Anti-proliferative activity of L-651,582 correlates with calcium-mediated regulation of nucleotide metabolism at phosphoribosyl pyrophosphate synthetase
- Merck Institute for Therapeutic Research, Rahway, NJ (USA)
L-651,582, 5-amino-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1, 2,3-triazole-4-carboxamide, is an antiproliferative and antiparasitic agent which inhibits nucleotide metabolism in mammalian cells. The drug equivalently inhibited 3H-hypoxanthine, 14C-adenine, and 14C-formate incorporation into nucleotide pools in Madin-Darby bovine kidney (MDBK) cells, suggesting depletion of the supply of phosphoribosyl pyrophosphate, (PRPP), required for each of these independent pathways. Inhibition of nucleotide metabolism correlated with inhibition of proliferation for three cell types with differing sensitivities toward the drug. L-651,582 inhibited incorporation of 3H-hypoxanthine into nucleotide pools with either glucose, uridine, or ribose as carbon source suggesting a block at PRPP synthetase, rather than a block in a pathway supplying ribose-5-phosphate. PRPP synthetase was not inhibited directly by the compound, indicating regulation of the enzyme in intact cells. Drug treatment did not kill cells but reduced the fraction of cells in S and G2/M while increasing the population in G1. Inhibition of uptake of 45Ca was demonstrated at concentrations identical to those required for inhibition of nucleotide metabolism or proliferation. Inhibition of cellular PRPP biosynthesis rates were also observed using EGTA to lower calcium levels. These data suggest a previously unrecognized link between calcium entry, the regulation of nucleotide biosynthesis at PRPP synthetase, and the rate of proliferation of mammalian cells.
- OSTI ID:
- 6374423
- Journal Information:
- Journal of Cellular Physiology; (USA), Journal Name: Journal of Cellular Physiology; (USA) Vol. 144:3; ISSN 0021-9541; ISSN JCLLA
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
ADENINES
ALCOHOLS
ALDEHYDES
ALKALINE EARTH METALS
AMINES
ANIMAL CELLS
ANIMALS
ANTIMETABOLITES
ANTINEOPLASTIC DRUGS
AROMATICS
AZAARENES
AZINES
BIOLOGICAL FUNCTIONS
CALCIUM
CARBOHYDRATES
CARBON 14 COMPOUNDS
CARBOXYLIC ACID SALTS
CARBOXYLIC ACIDS
CATTLE
CELL PROLIFERATION
CHELATING AGENTS
DOMESTIC ANIMALS
DRUGS
EGTA
ELEMENTS
ENZYMES
FORMATES
FUNCTIONS
GLUCOSE
GLYCOLS
HETEROCYCLIC COMPOUNDS
HEXOSES
HYDROGEN COMPOUNDS
HYDROXY COMPOUNDS
HYPOXANTHINE
INHIBITION
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
METABOLISM
METALS
MONOSACCHARIDES
NUCLEOSIDES
NUCLEOTIDES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PENTOSES
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
PURINES
PYRIMIDINES
RIBOSE
RIBOSIDES
RUMINANTS
SACCHARIDES
TRACER TECHNIQUES
TRANSFERASES
TRITIUM COMPOUNDS
URACILS
URIDINE
VERTEBRATES