The 'cytidine analog pathway': genes involved in transport and metabolism of the anti-cancer analogs of cytidine: gemcitabine and cytarabine [PubChem=596;3461;6253].
| PAG Title | The 'cytidine analog pathway': genes involved in transport and metabolism of the anti-cancer analogs of cytidine: gemcitabine and cytarabine [PubChem=596;3461;6253]. |
| PAG ID | MAX001655 |
| Type | A |
| Source Link |  MSigDB |
| Publication Reference | NA |
| PAG Description | Two cytidine analogues, gemcitabine (dFdC) and 1-beta-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 IC(50) values for both drugs in 197 ethnically defined Human Variation Panel lymphoblastoid cell lines. Genes with a high degree of association with IC(50) 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. |
| Species | Homo sapiens |
| Quality Metric Scores | nCoCo Score: 716 |
| Information Content | Rich |
| Other IDs | M19946 |
| Base PAG ID | MAX001655 |
| Human Phenotyte Annotation | |
| Curator | PAGER curation team |
| Curator Contact | PAGER-contact@googlegroups.com |
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