Effect of gallium on DNA synthesis by human T-cell lymphoblasts

Journal Article · Wed Jun 01 04:00:00 EDT 1988 · Cancer Res.; (United States)

OSTI ID:7195359

Hedley, D W; Tripp, E H; Slowiaczek, P; Mann, G J

We have studied the antiproliferative effects of gallium nitrate in cultured CCRF-CEM lymphoblasts. The 50% inhibitory dose for these cells was 120 microM, and after 24 h at a cytostatic concentration (480 microM) S-phase arrest was observed by DNA flow cytometry. Deoxyribonucleoside triphosphate pools were all reduced (dATP, dGTP, and dCTP by 50%, dTTP by 25%), suggesting inhibition of ribonucleotide reductase. Administration of tracer amounts (0.5 microM) of either (3H)uridine or (3H)deoxyuridine confirmed that DNA synthesis had been inhibited to 20% of control rates by gallium. Further, the flow of the ribonucleoside into the dTTP pool and DNA was selectively reduced compared to that of the deoxyribonucleoside. Gallium decreased the specific activity of dTTP labeled from uridine by 50%, whereas the specific activity of dTTP labeled from deoxyuridine was increased 2.5-fold. Thus counts in DNA derived from (3H)uridine were decreased by more than 80%, while counts in DNA derived from (3H)deoxyuridine were virtually unaltered. Uridine incorporation into RNA was not affected. Gallium did not significantly alter the capacity of permeabilized naive cells to incorporate (3H)dTTP into DNA, while 24-h gallium pretreatment (which increased the percentage of S-phase cells) produced a modest increase in (3H)dTTP incorporation, indicating that any effect of gallium on DNA polymerase alpha is minor. Gallium treatment did not induce or inhibit the repair of DNA single strand breaks. These data demonstrate that gallium inhibits replicative DNA synthesis, with the major specific enzyme target probably being ribonucleotide reductase.

• Research Organization: Univ. of Sydney, N.S.W. (Australia)
• OSTI ID: 7195359
• Journal Information: Cancer Res.; (United States), Journal Name: Cancer Res.; (United States) Vol. 48:11; ISSN CNREA
• Country of Publication: United States
• Language: English

Related Subjects

550901* -- Pathology-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
ANTIMETABOLITES
ANTINEOPLASTIC DRUGS
AZINES
BIOLOGICAL EFFECTS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CELL CULTURES
CELL FLOW SYSTEMS
CELL PROLIFERATION
CONNECTIVE TISSUE CELLS
DEOXYURIDINE
DNA
DNA REPLICATION
DRUGS
ENZYMES
GALLIUM COMPOUNDS
GALLIUM NITRATES
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
INHIBITION
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
LEUKOCYTES
LYMPHOCYTES
MATERIALS
NITRATES
NITROGEN COMPOUNDS
NUCLEIC ACID REPLICATION
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
OXIDOREDUCTASES
OXYGEN COMPOUNDS
PYRIMIDINES
RIBOSIDES
RNA
SOMATIC CELLS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
URACILS
URIDINE