TY - JOUR
T1 - Gemcitabine and cytosine arabinoside cytotoxicity
T2 - Association with lymphoblastoid cell expression
AU - Li, Ang
AU - Fridley, Brooke
AU - Kalari, Krishna
AU - Jenkins, Gregory
AU - Batzler, Anthony
AU - Safgren, Stephanie
AU - Hildebrandt, Michelle
AU - Ames, Matthew
AU - Schaid, Daniel
AU - Wang, Liewei
PY - 2008/9/1
Y1 - 2008/9/1
N2 - Two cytidine analogues, gemcitabine (dFdC) and 1-β-D- arabinofuranosylcytosine (AraC), show significant therapeutic effect in a variety of cancers. However, response to these drugs varies widely. Evidence from tumor biopsy samples shows that expression levels for genes involved in the cytidine transport, metabolism, and bioactivation pathway contribute to this variation in response. In the present study, we set out to test the hypothesis that variation in gene expression both within and outside of this "pathway" might influence sensitivity to gemcitabine and AraC. Specifically, Affymetrix U133 Plus 2.0 GeneChip and cytotoxicity assays were performed to obtain basal mRNA expression and IC50 values for both drugs in 197 ethnically defined Human Variation Panel lymphoblastoid cell lines. Genes with a high degree of association with IC50 values were involved mainly in cell death, cancer, cell cycle, and nucleic acid metabolism pathways. We validated selected significant genes by performing real-time quantitative reverse transcription-PCR and selected two representative candidates, NT5C3 (within the pathway) and FKBP5 (outside of the pathway), for functional validation. Those studies showed that down-regulation of NT5C3 and FKBP5 altered tumor cell sensitivity to both drugs. Our results suggest that cell-based model system studies, when combined with complementary functional characterization, may help to identify biomarkers for response to chemotherapy with these cytidine analogues.
AB - Two cytidine analogues, gemcitabine (dFdC) and 1-β-D- arabinofuranosylcytosine (AraC), show significant therapeutic effect in a variety of cancers. However, response to these drugs varies widely. Evidence from tumor biopsy samples shows that expression levels for genes involved in the cytidine transport, metabolism, and bioactivation pathway contribute to this variation in response. In the present study, we set out to test the hypothesis that variation in gene expression both within and outside of this "pathway" might influence sensitivity to gemcitabine and AraC. Specifically, Affymetrix U133 Plus 2.0 GeneChip and cytotoxicity assays were performed to obtain basal mRNA expression and IC50 values for both drugs in 197 ethnically defined Human Variation Panel lymphoblastoid cell lines. Genes with a high degree of association with IC50 values were involved mainly in cell death, cancer, cell cycle, and nucleic acid metabolism pathways. We validated selected significant genes by performing real-time quantitative reverse transcription-PCR and selected two representative candidates, NT5C3 (within the pathway) and FKBP5 (outside of the pathway), for functional validation. Those studies showed that down-regulation of NT5C3 and FKBP5 altered tumor cell sensitivity to both drugs. Our results suggest that cell-based model system studies, when combined with complementary functional characterization, may help to identify biomarkers for response to chemotherapy with these cytidine analogues.
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U2 - 10.1158/0008-5472.CAN-08-0405
DO - 10.1158/0008-5472.CAN-08-0405
M3 - Article
C2 - 18757419
AN - SCOPUS:52049100798
SN - 0008-5472
VL - 68
SP - 7050
EP - 7058
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -