title: Differential expression of uridine phosphorylase in tumors contributes to an improved fluoropyrimidine therapeutic activity.
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.
authors.affiliation: Department of Medical Microbiology, Immunology, and Cell Biology, Simmons/Cooper Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois, USA.
authors.forename: Deliang
authors.initials: D
authors.lastname: Cao
authors.forename: Amy
authors.initials: A
authors.lastname: Ziemba
authors.forename: James
authors.initials: J
authors.lastname: McCabe
authors.forename: Ruilan
authors.initials: R
authors.lastname: Yan
authors.forename: Laxiang
authors.initials: L
authors.lastname: Wan
authors.forename: Bradford
authors.initials: B
authors.lastname: Kim
authors.forename: Michael
authors.initials: M
authors.lastname: Gach
authors.forename: Stuart
authors.initials: S
authors.lastname: Flynn
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pizzorno
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use; D000069287:Capecitabine; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use; D011743:Pyrimidines / Q000378:metabolism / Q000627:therapeutic use; D016896:Treatment Outcome; D014543:Uridine Phosphorylase / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D011743:Pyrimidines; D003841:Deoxycytidine; D000069287:Capecitabine; D014543:Uridine Phosphorylase; D005472:Fluorouracil