The IMP dehydrogenase inhibitor mycophenolic acid antagonizes the CTP synthetase inhibitor 3-deazauridine in MOLT-3 human leukemia cells: a central role for phosphoribosyl pyrophosphate.
Mycophenolic acid, an inhibitor of the enzyme IMP dehydrogenase, antagonizes the CTP synthetase inhibitor 3-deazauridine in its anti-proliferative effects on MOLT-3 human T leukemia cells. No depletion of CTP occurred, and decreased amounts of 3-deazuridine-triphosphate were measured in cells incubated with mycophenolic acid and 3-deazuridine. Most probably, these phenomena are related to the increased amounts of PRPP observed, which can result in an increased pyrimidine biosynthesis de novo and, as a consequence, a decreased metabolism of 3-deazauridine via the salvage pathway.
van Berg
A A
AA
Academic Medical Center, University of Amsterdam, Department of Pediatrics, The Netherlands.
Mooyer
P A
PA
van Lenthe
H
H
Stet
E H
EH
De Abreu
R A
RA
van Kuilenburg
A B
AB
van Gennip
A H
AH
D015092:3-Deazauridine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019731:Carbon-Nitrogen Ligases; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007938:Leukemia; D008025:Ligases / Q000037:antagonists & inhibitors*; D009173:Mycophenolic Acid / Q000494:pharmacology*; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism*; D012265:Ribonucleotides / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D012265:Ribonucleotides; D015092:3-Deazauridine; D010754:Phosphoribosyl Pyrophosphate; D007168:IMP Dehydrogenase; D008025:Ligases; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase; D009173:Mycophenolic Acid