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 cyclopentenyl 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; however, 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 toxicity of agents that act on enzymes of the de novo pyrimidine pathway. Although the duration of action and potency of cyclopentenyl uracil are not ideal, this is the first demonstration of an effective inhibition of uridine salvage in the intact mouse with a non-cytotoxic agent. This makes possible the evaluation of concurrent inhibition of de novo and salvage routes to pyrimidine nucleotides as an approach to chemotherapy.
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
R L
RL
Cysyk
N
N
Malinowski
V
V
Marquez
D
D
Zaharevitz
E M
EM
August
J D
JD
Moyer
D000818:Animals; D007939:Leukemia L1210 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011742:Pyrimidine Nucleotides / Q000096:biosynthesis; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D014500:Uracil Nucleotides / Q000378:metabolism; D014529:Uridine / Q000378:metabolism*; D014541:Uridine Kinase / Q000037:antagonists & inhibitors*
D011742:Pyrimidine Nucleotides; D014500:Uracil Nucleotides; D014498:Uracil; C068989:cyclopentenyluracil; D014541:Uridine Kinase; D014529:Uridine