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Phase II study of TS-1+CPT-11+BV followed by TS-1+L-OHP+BV in unresectable advanced colorectal cancer with RAS mutation

ABSTRACT: Interventions: SOX+BEV and IRIS+BEV sequential therapy Primary outcome(s): Second progression free survival Study Design: Single arm Non-randomized

DISEASE(S): Colorectal Cancer

PROVIDER: 2630227 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Phase II/III Trial of CPT-11/5-FU/l-LV Versus CPT-11/TS-1 as Second Line Chemotherapy of Unresectable Colorectal Cancer

Project description:This study is designed as Phase II/III. Phase II is aimed to evaluate safety and efficacy of IRIS, and feasibility of FOLFIRI. Phase III is aimed to verify inferiority of the progression free survival of IRIS in comparison with FOLFIRI.

| 2025803 | ecrin-mdr-crc

Multicenter Phase II sequential study of S-1/Oxaliplatin (SOX) and Bevacizumab as first line therapy followed by S-1/Irinotecan (IRIS) and Cetuximab as second line in patients with metastatic colorectal cancer. : A SOBIC study

Project description:Interventions: 1st line SOX+BV 2nd line IRIS+Cmab IRIS+Bmab IRIS Primary outcome(s): Second PFS (progression-free survival) Study Design: Single arm Non-randomized

| 2619466 | ecrin-mdr-crc

Sequentially acting Sox transcription factors in neural lineage development [RNA-seq]

Project description:We report sequential binding but unique functions of different Sox transcription factors during distinct stages of neural differentiation

2011-11-01 | GSE33060 | GEO

Sequentially acting Sox transcription factors in neural lineage development [ChIP-seq]

Project description:We report sequential binding but unique functions of different Sox transcription factors during distinct stages of neural differentiation

2011-11-01 | GSE33059 | GEO

Irinotecan (CPT-11) chemotherapy alters intestinal microbiota in tumour bearing rats.

Project description:Intestinal microbiota mediate toxicity of irinotecan (CPT-11) cancer therapies and cause systemic infection after CPT-11-induced loss of barrier function. The intestinal microbiota and their functions are thus potential targets for treatment to mitigate CPT-11 toxicity. However, microbiota changes during CPT-11 therapy remain poorly described. This study analysed changes in intestinal microbiota induced by CPT-11 chemotherapy. Qualitative and quantitative taxonomic analyses, and functional analyses were combined to characterize intestinal microbiota during CPT-11-based chemotherapy, and in presence or absence of oral glutamine, a treatment known to reduce CPT-11 toxicity. In the first set of experiments tumour-bearing rats received a dose-intensive CPT-11 regimen (125 mg kg(-1)×3 days), with or without oral glutamine bolus (0.75 g kg(-1)). In a subsequent more clinically-oriented chemotherapy regimen, rats received two cycles of CPT-11 (50 mg kg(-1)) followed by 5-flurouracil (50 mg kg(-1)). The analysis of fecal samples over time demonstrated that tumours changed the composition of intestinal microbiota, increasing the abundance of clostrridial clusters I, XI, and Enterobacteriaceae. CPT-11 chemotherapy increased cecal Clostridium cluster XI and Enterobacteriaceae, particularly after the dose-intensive therapy. Glutamine treatment prevented the reduced abundance of major bacterial groups after CPT-11 administration; i.e. total bacteria, Clostridium cluster VI, and the Bacteroides-group. Virulence factor/toxin genes of pathogenic Escherichia coli and Clostridium difficile were not detected in the cecal microbiota. In conclusion, both colon cancer implantation and CPT-11-based chemotherapies disrupted the intestinal microbiota. Oral glutamine partially mitigated CPT-11 toxicity and induced temporary changes of the intestinal microbiota.

| S-EPMC3406026 | biostudies-literature

Molecular insights into microbial ?-glucuronidase inhibition to abrogate CPT-11 toxicity.

