Association of thymidylate synthase variants with 5-fluorouracil cytotoxicity
| Autor: | Jane L Yen-Revollo, Shiow J. Lin, Michael A. Province, Aldi T. Kraja, Eric Peters, Howard L. McLeod, Sharon Marsh |
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| Rok vydání: | 2009 |
| Předmět: |
Genetics
Antimetabolites Antineoplastic biology Drug-Related Side Effects and Adverse Reactions Haplotype Single-nucleotide polymorphism Thymidylate Synthase Thymidylate synthase Polymorphism Single Nucleotide Pedigree Polymorphism (computer science) Cell Line Tumor Genotype biology.protein Molecular Medicine SNP Humans Fluorouracil General Pharmacology Toxicology and Pharmaceutics International HapMap Project Drug Screening Assays Antitumor Molecular Biology Genotyping Genetics (clinical) |
| Zdroj: | Pharmacogenetics and genomics. 19(5) |
| ISSN: | 1744-6872 |
| Popis: | Identifying relevant cytotoxicity genes using an ex-vivo lymphoblastoid cell line (LCLs) model has distinct advantages for pharmacogenomic discovery studies of cancer chemotherapy, including standardized treatment conditions, availability of large numbers of samples, and publicly available genotypic data. However, there is little proof of principal data to confirm the promise of this approach. One of the known targets of 5-fluorouracil (5-FU) treatment is thymidylate synthase (TYMS). We hypothesized that genetic variants in TYMS would alter cytotoxicity because of 5-FU treatment using a LCL model system. LCLs from the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees (N=427) were treated with eight concentrations of 5-FU for 72 h, and cytotoxicity was determined using an Alamar Blue assay. For a subset of the 30 International Haplotype Mapping project (HapMap) trios, genotype data for 46 single-nucleotide polymorphism (SNP) variants encompassing the TYMS gene were downloaded from the HapMap website. Using a mixed models approach, each SNP was tested for association to 5-FU cytotoxicity in the subset of HapMap trios. Putatively associated SNPs (P |
| Databáze: | OpenAIRE |
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