Use of oral uridine as a substitute for parenteral uridine rescue of 5-fluorouracil therapy,with and without the uridine phosphorylase inhibitor 5-benzylacyclouridine

Summary Initial clinical trials have demonstrated that uridine (Urd) rescue given i.v. over at least 3 days can ameliorate 5-fluorouracil (FUra) toxicity; to avoid Urd-induced phlebitis in the peripheral veins of patients, a central vein is used. The latter necessity, along with the need for 3 days of i.v. administration, makes Urd rescue by parenteral means a cumbersome and complicated clinical procedure. It would appear preferable to use oral Urd; however, the oral Urd dose in the clinic is limited, as high doses cause diarrhea. Therefore, using a tumor-bearing murine model we investigated as to whether low doses of oral Urd coupled with a Urd phosphorylase inhibitor benzylacyclouridine (BAU), would effect safe rescue of FUra toxicity with preservation of antitumor activity. A high-dose FUra-containing drug combination that included parenteral Urd rescue was used as a control; other groups of tumor-bearing mice received the same drug combination, except that p.o. Urd was substituted for i.p. Urd. In the absence of BAU, p.o. Urd could effect rescue while maintaining an antitumor effect comparable to that obtained with i.p. Urd. When given concomitantly with BAU, a 50% reduction in the oral Urd dose (i.e., from 4,000 to 2,000 mg/kg) enabled the achievement of a comparable therapeutic index. Intraperitoneal Urd produces very high (6–8 mM) plasma and tissue Urd levels, which remain above 100 M for at least 6 h. In contrast, neither oral Urd nor oral BAU alone raised plasma Urd concentrations above about 50 M. However, the combination of oral Urd plus oral BAU gave a peak plasma Urd level of about 300 M, and the level was maintained above 100 M for 6 h. Following oral Urd administration, gut tissue levels of Urd were in the mM range and those of BAU were in the range of 10–20 g/g tissue, a level sufficient to result in substantial inhibition of Urd phosphorylase. Oral Urd plus oral BAU appears to be a promising clinical alternative to parenteral administration of Urd for selective rescue of FUra toxicity.Abbreviations used BAU benzylacyclouridine - FUra 5-fluorouracil - (FUra)RNA RNA containing incorporated FUra - LV leucovorin - MTX methotrexate - PALA N-phosphonacetyl-l-aspartate - Urd uridineSupported in part by Public Health Service grant CA 25842 from the national Cancer Institute, National Institutes of Health, Department of Health and Human Services, and in part by a grant from the Chemotherapy Foundation of New York