Mechanism of purine antimetabolites and purine nucleodise imbalance
Purine starvation is responsible for the cytotoxic effects of many purine antimetabolites. Guanine nucleotide depletion leads to a drastic DNA synthesis inhibition while adenine nucleotide depletion interferes with other vital functions before inhibiting DNA synthesis. To investigate the mechanism of these distinct effects, kinetics studies of adenine and guanine tracer incorporation into nucleotide pools and DNA were performed in S-49 cells. To address the question whether the cellular dGTP pool is compartmentalized, ({sup 14}C)Gua and ({sup 3}H)Guo tracer experiments were performed in a double mutant S-49 cell line, dGuo-L, with purine nucleoside phosphorylase (PNP) deficiency and dGTP feedback resistant ribonucleotide reductase (RR). While RR inhibition by dGTP was proposed as the cytotoxic mechanism in PNP immunodeficiency, additional effects of dGuo were studied in S-49 cells and human peripheral blood T lymphocytes (PBTL). RNA synthesis but not DNA synthesis was among the earliest targets of dGuo toxicity, and dGuo exerted cytotoxicity in resting PBTL before DNA synthesis. Three transformed T cells lines, PEER, HPB-ALL and HPB-MLT, were selected and characterized for cell surface markers and their sensitivities to dAdo and deoxycoformycin, an ADA inhibitor.
- Research Organization:
- California Univ., San Francisco, CA (USA)
- OSTI ID:
- 6940368
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
ADENINES
AMINES
ANIMAL CELLS
ANIMALS
ANTIMETABOLITES
AROMATICS
AZAARENES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL FUNCTIONS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CARBON 14 COMPOUNDS
CONNECTIVE TISSUE CELLS
DNA REPLICATION
DRUGS
ENZYME ACTIVITY
ENZYMES
FUNCTIONS
GUANINE
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
HYDROXY COMPOUNDS
INHIBITION
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
LEUKOCYTES
LYMPHOCYTES
MAMMALS
MAN
MATERIALS
NUCLEIC ACID REPLICATION
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
OXIDOREDUCTASES
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
PRIMATES
PURINES
REACTION KINETICS
SOMATIC CELLS
TRACER TECHNIQUES
TRANSFERASES
TRITIUM COMPOUNDS
VERTEBRATES