DNA repair following incorporation of 5-fluorouracil into DNA of mouse bone marrow cells.
5-Fluorouracil (FUra) was previously demonstrated to be incorporated into DNA at cytotoxic concentrations in mouse bone marrow cells. Subsequently, we showed that under these conditions FUra exhibited a time-dependent removal from DNA accompanied by a decrease in DNA strand length. In the present study we utilized hydroxyurea to inhibit semiconservative DNA synthesis while monitoring DNA repair by measuring the incorporation of [3H]dThd into double-stranded DNA (DNAds), which can be separated from DNA at the replication fork (DNAss) by benzoylated-naphthoylated-DEAE cellulose. Under these conditions we assessed DNA repair in cells that had previously been exposed for 1 h to varying cytotoxic concentrations of FUra. The results demonstrate an increase in labelling of DNAds with increasing FUra concentrations, with no appreciable increase in incorporation of label into DNAss. In conclusion, this study demonstrates that DNA repair occurs following incorporation of FUra. The failure to repair DNA damage at higher FUra concentrations may have a role in the cytotoxicity of this drug.
Schuetz
J D
JD
Department of Pharmacology and Comprehensive Cancer Center, University of Alabama, Birmingham 35294.
Wallace
H J
HJ
Diasio
R B
RB
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D001854:Bone Marrow Cells; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D006918:Hydroxyurea / Q000494:pharmacology; D008297:Male; D051379:Mice
D004277:DNA, Single-Stranded; D004247:DNA; D005472:Fluorouracil; D006918:Hydroxyurea