DNA lesions in human neoplastic cells and cytotoxicity of 5-fluoropyrimidines.

Abstract

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.