Combined action of acivicin and D-galactosamine on pyrimidine nucleotide metabolism in hepatoma cells.
The glutamine antagonist acivicin, L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, strongly reduced CTP and GTP contents in AS-30D rat hepatoma cells in suspension. UTP only dropped to 63% of the respective control after 4 hr; however, by combining acivicin with the uridylate-trapping sugar analogue D-galactosamine, a synergistic decrease in UTP contents to 7% of control was induced. Incorporation of 14CO2 into purine and pyrimidine nucleotides followed by radio-high performance liquid chromatography showed marked inhibition of purine and pyrimidine biosynthesis de novo; the latter was reduced to 35% of control. The inhibitory potency of acivicin on glutamine-dependent carbamoyl-phosphate synthetase and consequently on de novo uracil nucleotide formation was also reflected by the complete suppression of the D-galactosamine-induced rise in total uridylate. Induction of UTP deficiency by interference with the first and rate-limiting step in pyrimidine biosynthesis de novo together with a trapping of uridylate by D-galactosamine may provide a promising approach to the chemotherapy of hepatocellular carcinoma.
D000818:Animals; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000037:antagonists & inhibitors; D004347:Drug Interactions; D005260:Female; D005688:Galactosamine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology*; D011742:Pyrimidine Nucleotides / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains
D007555:Isoxazoles; D010080:Oxazoles; D011742:Pyrimidine Nucleotides; D005688:Galactosamine; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); C006303:acivicin