Differential expression of uridine phosphorylase in tumors contributes to an improved fluoropyrimidine therapeutic activity

Deliang Cao, Amy Ziemba, James McCabe, Ruilan Yan, Laxiang Wan, Bradford Kim, Michael Gach, Stuart Flynn, Giuseppe Pizzorno

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Abrogation of uridine phosphorylase (UPase) leads to abnormalities in pyrimidine metabolism and host protection against 5-fluorouracil (5-FU) toxicity. We elucidated the effects on the metabolism and antitumor efficacy of 5-FU and capecitabine (N 4-pentyloxycarbonyl-5′-deoxy-5- fluorocytidine) in our UPase knockout(UPase -/-) model. Treatment with 5-FU (85 mg/kg) or capecitabine (1,000 mg/kg) five days a week for four weeks caused severe toxicity and structural damage to the intestines of wild-type (WT) mice, but not in UPase -/- animals. Capecitabine treatment resulted in a 70% decrease in blood cell counts of WT animals, with only a marginal effect in UPase -/- mice. UPase expressing colon 38 tumors implanted in UPase -/- mice revealed an improved therapeutic efficacy when treated with 5-FU and capecitabine because of the higher maximum tolerated dose for fluoropyrimidines achievable in UPase -/- mice. 19F-MRS evaluation of capecitabine metabolism in tumors revealed similar activation of the prodrug in UPase -/- mice compared with WT. In WT mice, approximately 60% of capecitabine was transformed over three hours into its active metabolites, whereas 80% was transformed in tumors implanted in UPase -/- mice. In UPase -/- mice, prolonged retention of 50dFUR allowed a proportional increase in tumor tissue. The similar presence of fluorinated catabolic species confirms that dihydropyrimidine dehydrogenase activity was not altered in UPase -/- mice. Overall, these results indicate the importance of UPase in the activation of fluoropyrimidines, the effect of uridine in protecting normal tissues, and the role for tumor-specific modulation of the phosphorolytic activity in 5-FU or capecitabine-based chemotherapy.

Original languageEnglish (US)
Pages (from-to)2330-2339
Number of pages10
JournalMolecular Cancer Therapeutics
Volume10
Issue number12
DOIs
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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