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. (19)F-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 5'dFUR 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.
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Authors | Deliang Cao, Amy Ziemba, James McCabe, Ruilan Yan, Laxiang Wan, Bradford Kim, Michael Gach, Stuart Flynn, Giuseppe Pizzorno |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 10
Issue 12
Pg. 2330-9
(Dec 2011)
ISSN: 1538-8514 [Electronic] United States |
PMID | 21954436
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Antimetabolites, Antineoplastic
- Prodrugs
- Pyrimidines
- Deoxycytidine
- Capecitabine
- Uridine Phosphorylase
- Fluorouracil
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Topics |
- Animals
- Antimetabolites, Antineoplastic
(metabolism, therapeutic use)
- Capecitabine
- Cell Line, Tumor
- Deoxycytidine
(analogs & derivatives, therapeutic use)
- Drug Evaluation, Preclinical
- Drug Resistance, Neoplasm
(genetics)
- Fluorouracil
(analogs & derivatives, metabolism, therapeutic use)
- Gene Expression Regulation, Enzymologic
(drug effects, physiology)
- Gene Expression Regulation, Neoplastic
(drug effects, physiology)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neoplasms
(drug therapy, enzymology, genetics, metabolism)
- Prodrugs
(metabolism, therapeutic use)
- Pyrimidines
(metabolism, therapeutic use)
- Treatment Outcome
- Uridine Phosphorylase
(genetics, metabolism, physiology)
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