Effects of acivicin and dichloroallyl lawsone upon pyrimidine biosynthesis in mouse L1210 leukemia cells
Acivicin (NSC 163501) and dichloroallyl lawsone (NSC 126771) are potent inhibitors of nucleotide biosynthesis with consequent anti-cancer activity against certain experimental tumors. To determine in detail the metabolic events induced by each inhibitor, we have devised a new two-dimensional chromatographic procedure for measurement of the concentrations of all pyrimidine intermediates and some purine nucleotides from 100 microliter of an extract of cells grown in the presence of (/sup 14/C)bicarbonate. Addition of acivicin (25 microM) to mouse L1210 leukemia cells causes severe depletion in the cellular levels of CTP and GTP, accumulation of uridine nucleotides, and abrupt but transient increases in the concentrations of the early intermediates of both the pyrimidine and purine pathways. Addition of dichloroallyl lawsone (25 microM) results in a rapid depletion of uridine and cytidine nucleotides; carbamyl aspartate and dihydroorotate accumulate to high levels in an equilibrium ratio of 20.5:1, and orotate, orotidine, and UMP increase transiently before decreasing to levels approaching their original steady states. The predominant inhibitory effects of acivicin are upon the reactions UTP----CTP and XMP----GMP, but there is also an initial transient activation of both the pyrimidine and purine pathways by acivicin. The data obtained with dichloroallyl lawsone are consistent with inhibition of the conversion of UMP----UDP initially followed by potent inhibition of dihydroorotate----orotate.
- Research Organization:
- Univ. of Melbourne, Parkville, Victoria
- OSTI ID:
- 6846715
- Journal Information:
- J. Biol. Chem.; (United States), Vol. 32
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ANTINEOPLASTIC DRUGS
BIOLOGICAL EFFECTS
PYRIMIDINES
BIOSYNTHESIS
CARBON 14 COMPOUNDS
EXPERIMENTAL NEOPLASMS
INHIBITION
LEUKEMIA
METABOLISM
MICE
OXAZOLES
ANIMALS
AZINES
AZOLES
DISEASES
DRUGS
HEMIC DISEASES
HETEROCYCLIC COMPOUNDS
LABELLED COMPOUNDS
MAMMALS
NEOPLASMS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
RODENTS
SYNTHESIS
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology