013) recently published a study based on the use of microarray data to classify colorectal cancer (CRC) samples. The classification claimed to have strong clinical implications, as reflected in the paper title: “A colorectal cancer classification system that associates cellular phenotype and responses to therapy”. They defined five subtypes: (i) inflammatory; (ii) goblet-like; (iii) enterocyte; (iv) transit-amplifying; and (v) stem-like. Based on drug sensitivity data from 21 patients, they also reported that the so-called stem-like subtype show differential sensitivity to FOLFIRI. This is the key result in their publication, since it implies a direct relation between the subtype and the choice of CRC therapy (i.e. FOLFIRI response). However, our analyses using the same drug sensitivity data and results from additional patients showed that the CRC classification reported by Sadanandam et al. is not predictive of FOLFIRI response.
2014-09-10 | GSE54483 | GEO