Sister chromatid exchanges and DNA topoisomerase II inhibitors: effect of low concentrations of etoposide (VP-16) in ataxia telangiectasia lymphoblastoid cell lines

The correlation between etoposide (VP-16) cytotoxicity and the induction of sister chromatid exchanges (SCEs) suggested that the promotion of DNA recombination events may be crucial for the activity of antitopoisomerase drugs. To further evaluate this hypothesis, we investigated the correlation between VP-16 induction of SCEs, chromosomal aberrations and cell cycle alterations in lymphoblastoid cell lines derived from patients affected by ataxia telangiectasia(AT), whose cells are known as hypersensitive to the cytotoxic and clastogenic activity of DNA topoisomerase II inhibitors. Our present study has shown that AT homozygous and heterozygous cell lines exposed to low VP-16 concentrations, although hypersensitive to the induction of chromosomal aberrations, exhibit an induction of SCEs comparable to that found in normal cell lines. Moreover, while the clastogenic effect of the drug was directly correlated to the reduction of the mitotic index, the enhancement of SCE frequencies, obtained over the same range of VP-16 concentrations, was not paralleled by a modification of proliferation index. Thus, these results suggest that etoposide retains in AT cells a strong clastogenic and cytostatic activity which is independent from DNA recombination events and which may be important for the induction of cell death by this kind of drug. (C) 1998 Elsevier Science B.V.