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• W2030120272 abstract "Muscle invasive bladder cancer is treated by cystectomy or radiation therapy-based approaches, and both neoadjuvant chemotherapy and concurrent chemoradiation improve survival rates modestly. Tailoring which chemotherapeutic drug is used in combination by use of predictive biomarkers may improve clinical outcome further. The antimetabolite gemcitabine is an effective radiosensitizer in many cancers, including bladder. We aim to investigate proteins key in the uptake and metabolism of gemcitabine as potential predictive biomarkers for response to this drug in bladder cancer cell lines: hENT1 is a transporter involved in cellular entry of gemcitabine; ribonucleoside-diphosphate reductase subunits 1 and 2 (RRM1 and RRM2) can be inhibited by gemcitabine, thus decreasing endogenous levels of deoxyribonucleotides needed for DNA replication; cytidine deaminase (CDA) can convert gemcitabine to an inactive uridine form; and deoxycytidine kinase (dCK) is a kinase critical in the conversion of gemcitabine from prodrug to active antimetabolite. RT112 and CAL29 bladder cancer cell lines were treated with gemcitabine for 24 h prior to replating at appropriate cell density and irradiated with 0- 8 Gy for clonogenic survival assay. Cells were stained with propidium iodide for flow cytometry analysis of the cell cycle. Transient knockdown of hENT1, RRM1, CDA and dCK was achieved using a standard siRNA transfection protocol. Western blots and qPCR were performed to establish protein and mRNA levels, respectively. Gemcitabine radiosensitized RT112 and CAL29 bladder cancer cell lines after 24 h exposure to 20 nM drug, with sensitizer enhancement ratios of 1.36 and 1.45, respectively. Radiosensitization corresponds to an accumulation of greater than 85 % cells in S phase. Knockdown of hENT1, RRM1 and CDA has no significant impact on gemcitabine radiosensitivity. However, cells that have reduced dCK levels by siRNA display resistance to gemcitabine. Furthermore, cells conditioned to become resistant to 10 M gemcitabine had a striking reduction in dCK, both at the protein level (undetectable on western blot) and 50% reduction of mRNA. Sensitivity to gemcitabine can be restored by transient overexpression of dCK in CAL29 cells, but gemcitabine-resistant RT112 cells appear not to be resensitized with transient overexpression of dCK. We aim to test RT112 cells that have stable overexpression of dCK. Gemcitabine is an effective radiosensitizer in bladder cancer cell lines. Knockdown of dCK confers resistance to gemcitabine, consistent with reduction of dCK in cells with acquired gemcitabine resistance. Sensitivity is restored by dCK overexpression in one resistant cell line. We aim to further investigate dCK as a potential biomarker for gemcitabine response." @default.
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• W2030120272 date "2012-11-01" @default.
• W2030120272 modified "2023-10-05" @default.
• W2030120272 title "Predictive Biomarkers for Gemcitabine as a Chemoradiosensitizer in Bladder Cancer" @default.
• W2030120272 doi "https://doi.org/10.1016/j.ijrobp.2012.07.1913" @default.
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