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Ribonucleotide reductase M1 (RRM1) 2464G>A polymorphism shows an association with gemcitabine chemosensitivity in cancer cell lines

 Woo Sun Kwon  ;  Sun Young Rha  ;  Yeon Ho Choi  ;  Jung Ok Lee  ;  Kyu Hyun Park  ;  Jae Joon Jung  ;  Tae Soo Kim  ;  Hei-Cheul Jeung  ;  Hyun Cheol Chung 
 PHARMACOGENETICS AND GENOMICS, Vol.16(6) : 429-438, 2006 
Journal Title
Issue Date
Antimetabolites, Antineoplastic/pharmacology* ; Brain Neoplasms/genetics ; Breast Neoplasms/genetics ; Cell Line, Tumor ; Colorectal Neoplasms/genetics ; DCMP Deaminase/biosynthesis ; DCMP Deaminase/genetics ; Deoxycytidine/analogs & derivatives* ; Deoxycytidine/pharmacology ; Deoxycytidine Kinase/biosynthesis ; Deoxycytidine Kinase/genetics ; Drug Resistance, Neoplasm/genetics ; Female ; Humans ; In Vitro Techniques ; Inhibitory Concentration 50 ; Lung Neoplasms/genetics ; Polymorphism, Genetic* ; Polymorphism, Single Nucleotide ; Stomach Neoplasms/genetics ; Tumor Suppressor Proteins/genetics*
gemcitabine ; pharmacogenetics ; single nucleotide polymorphism (SNP) ; ribonucleotide reductase M1 (RRM1)
OBJECTIVES: Significant variability in the efficacy and toxicity of an anticancer drug is observed in cancer patients. Currently, there are no standard tools for prediction of a patient's tumor response or his risk of adverse events to chemotherapy.
METHODS: We investigate an association between polymorphisms of gemcitabine metabolism-related genes and its chemosensitivity in vitro using 62 human cancer cell lines of various origins. Polymorphisms of gemcitabine metabolism-related genes of deoxycytidine monophosphate deaminase (DCTD), deoxycytidine kinase (DCK) and ribonucleotide reductase M1 (RRM1) were evaluated using the CEQ8000 Genetic analysis system and GeneDoc software. Chemosensitivity of gemcitabine was expressed as an IC50 using MTT assay.
RESULTS: The frequency of the polymorphisms was 21% in DCTD 315T>C, 45.2% in RRM1 1082C>A, 59.7% in RRM1 2455A>G, and 79% in RRM1 2464G>A. When examining the association between these polymorphisms and IC50, only the RRM1 2464G>A showed the tendency to be more chemosensitive to gemcitabine (P=0.011), and haplotypes containing 2464G>A polymorphism also showed the association with chemosensitivity when compared to wild-type RRM1 (G2464G). We could not see the significant differences of mRNA expression level with real-time PCR between cell lines according to G2464A polymorphism. In oligonucleotide microarray 73 GenBank Accession Number (69 genes) were selected which expressed differently between RRM1 wild-type and the G2464A polymorphism.
CONCLUSIONS: RRM1 2464G>A polymorphism demonstrated an association with gemcitabine sensitivity, which needs functional studies with co-expressing genes and prospective clinical studies for the clinical application as a predictive bio-marker.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Woo Sun(권우선) ORCID logo https://orcid.org/0000-0003-0268-5624
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
Jeung, Hei Cheul(정희철) ORCID logo https://orcid.org/0000-0003-0952-3679
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