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 chromat...

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Bibliographic Details
Published in:The Journal of biological chemistry 1986-11, Vol.261 (32), p.14891-14895
Main Authors: Kemp, A J, Lyons, S D, Christopherson, R I
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Applied sciences
Bicarbonates - metabolism
Biological and medical sciences
Carbon Radioisotopes
Cytidine Triphosphate - biosynthesis
Exact sciences and technology
General aspects
Guanosine Triphosphate - biosynthesis
Isoxazoles - pharmacology
Kinetics
Leukemia L1210 - metabolism
Medical sciences
Mice
Naphthoquinones - pharmacology
Other techniques and industries
Oxazoles - pharmacology
Pharmacology. Drug treatments
Pyrimidines - biosynthesis
Uracil Nucleotides - biosynthesis
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Summary: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 [14C]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.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(18)66800-0