Abstract
Abstract Fluorouracil (5-FU) a commonly used drug in the treatment of cancer is hampered by a short unpredictable plasma half-life, which complicates dose modulation to minimize toxicity and improve efficacy of 5-FU treatment. Strategies to improve on the unfavorable pharmacokinetic properties of 5-FU, currently under clinical trial, involve targeting of the catabolic enzyme dihydropyrmidine dehydrogenase (DPD).This requires understanding the mechanisms regulating the expression of DPD and the inducibility of 5-FU catabolism, which is inadequately investigated. By performing in silico analysis we were able to identify putative p53 binding sites in the proximity of the dihydropyrimidine dehydrogenase gene (DPYD) and confirm by chromatin immunoprecipitation (ChIP) that p53 increasingly locates to a binding site (about 1.8 ± 0.05 fold over untreated control) downstream of DPYD (P53DBS) following a single IV bolus of 5-FU (150 mg/kg bw) in mouse liver. Indeed, DPYD mRNA increased by 1.8 fold and protein by 1.8 fold (P< 0.0005) respectively in a time- and p53-dependent manner in the liver of treated with 5-FU. Our ongoing studies are focused on assessing p53-dependent regulation of DPD-activity and the resulting change in 5-FU bioavailability We suggest that p53 can regulate an important step of pyrimidine-catabolism and targeting p53 in the context of 5-FU therapy of malignancies carrying p53 mutations may be another strategy to improve treatment efficacy. Citation Format: Prashanth R. Gokare, Niklas Finnberg, Joshua Allen, Jenny Dai, Wafik El-Deiry. p53-dependent expression of the fluorouracil (5-FU) catabolic enzyme dihydropyrimidine dehydrogenase (DPD) in mouse liver. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2197. doi:10.1158/1538-7445.AM2013-2197
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