Synergistic effect of aphidicolin and 1-beta-D-arabinofuranosylcytosine on the repair of gamma-ray-induced DNA damage in normal human fibroblasts.
The effects on enzymatic DNA repair of aphidicolin and 1-beta-D-arabinofuranosylcytosine (araC), two potent inhibitors of long-patch excision repair, were investigated in cultured human cells exposed to 60Co gamma-radiation. Using alkaline-sucrose velocity sedimentation analysis, both drugs were shown to inhibit markedly the repair of radioproducts in cultures exposed to greater than or equal to 150 Gy, indicating that a significant component of gamma-ray-induced DNA damage is operated on by a long-patch excision pathway. Moreover, while the extent of repair inhibited by aphidicolin was comparable to that suppressed by araC, combined exposure of irradiated cultures to the two drugs elicited a synergistic response. Specifically, in all three normal fibroblast strains examined, the yield of aphidicolin- or araC-detectable sites (lesions whose repair could be blocked by each drug alone) observed during the first 2 h after irradiation with 150 Gy ranged from 0.8 to 1.2 per 10(8) daltons genomic DNA, whereas the incidence of sites detected by combined exposure to the inhibitors was increased 4-fold (i.e. 3.8 per 10(8) daltons). This difference in site yield leads us to propose that simultaneous administration of aphidicolin and araC serves to block, in addition to long-patch repair, a second mode of excision repair which is refractory to each drug alone.
Department of Medicine, Cross Cancer Institute, Alberta, Canada.
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R
Mirzayans
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B
Andrais
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MC
Paterson
D016590:Aphidicolin / Q000494:pharmacology*; D002499:Centrifugation, Density Gradient; D003037:Cobalt Radioisotopes; D003561:Cytarabine / Q000494:pharmacology*; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004357:Drug Synergism; D005347:Fibroblasts; D005720:Gamma Rays; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D011829:Radiation Dosage; D014466:Ultraviolet Rays
D003037:Cobalt Radioisotopes; D003561:Cytarabine; D016590:Aphidicolin; D004247:DNA; D006918:Hydroxyurea