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 in our UPase knockout (UPase −/−) model. Treatment with 5-FU (85 mg/kg) or Capecitabine (1000 mg/kg) 5 days a week for 4 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 due to the higher maximum tolerated dose for fluoropyrimidines achievable in UPase −/− mice. 19F-MRS evaluation of Capecitabine metabolism in tumors revealed similar activation of the pro-drug in UPase −/− mice compared to WT. In WT mice, approximately 60% of Capecitabine was transformed over 3 hours into its active metabolites, while 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.

Colonic transcriptional response to 1α,25(OH) 2 vitamin D 3 in African- and European-Americans

“…Uridine-induced DNA damage was also confirmed in multiple cell lines (48). Interestingly, tissue uridine levels have been implicated as being protective of 5-FU-induced damage in the colon (49), and AA experience fewer gastrointestinal side effects in response to 5-FU, leading to the hypothesis that AA might have higher colonic uridine levels. Taken together, these findings provide rationale for further investigation of inter-ethnic differences in 1α,25(OH) 2 D 3 regulation of UPP1 , uridine homeostasis and DNA damage in the colon.…”

Therapeutic drug monitoring of 5-fluorouracil

“…The first 2 steps take place primarily in the liver, while the 3 rd and final step is catalyzed by thymidine phosphorylase (TP) and uridine phosphorylase (UP) [45–48], and this occurs in both normal and tumor tissue. It has been shown that both TP and UP are expressed at higher levels within tumor tissue when compared to normal tissue, thereby leading to preferential conversion to 5-FU in tumor tissue with decreased systemic 5-FU exposure [49].…”

Disruption of uridine homeostasis links liver pyrimidine metabolism to lipid accumulation

“…UPase Ϫ / Ϫ mice with genetic deletion of UPP1 gene exhibited a 6-fold increase and a 3-fold increase in the plasma and liver uridine concentration, respectively ( 15,16 ). In this study, we generate a transgenic UPase1 -TG mouse strain with genetic knock-in of mouse UPP1 gene.…”