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J. Biol. Chem., Vol. 267, Issue 19, 13150-13153, Jul, 1992
SH Elsea, N Osheroff and JL Nitiss
The quinolone CP-115,953 (6,8-difluoro-7-(4-hydroxyphenyl)-1-
cyclopropyl-4- quinolone-3-carboxylic acid) represents a novel mechanistic
class of drugs with potent activity against eukaryotic topoisomerase II in
vitro (Robinson, M. J., Martin, B. A., Gootz, T. D., McGuirk, P. R.,
Moynihan, M., Sutcliffe, J. A., and Osheroff, N. (1991) J. Biol. Chem. 266,
14585-14592). Although the quinolone is highly toxic to mammalian cells in
culture, its mechanism of cytotoxic action is not known. Therefore, yeast
was used as a model system to determine whether topoisomerase II is the
primary target responsible for the in vivo effects of CP-115,953. The
quinolone was equipotent to etoposide at enhancing DNA breakage mediated by
the Saccharomyces cerevisiae type II enzyme. Moreover, at concentrations as
low as 5 microM, CP-115,953 was cytotoxic to yeast cells that carried wild
type topoisomerase II (TOP2+). By utilizing a yeast strain that expressed
the top2-1 temperature-sensitive mutant, the effect of topoisomerase II
activity on quinolone cytotoxicity was determined. At the permissive
temperature of 25 degrees C, cells were highly sensitive to CP-115,953.
However, at the semipermissive temperature of 30 degrees C (where in vivo
enzyme activity is present but is greatly diminished), cells displayed only
marginal sensitivity to the quinolone at concentrations as high as 50
microM. These results strongly suggest that topoisomerase II is the primary
physiological target responsible for quinolone cytotoxicity and that
CP-115,953 kills cells by converting the type II enzyme into a cellular
poison.
Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP- 115,953 in yeast
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
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