Correlations between intercalator-induced DNA strand breaks and sister chromatid exchanges, mutations, and cytotoxicity in Chinese hamster cells.
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, we measured DNA strand breaks (SSB and DSB), sister chromatid exchanges (SCE), mutations at the hypoxanthine:guanine phosphoribosyltransferase locus, and cell killing. Further, we correlated DNA strand breakage with the three 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, we found more SCE, mutations, and cytotoxicity per SSB in cells treated with 5-iminodaunorubicin than in those treated with 4'-(9-acridinylamino)methanesulfon-m-anisidide. These data show that 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.
Pommier
Y
Y
Zwelling
L A
LA
Kao-Shan
C S
CS
Whang-Peng
J
J
Bradley
M O
MO
D000609:Aminoacridines / Q000633:toxicity; D000677:Amsacrine; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA; D004264:DNA Topoisomerases, Type I / Q000032:analysis; D004277:DNA, Single-Stranded; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000633:toxicity; D007364:Intercalating Agents / Q000633:toxicity*; D009154:Mutation; D012854:Sister Chromatid Exchange / Q000187:drug effects*
D000609:Aminoacridines; D004277:DNA, Single-Stranded; D007364:Intercalating Agents; D000677:Amsacrine; D004247:DNA; D004264:DNA Topoisomerases, Type I; C018979:5-iminodaunorubicin; D003630:Daunorubicin