DNA lesions in human neoplastic cells and cytotoxicity of 5-fluoropyrimidines.
We have examined the induction of alkali-labile regions in DNA of human neoplastic cells treated with 5-fluorouracil and 5-fluorodeoxyuridine. 5-Fluorouracil induces DNA lesions by two mechanisms: incorporation of drug into DNA and a second mechanism not involving the incorporation. The second mechanism is seen in cells treated with aphidicolin, a specific inhibitor of DNA polymerase alpha, to stop the movement of the DNA replication forks. 5-Fluorodeoxyuridine is not incorporated into DNA of these cells; only the second mechanism of induction of alkali-labile DNA is detected. The second mechanism is in all probability due to inefficient DNA repair of normally occurring defects in purine and pyrimidine residues. Furthermore there is a correlation between increasing levels of alkali-labile regions in the DNA and cytotoxicity of the drugs. This may be one explanation for the cytocidal effects of 5-fluoropyrimidines.
D016590:Aphidicolin; D002470:Cell Survival / Q000187:drug effects; D002499:Centrifugation, Density Gradient; D004273:DNA, Neoplasm / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology; D005467:Floxuridine / Q000494:pharmacology*; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D009369:Neoplasms / Q000032:analysis*; D013997:Time Factors
D004273:DNA, Neoplasm; D004224:Diterpenes; D005467:Floxuridine; D016590:Aphidicolin; D005472:Fluorouracil; D008727:Methotrexate