Abstract 4390: Role of uridine phosphorylase 2 in fluoropyrimidine activation and host toxicity

Abstract

Abstract Uridine phosphorylase (UPP) and thymidine phosphorylase (TPP) both catalyze the reversible conversion of uridine, deoxyuridine and thymidine to the corresponding free bases and ribose or deoxyribose-1-phosphate. They play a pivotal role in the metabolism of pyrimidine analogs used in cancer chemotherapy. Recently, a novel pyrimidine phosphorylase has been identified, named Uridine Phosphorylase 2 (UPP-2). In human tissues, UPP-2 is predominantly expressed in kidney cells, while in mouse tissue it is predominately expressed in the liver. We have recently screened a panel of human kidney and liver tissues by real-time PCR. The data concurred with high expression in kidney, but also a significant level of the UPP2 transcript was identified in human liver, albeit 10% of the level in kidney. It is critical for chemotherapeutic agents to be selective for tumor tissue sparing the surrounding normal tissues from toxic anti-proliferative effects, yet few agents have been designed to be selectively activated in tumor tissue. Capecitabine and 5′-deoxy-5-fluorouridine (5′-DFUR) are two successful prodrugs that are metabolized to 5-FU mainly in tumor tissue due to an increased phosphorolytic activity because of an elevated presence of UPP and TPP. Several organs and tissues, including liver, express the same phosphorolytic enzymes resulting in the activation to 5-FU with consequent toxic effects. We previously determined that the UPP-2 isoform is overexpressed 4-fold in the liver of UPP/TPP double-knockout mice (DKO) and contemplated what role UPP2 may play in 5′-DFUR activation and toxicity. Both the physiological role of UPP-2 in nucleoside metabolism and the pyrimidine homeostatic regulation of UPP-1 and UPP-2 in liver are presently unclear. Wild-type (WT) and DKO mice were treated with 500 or 750 mg/kg of 5′-DFUR daily Monday through Friday for up to 6 weeks. A 1,000 mg/kg dosage group was included for DKO animals only, as WT mice display severe toxicity after only a few days of treatment at this high dosage. Both WT treatment groups had significant weight loss after the first week of treatment, while DKO animals across all treatment groups did not display weight loss until the third week of 5′-DFUR administration. 5-FU levels in mouse serum were evaluated 3 hours after 5′-DFUR administration. Interestingly, circulating 5-FU was detectable within the DKO treatment group. This indicates UPP-2 may contribute to 5’DFUR conversion into 5-FU. 5-Benzyl-acyclo-uridine (BAU) is a potent inhibitor of UPP1. We therefore evaluated its effect on UPP2 activity, and by in vivo 19F-NMR identified a significant inhibitory activity against UPP2 by nullifying the activation of 5′-DFUR. It will be important to further quantify and discern the role of UPP-2 in prodrug activation and in normal tissue toxicities since we were not able to identify any tumor type expressing this second uridine phosphorolytic activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4390. doi:10.1158/1538-7445.AM2011-4390