YEAST-CELLS EXPRESSING DIFFERENTIAL LEVELS OF HUMAN OR YEAST DNA TOPOISOMERASE-II - A POTENT TOOL FOR IDENTIFICATION AND CHARACTERIZATION OF TOPOISOMERASE II-TARGETING ANTITUMOR AGENTS
B. Vanhille et Bt. Hill, YEAST-CELLS EXPRESSING DIFFERENTIAL LEVELS OF HUMAN OR YEAST DNA TOPOISOMERASE-II - A POTENT TOOL FOR IDENTIFICATION AND CHARACTERIZATION OF TOPOISOMERASE II-TARGETING ANTITUMOR AGENTS, Cancer chemotherapy and pharmacology, 42(5), 1998, pp. 345-356
Purpose: To identify and characterize the specificity and potency of t
opoisomerase II-interacting antitumour drugs in an in vivo model utili
zing the yeast Saccharomyces cerevisiae. Methods: Four yeast transform
ants were selected for the expression of either human or yeast DNA top
oisomerase II at different, biologically relevant, levels under the ti
ght control of promoters of various strengths. Results: Analyses of 24
drugs permitted their classification into three distinct groups, depe
nding on whether they induced topoisomerase II-related cytotoxicity (e
toposide), showed nonspecific cytotoxicity (camptothecin), or exerted
no cytotoxicity at all (vinorelbine). Within the first group different
patterns of action were distinguishable: (1) classical topoisomerase
II expression-dependent cytotoxicity for both species of enzyme (e.g.
etoposide, amsacrine, doxorubicin, actinomycin D), although amsacrine
and TOP 53 were more active, respectively, on human and yeast topoisom
erase II; and (2) compounds that appeared to poison only one species o
i topoisomerase II with, for example, genistein and the bisdioxopipera
zine ICRF-193 lethally targeting only the human type, and mitoxantrone
only the yeast isozyme. Three of the 16 known topoisomerase IT inhibi
tors tested were not correctly identified with this assay, possibly ow
ing to restricted cell wall permeability or to the absence of correct
processing pathways such as, for example, in the case of the prodrug e
topophos. Conclusion: This methodology, in vivo in yeast, selected for
a large range of potent topoisomerase II-targeting anticancer agents.
Of particular interest in this yeast model, and in contrast to yeast
topoisomerase II, human topoisomerase II was shown to confer dominant
sensitivity in the presence of the series of bisdioxopiperazine deriva
tives tested. This assay therefore has the potential easily to identif
y and characterize the potency and specificity of synthesized anticanc
er drugs with modified original chemical structures or those present,
for example, in natural plant extracts or marine organisms.