Sister Chromatid Exchanges, Chromosomal Aberrations, and Cytotoxicity Produced by Antitumor Topoisomerase II Inhibitors in Sensitive (DC3F) and Resistant (DC3F/9-OHE) Chinese Hamster Cells

Yves Pommier, Donna Kerrigan, Joseph M. Covey, Chien Song Kao-Shan, Jacqueline Whang-Peng

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Abstract

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-acridin-ylamino)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.

Original languageEnglish
Pages (from-to)512-516
Number of pages5
JournalCancer Research
Volume48
Issue number3
Publication statusPublished - Jan 1 1988
Externally publishedYes

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Topoisomerase II Inhibitors
Sister Chromatid Exchange
Cricetulus
Chromosome Aberrations
elliptinium
Etoposide
Type II DNA Topoisomerase
Pharmaceutical Preparations
Camptothecin
DNA Breaks
Mitomycin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sister Chromatid Exchanges, Chromosomal Aberrations, and Cytotoxicity Produced by Antitumor Topoisomerase II Inhibitors in Sensitive (DC3F) and Resistant (DC3F/9-OHE) Chinese Hamster Cells. / Pommier, Yves; Kerrigan, Donna; Covey, Joseph M.; Kao-Shan, Chien Song; Whang-Peng, Jacqueline.

In: Cancer Research, Vol. 48, No. 3, 01.01.1988, p. 512-516.

Research output: Contribution to journalArticle

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abstract = "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-acridin-ylamino)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.",
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