BACKGROUND: To investigate whether single nucleotide polymorphisms (SNPs) in gemcitabine (GMB) metabolism genes were associated with clinical outcome in pre-treated metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: SNPs of hCNT1, hENT1, CDA, dCTD and RRM1 genes were evaluated in 95 mCRC patients and detected using TaqMan genotyping assays. Association of genotypes with overall response rate (ORR), time to progression (TTP) and overall survival (OS) was tested by univariate and multivariate analysis. RRM1 -37A>C polymorphism was correlated with GMB IC50 value and with the RRM1 gene expression level in CRC cell lines. RESULTS: The ORR was 38.9%. The median TTP and OS were 4 and 14.3 months, respectively. By multivariate analysis, patients carrying the RRM1 -37CC genotype or the CDA A-76 C-containing allele had a significantly higher likelihood of achieving a tumour response. RRM1 -37A>C polymorphism remained associated with clinical efficacy (TTP). In vitro experiments, in CRC cell lines, showed that the RRM1 A-37C genotype was associated with the levels of RRM1 expression and with GMB IC50 values. Finally, the down-regulation of RRM1 with a specific siRNA strongly influenced GMB sensitivity. CONCLUSION: RRM1 -37A>C polymorphism may represent a useful biomarker to select mCRC patients most likely to benefit from GMB-based salvage therapy.
BACKGROUND: To investigate whether single nucleotide polymorphisms (SNPs) in gemcitabine (GMB) metabolism genes were associated with clinical outcome in pre-treated metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: SNPs of hCNT1, hENT1, CDA, dCTD and RRM1 genes were evaluated in 95 mCRC patients and detected using TaqMan genotyping assays. Association of genotypes with overall response rate (ORR), time to progression (TTP) and overall survival (OS) was tested by univariate and multivariate analysis. RRM1 -37A>C polymorphism was correlated with GMB IC50 value and with the RRM1 gene expression level in CRC cell lines. RESULTS: The ORR was 38.9%. The median TTP and OS were 4 and 14.3 months, respectively. By multivariate analysis, patients carrying the RRM1 -37CC genotype or the CDAA-76 C-containing allele had a significantly higher likelihood of achieving a tumour response. RRM1 -37A>C polymorphism remained associated with clinical efficacy (TTP). In vitro experiments, in CRC cell lines, showed that the RRM1A-37C genotype was associated with the levels of RRM1 expression and with GMB IC50 values. Finally, the down-regulation of RRM1 with a specific siRNA strongly influenced GMB sensitivity. CONCLUSION:RRM1 -37A>C polymorphism may represent a useful biomarker to select mCRC patients most likely to benefit from GMB-based salvage therapy.
Authors: Xueyuan Cao; Amit K Mitra; Stanley Pounds; Kristine R Crews; Varsha Gandhi; William Plunkett; M Eileen Dolan; Christine Hartford; Susana Raimondi; Dario Campana; James Downing; Jeffrey E Rubnitz; Raul C Ribeiro; Jatinder K Lamba Journal: Pharmacogenomics Date: 2013-09 Impact factor: 2.533
Authors: Sevtap Savas; Jingxiong Xu; Salem Werdyani; Konstantin Shestopaloff; Elizabeth Dicks; Jane Green; Patrick Parfrey; Roger Green; Wei Xu Journal: Biomed Res Int Date: 2015-05-12 Impact factor: 3.411
Authors: Song Xue; Shu Xiao-Hong; Sha Lin; Bian Jie; Wang Li-Li; Gu Jia-Yao; Shi Shun; Li Pei-Nan; Wu Mo-Li; Wang Qian; Chen Xiao-Yan; Kong Qing-You; Zhang Peng; Li Hong; Liu Jia Journal: Oncotarget Date: 2016-11-15