Tissue-specific enhancement of uridine utilization and 5-fluorouracil therapy in mice by benzylacyclouridine

Benzylacyclouridine (BAU), a potent inhibitor of uridine phosphorylase, delays the disappearance of uridine from plasma, affects the utilization of uridine by selected tissues, and enhances the therapeutic effects of 5-fluorouracil (FUra) in female C57BL/6 mice. A single 30-mg/kg i.v. injection of BAU lengthens the plasma half-life of both a tracer dose of [3H]uridine (3 micrograms/kg) and a pharmacological dose of uridine (250 mg/kg) by 250 and 83%, respectively. This dose of BAU also increases the normal plasma concentration of uridine about 4-fold to 9 microM and sustains these levels for 4 h. Four injections of BAU at 30 mg/kg over 6 h or a single injection at 240 mg/kg increases the plasma concentration of uridine over 10-fold to approximately 50 microM. In addition to affecting the pharmacokinetics of uridine, a 30-mg/kg dose of BAU selectively increases up to 4-fold the ability of normal host tissues to salvage a tracer dose of [3H]uridine for nucleic acid biosynthesis, the uracil nucleotide pool size, and the incorporation of uridine into nucleic acids. However, uridine salvage from plasma by colon tumor 38 is increased only slightly by BAU, while the uracil nucleotide pool size and uridine incorporation into tumor nucleic acids are actually decreased by 15 and 37%. The selective effect of BAU on uridine utilization is reflected in the ability of BAU to modify FUra-induced host toxicity. The dose of FUra required to kill 50% of the treated normal mice (350 mg/kg) is modestly increased by "rescue" regimens consisting of the subsequent administration of repeated injections of either BAU alone (30 mg/kg/injection) or uridine alone (250 mg/kg/injection). However, an increase of 54% is achieved when repeated injections of the combination of BAU and uridine are administered. In C57BL/6 mice bearing advanced transplants of colon tumor 38, the period of tumor growth inhibition resulting from multiple courses of FUra-containing drug regimens can be increased by the delayed administration of BAU alone or BAU combined with uridine.