Inhibition of DNA excision repair in human cells by Arabinofuranosyl cytosine: effect on normal and xeroderma pigmentosum cells

Journal Article · Mon Jan 01 04:00:00 EST 1979 · Mol. Pharmacol.; (United States)

OSTI ID:5415215

Dunn, W C; Regan, J D

The antineoplastic agent arabinofuranosyl cytosine (ara-C) produces an inhibition of the pyrimidine dimer excision system of human DNA repair. Alkaline sucrose gradient analysis of DNA from normal human skin fibroblasts exposed to 20 J/m/sup 2/ of ultraviolet radiation (254 nm) shows an accumulation of DNA single-strand breaks when DNA repair is attempted in the presence of 10 ..mu..M ara-C. Cells from complementaion groups of xeroderma pigmentosum that are defective in early steps of excision repair show reduced numbers of DNA single strand breaks/10/sup 8/ daltons when compared with normal cells. Cesium chloride gradient analysis of radioactive precurser uptake during repair replication indicates that ara-C causes a 6 to 56% reduction in the number of nucleotide bases inserted into the DNA at concentrations of 1 and 10 ..mu..M, respectively. These concentrations result in the substitution for deoxycytidine (dCyd) by ara-C of 40 and 100%, respectively, in repaired regions. Repair inhibition is reversed by 50% upon removal of ara-C and by > 95% with the addition of 100 ..mu..M dCyd. Chromatography of digested DNA shows that incorporated ara-C is not removed during dCyd reversal, suggesting that ara-C incorporation per se does not play a significant role in the inhibition of repair synthesis. The repair inhibition observed here is dependent on 2 mM hydroxyurea, presumably due to reduction in the intracellular pool of dCyd. The overall results suggest the possibility that ara-C is a weak competitive inhibitor of DNA polymerases associated with ultraviolet-induced excision repair.

• Research Organization: Oak Ridge National Lab., TN
• OSTI ID: 5415215
• Journal Information: Mol. Pharmacol.; (United States), Journal Name: Mol. Pharmacol.; (United States) Vol. 15; ISSN MOPMA
• Country of Publication: United States
• Language: English

Related Subjects

550200* -- Biochemistry
550300 -- Cytology
59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
ANIMALS
ANTINEOPLASTIC DRUGS
AZINES
BIOCHEMISTRY
BIOLOGICAL EFFECTS
BIOLOGICAL RADIATION EFFECTS
BIOLOGICAL RECOVERY
BIOLOGICAL REPAIR
CHEMISTRY
CONNECTIVE TISSUE CELLS
DIMERS
DNA
DRUGS
ELECTROMAGNETIC RADIATION
ENZYMES
FIBROBLASTS
HETEROCYCLIC COMPOUNDS
INHIBITION
MAMMALS
MAN
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHARMACOLOGY
POLYMERASES
PRIMATES
PYRIMIDINES
RADIATION EFFECTS
RADIATIONS
RECOVERY
REPAIR
SOMATIC CELLS
STRAND BREAKS
ULTRAVIOLET RADIATION
VERTEBRATES
XP CELLS