Project description:Bacterial ?-glucuronidases expressed by the symbiotic intestinal microbiota appear to play important roles in drug-induced epithelial cell toxicity in the gastrointestinal (GI) tract. For the anticancer drug CPT-11 (irinotecan) and the nonsteroidal anti-inflammatory drug diclofenac, it has been shown that removal of the glucuronide moieties from drug metabolites by bacterial ?-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption of bacterial ?-glucuronidases by small molecule inhibitors alleviates these side effects, which, for CPT-11 {7-ethyl-10-[4-(1-piperidino)-1-piperidino]}, can be dose limiting. Here we characterize novel microbial ?-glucuronidase inhibitors that inhibit Escherichia coli ?-glucuronidase in vitro with Ki values between 180 nM and 2 ?M, and disrupt the enzyme in E. coli cells, with EC50 values as low as 300 nM. All compounds are selective for E. coli ?-glucuronidase without inhibiting purified mammalian ?-glucuronidase, and they do not impact the survival of either bacterial or mammalian cells. The 2.8 Å resolution crystal structure of one inhibitor bound to E. coli ?-glucuronidase demonstrates that it contacts and orders only a portion of the "bacterial loop" present in microbial, but not mammalian, ?-glucuronidases. The most potent compound examined in this group was found to protect mice against CPT-11-induced diarrhea. Taken together, these data advance our understanding of the chemical and structural basis of selective microbial ?-glucuronidase inhibition, which may improve human drug efficacy and toxicity.

| S-EPMC3716326 | biostudies-literature

Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11).

Project description:Camptothecin (CPT)-11 (irinotecan) has been used widely for cancer treatment, particularly metastatic colorectal cancer. However, up to 40% of treated patients suffer from severe late diarrhea, which prevents CPT-11 dose intensification and efficacy. CPT-11 is a prodrug that is hydrolyzed by hepatic and intestinal carboxylesterase to form SN-38, which in turn is detoxified primarily through UDP-glucuronosyltransferase 1A1 (UGT1A1)-catalyzed glucuronidation. To better understand the mechanism associated with toxicity, we generated tissue-specific Ugt1 locus conditional knockout mouse models and examined the role of glucuronidation in protecting against irinotecan-induced toxicity. We targeted the deletion of the Ugt1 locus and the Ugt1a1 gene specifically in the liver (Ugt1(?Hep)) and the intestine (Ugt1(?GI)). Control (Ugt1(F/F)), Ugt1(?Hep), and Ugt1(?GI) adult male mice were treated with different concentrations of CPT-11 daily for four consecutive days. Toxicities were evaluated with regard to tissue glucuronidation potential. CPT-11-treated Ugt1(?Hep) mice showed a similar lethality rate to the CPT-11-treated Ugt1(F/F) mice. However, Ugt1(?GI) mice were highly susceptible to CPT-11-induced diarrhea, developing severe and lethal mucositis at much lower CPT-11 doses, a result of the proliferative cell loss and inflammation in the intestinal tract. Comparative expression levels of UGT1A1 in intestinal tumors and normal surrounding tissue are dramatically different, providing for the opportunity to improve therapy by differential gene regulation. Intestinal expression of the UGT1A proteins is critical toward the detoxification of SN-38, whereas induction of the UGT1A1 gene may serve to limit toxicity and improve the efficacy associated with CPT-11 treatment.

| S-EPMC3839688 | biostudies-literature

Sequentially acting Sox transcription factors in neural lineage development [ChIP-seq]

Project description:We report sequential binding but unique functions of different Sox transcription factors during distinct stages of neural differentiation Examination of genome-wide Sox2, Sox3 and Sox11 transcription factor binding during different stages of neurogenesis.

2011-11-01 | E-GEOD-33059 | biostudies-arrayexpress

Single-Cell Analysis Reveals Cellular Reprogramming in Advanced Colon Cancer Following FOLFOX-Bevacizumab Treatment

Project description:The combination of FOLFOX and bevacizumab (FOLFOX-Bev) is a promising treatment for advanced colorectal cancer (CRC). To gain insights into the cellular changes associated with FOLFOX-Bev treatment, we conducted single-cell transcriptomic analysis of CRC samples derived from a patient before and after treatment. Our results show that cancer cells with high proliferative, metastatic, and pro-angiogenic properties respond better to FOLFOX-Bev treatment. Moreover, FOLFOX-Bev enhances CD8+ T cell cytotoxicity, thereby boosting the anti-tumor immune response. Conversely, FOLFOX-Bev impairs the functionality of tumor-associated macrophages, plasma cells, and cancer-associated fibroblasts, leading to a decrease in VEGFB-mediated angiogenesis. Furthermore, FOLFOX-Bev treatment reset intercellular communication, which could potentially affect the function of non-cancer cells. Our findings provide valuable insights into the molecular mechanisms underlying the response of advanced CRC to FOLFOX-Bev treatment and highlight potential targets for improving the efficacy of this treatment strategy.

2023-07-20 | GSE232525 | GEO

Sequentially acting Sox transcription factors in neural lineage development [microarray]

Project description:We report sequential binding but unique functions of different Sox transcription factors during distinct stages of neural differentiation We used microarray to examine the molecular function of Sox3 in neural progenitor cells.

2011-11-01 | GSE33061 | GEO

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