Relationship Between Platinum Levels in the Blood and Neurotoxicity in Patients Who Are Receiving Oxaliplatin for Gastrointestinal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Gastrointestinal Neoplasms,Neurotoxicity Syndromes,Cancer
PROVIDER: 2025107 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:RATIONALE: Studying samples of blood in the laboratory from patients receiving oxaliplatin for cancer may help doctors learn more about changes that occur in DNA and identify biomarkers related to neurotoxicity.
PURPOSE: This phase II trial is studying biomarkers in predicting neurotoxicity in patients with colorectal cancer receiving oxaliplatin.
| 2071054 | ecrin-mdr-crc
Project description:Interventions: 1.Nerve Conduction Velocity 2.tuning fork
Primary outcome(s): 1. Collation between NCV and oxaliplatin induced neurotoxicity 2. Collation between tuning fork and oxaliplatin induced neurotoxicity 3. Analyze the mechanism of oxaliplatin induced neurotoxicity
Study Design: Single arm Non-randomized
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Project description:Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States, with a five-year survival rate of 65%. Oxaliplatin was the first platinum drug shown to improve CRC patient outcomes and is now a common adjuvant therapy for advanced disease, yet 90% of patients develop resistance. Oxaliplatin was developed as a third-generation derivative of cisplatin, but recent evidence points to divergent modes of action. Here, genome-wide CRISPR activation and knockout screens were conducted to identify genetic changes that confer resistance to oxaliplatin in two CRC cell lines with distinct molecular backgrounds (SW620 and RKO). Guide RNAs corresponding to the neutral amino acid transporter SLC43A1 (LAT3) were the most significantly enriched in knockout screens and depleted in activation screens, suggesting a potential role for LAT3 in modulating oxaliplatin resistance. In vitro CRISPR knockout and overexpression of LAT3 in SW620 and RKO cell lines confirm increased resistance or sensitivity to oxaliplatin, respectively. Further analysis demonstrates that increased LAT3 levels corrrelate with increased intracellular levels of oxaliplatin, increased levels of DNA-platinum adducts and DNA damage, demonstrating that enhanced LAT3-mediated uptake of oxaliplatin can exert its expected mechanism of action and induce cytotoxicity. These findings may lead to a better understanding of oxaliplatin’s mode of action in CRC and can provide new insights into the interplay between essential nutrient uptake and drug transport.
2025-04-22 | GSE294894 | GEO
Project description:Platinum-based chemotherapies, including oxaliplatin, are a mainstay in solid tumor treatment and induce cell death by forming intrastrand dinucleotide DNA adducts. Despite their common use, they are highly toxic and approximately half of patients have tumors that are either intrinsically resistant, or that develop resistance. Studies suggest that this resistance is mediated by variations in DNA repair levels or net drug influx. We aimed to better define the roles of nucleotide excision repair and DNA damage formation in platinum resistance by profiling DNA damage levels and repair efficiency in a panel of seven oxaliplatin-sensitive and three oxaliplatin-resistant colorectal cancer cell lines. We assayed repair indirectly as toxicity, and directly measured bulky adduct formation and removal from the genome by slot blot, repair capacity by excision assay, and mapped repair events genome-wide at single nucleotide resolution using XR-Seq. Using this comprehensive approach of combining novel methods and in some cases using proxies for oxaliplatin-DNA damage, we found no significant difference in repair efficiency that could explain the relative sensitivity and resistance of our cell lines. In contrast, the overall levels of oxaliplatin-DNA damage were significantly lower in resistant cells, indicating that decreased formation of damage, rather than increased repair of that damage, is a major determinant of oxaliplatin resistance. Analysis of gene expression using our XR-seq data showed upregulation of membrane transport pathways in resistant cells, and these pathways may contribute to resistance. Additional research is needed to characterize factors mitigating cellular DNA damage formation by platinum compounds.
2020-05-10 | GSE146473 | GEO
Project description:Acute exposure to acrylamide (ACR), a type-2 alkene, may lead to a ataxia, skeletal muscles weakness and numbness of the extremities in exposed human and laboratory animals. Recently, a zebrafish model for ACR neurotoxicity mimicking most of the pathophysiological processes described in mammalian models, was generated in 8 days post-fertilization larvae. In order to better understand the predictive value of the zebrafish larvae model of acute ACR neurotoxicity, in the present manuscript the ACR acute neurotoxicity has been characterized in the brain of adult zebrafish, and the results compared with those obtained with the whole-larvae. Although qualitative and quantitative analysis of the data shows important differences in the ACR effects between the adult brain and the whole-larvae, the overall effects of ACR in adult zebrafish, including a significant decrease in locomotor activity, altered expression of transcriptional markers of proteins involved in synaptic vesicle cycle, presence of ACR-adducts on cysteine residues of some synaptic proteins, and changes in the profile of some neurotransmitter systems, are similar to those described in the larvae. Thus, these results support the suitability of the zebrafish ACR acute neurotoxicity recently developed in larvae for screening of molecules with therapeutic value to treat this toxic neuropathy.
2018-10-19 | PXD008993 | Pride
Project description:The therapeutical efficacy of cisplatin and oxaliplatin depends on the balance between the DNA damage induction and the DNA damage response of tumor cells. Based on clinical evidence, oxaliplatin is administered to cisplatin-unresponsive cancers, but the underlying molecular causes for this tumor specificity are not clear. Hence, stratification of patients based on DNA repair profiling is not sufficiently utilized for treatment selection. Using a combination of genetic, transcriptomic and imaging approaches, we identified factors that promote global genome nucleotide excision repair (GG-NER) of DNA-platinum adducts induced by oxaliplatin, but not by cisplatin. We show that oxaliplatin-DNA lesions are a poor substrate for GG-NER initiating factor XPC and that DDB2 and HMGA2 are required for efficient binding of XPC to oxaliplatin lesions and subsequent GG-NER initiation. Loss of DDB2 and HMGA2 therefore leads to hypersensitivity to oxaliplatin but not to cisplatin. As a result, low DDB2 levels in different colon cancer cells are associated with GG-NER deficiency and oxaliplatin hypersensitivity. Finally, we show that colon cancer patients with low DDB2 levels have a better prognosis after oxaliplatin treatment than patients with high DDB2 expression. We therefore propose that DDB2 is a promising predictive marker of oxaliplatin treatment efficiency in colon cancer.
2023-12-14 | GSE227871 | GEO
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
2025-05-13 | GSE293251 | GEO
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
2025-05-13 | GSE293255 | GEO
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
2025-05-13 | GSE293253 | GEO
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
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