CYCLOPENTENYL URACIL - AN EFFECTIVE INHIBITOR OF URIDINE SALVAGE IN-VIVO

Cyclopentenyl uracil, a non-cytotoxic inhibitor of uridine kinase, was found to effectively block the salvage of circulating uridine by host and tumor tissues in the intact mouse. Dose-response characteristics of the inhibition were determined. Large doses (1 g/kg) of cyclopenten yl uracil were required, and the effect of a single dose fell rapidly over a 24-hr period. A sustained inhibition of uridine salvage of >64- 79% could be maintained by multiple doses of 1 g/kg given on an every 8-hr schedule. Mice given cyclopentenyl uracil (1 g/kg) every 8 hr for 5 days continued to gain weight and showed no signs of toxicity; howe ver, the combination of cyclopentenyl uracil with a non-toxic dose of N-(phosphonacetyl)-L-aspartic acid (PALA; 200 mg/kg daily for 5 days) was lethal to mice, indicating that circulating uridine modifies the t oxicity of agents that act on enzymes of the de novo pyrimidine pathwa y. Although the duration of action and potency of cyclopentenyl uracil are not ideal, this is the first demonstration of an effective inhibi tion of uridine salvage in the intact mouse with a non-cytotoxic agent . This makes possible the evaluation of concurrent inhibition of de no vo and salvage routes to pyrimidine nucleotides as an approach to chem otherapy.