Anti-proliferative activity of L-651,582 correlates with calcium-mediated regulation of nucleotide metabolism at phosphoribosyl pyrophosphate synthetase

Journal Article · Sat Sep 01 00:00:00 EDT 1990 · Journal of Cellular Physiology; (USA)

DOI:https://doi.org/10.1002/jcp.1041440313· OSTI ID:6374423

Hupe, D J; Behrens, N D; Boltz, R ^[1]

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1. 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), Vol. 144:3; ISSN 0021-9541
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
CELL PROLIFERATION
ANTINEOPLASTIC DRUGS
BIOLOGICAL FUNCTIONS
NUCLEOTIDES
METABOLISM
ADENINES
CALCIUM
CARBON 14 COMPOUNDS
CATTLE
EGTA
FORMATES
GLUCOSE
HYPOXANTHINE
INHIBITION
PHOSPHOTRANSFERASES
RIBOSE
TRACER TECHNIQUES
TRITIUM COMPOUNDS
URIDINE
ALCOHOLS
ALDEHYDES
ALKALINE EARTH METALS
AMINES
ANIMALS
ANTIMETABOLITES
AROMATICS
AZAARENES
AZINES
CARBOHYDRATES
CARBOXYLIC ACID SALTS
CARBOXYLIC ACIDS
CHELATING AGENTS
DOMESTIC ANIMALS
DRUGS
ELEMENTS
ENZYMES
FUNCTIONS
GLYCOLS
HETEROCYCLIC COMPOUNDS
HEXOSES
HYDROGEN COMPOUNDS
HYDROXY COMPOUNDS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
METALS
MONOSACCHARIDES
NUCLEOSIDES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PENTOSES
PHOSPHORUS-GROUP TRANSFERASES
PURINES
PYRIMIDINES
RIBOSIDES
RUMINANTS
SACCHARIDES
TRANSFERASES
URACILS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques