Sister chromatid exchanges, chromosomal aberrations, and cytotoxicity produced by antitumor topoisomerase II inhibitors in sensitive (DC3F) and resistant (DC3F/9-OHE) Chinese hamster cells.
4'-(9-Acridinylamino)methanesulfon-m-anisidide, etoposide, and 2-methyl-9-hydroxyellipticinium are antitumor topoisomerase II (topo II) inhibitors. The relationship between drug-induced sister chromatid exchanges (SCEs) or chromosomal aberrations and cytotoxicity was investigated in Chinese hamster cells sensitive (DC3F) and resistant (DC3F/9-OHE) to topo II inhibitors. Thirty-min drug treatments produced SCEs and chromosomal aberrations in sensitive (DC3F) cells, 4'-(9-acridinylamino)methanesulfon-m-anisidide being more potent than etoposide or 2-methyl-9-hydroxyellipticinium at equimolar concentrations. Comparable treatments of resistant (DC3F/9-OHE) cells did not produce chromosomal damage. The cytotoxicity of 4'-(9-Acridinylamino)-methanesulfon-m-anisidide was also greater than that of etoposide or 2-methyl-9-hydroxyellipticinium in DC3F cells, and no cytotoxicity was observed in DC3F/9-OHE at drug concentrations that produced more than two logs of cell kill in DC3F cells. A plot of cytotoxicity versus SCEs showed a good correlation between the two parameters. Therefore, short treatments of mammalian cells with topo II inhibitors produce reversible topo II-mediated DNA breaks which are associated with chromosomal aberrations and SCEs whose number correlates with cytotoxicity. In addition, topo II mutant DC3F/9-OHE cells were more sensitive than DC3F cells to the chromosomal, DNA cross-linking and cytotoxic effects of mitomycin C and were equally sensitive to the cytotoxic effect of camptothecin.
Pommier
Y
Y
Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland 20892.
Kerrigan
D
D
Covey
J M
JM
Kao-Shan
C S
CS
Whang-Peng
J
J
D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002869:Chromosome Aberrations; D006224:Cricetinae; D004351:Drug Resistance; D004611:Ellipticines / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D016685:Mitomycin; D008937:Mitomycins / Q000494:pharmacology; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D059005:Topoisomerase II Inhibitors
D004611:Ellipticines; D008937:Mitomycins; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; C027767:elliptinium; D016685:Mitomycin; D005047:Etoposide; D002166:Camptothecin