CORRELATIONS BETWEEN INTERCALATOR-INDUCED DNA STRAND BREAKS AND SISTER CHROMATID EXCHANGES, MUTATIONS, AND CYTO-TOXICITY IN CHINESE-HAMSTER CELLS

Abstract

Intercalator-induced DNA strand breaks in mammalian cells represent topoisomerase II:DNA complexes trapped by intercalators. These complexes are detected as protein-associated DNA single-strand breaks (SSB) and DNA double-strand breaks (DSB) by filter elution. Using Chinese hamster lung fibroblasts (V79 cells) that were treated for 30 min with various concentrations of 4''-(9-acridinylamino)methanesulfon-m-anisidide or 5-iminodaunorubicin, DNA strand breaks (SSB and DSB), sister chromatid exchanges (SCE), mutations at the hypoxanthine:guanine phosphoribosyltransferase locus and cell killing were measured. DNA strand breakage was correlated with the 3 other parameters. Both drugs induced SCE, mutations and cell killing at concentrations which also produced reversible DNA strand breaks. While the quantity of DSB correlated with SCE, mutations and cytotoxicity for both drugs, more SCE, mutations and cytotoxicity per SSB in cells treated with 5-iminodaunorubicin were found than in those treated with 4''-(9-acridinylamino)methanesulfon-m-anisidide. The DSB (but not the SSB) induced by 4''-(9-acridinylamino)methanesulfon-m-anisidide and 5-iminodaunorubicin at DNA topoisomerase II binding sites correlated closely with SCE, mutations and cell killing and could therefore be responsible for their production.