RT Journal Article
SR Electronic
T1 Inhibition of DNA Excision Repair in Human Cells by Arabinofuranosyl Cytosine: Effect on Normal and Xeroderma Pigmentosum Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 367
OP 374
VO 15
IS 2
A1 WILLIAM C. DUNN
A1 JAMES D. REGAN
YR 1979
UL http://molpharm.aspetjournals.org/content/15/2/367.abstract
AB 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/m2 of ultraviolet radiation (254 nm) shows an accumulation of DNA single-strand breaks when DNA repair is attempted in the presence of 10 µM ara-C. Cells from complementation groups of xeroderma pigmentosum that are defective in early steps of excision repair show reduced numbers of DNA single strand breaks/108 daltons when compared with normal cells. Cesium chloride gradient analysis of radioactive precurser uptake during repair replication indicates that ara-C causes a 6-56% reduction in the number of nucleotide bases inserted into the DNA at concentrations of 1 and 10 µM, 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 µM 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.