INDUCTION OF CHROMOSOMAL-ABERRATIONS, CYTOTOXICITY, AND MORPHOLOGICALTRANSFORMATION IN MAMMALIAN-CELLS BY THE ANTIPARASITIC DRUG FLUBENDAZOLE AND THE ANTINEOPLASTIC DRUG HARRINGTONINE
Nj. Huang et al., INDUCTION OF CHROMOSOMAL-ABERRATIONS, CYTOTOXICITY, AND MORPHOLOGICALTRANSFORMATION IN MAMMALIAN-CELLS BY THE ANTIPARASITIC DRUG FLUBENDAZOLE AND THE ANTINEOPLASTIC DRUG HARRINGTONINE, Fundamental and applied toxicology, 22(2), 1994, pp. 304-313
The antiparasitic drug flubendazole and the antineoplastic compound ha
rringtonine were studied for ability to induce chromosomal damage in C
hinese hamster lung (CHL) cells and cytotoxicity and morphological tra
nsformation in C3H/10T1/2 Cl8 (10T1/2) mouse embryo fibroblasts. Flube
ndazole caused a dose- and time-dependent induction of polyploidy in C
HL cells. In cells treated with 0.78 mu g/ml flubendazole, the yield o
f polyploid cells was 95%. Harringtonine caused a dose- and time-depen
dent induction of chromosome breaks, and 0.195 mu g/ml harringtonine i
nduced chromosome breaks in 47% of CHL cells. Both flubendazole and ha
rringtonine caused dose-dependent cytotoxicity to 10T1/2 cells at conc
entration ranges of 0.04-1.60 and 0.05-0.8 mu g/ml, respectively. Flub
endazole and harringtonine at concentrations of 0.08-0.4 and 0.4-0.8 m
u g/ml, respectively, induced morphological transformation (predominan
tly type II foci) in 10T1/2 cells. Three of four harringtonine-transfo
rmed cell lines and two of four flubendazole-transformed cell lines fo
rmed foci in reconstruction experiments with non-transformed 10T1/2 ce
lls. All four harringtonine-transformed and all four flubendazole-tran
sformed cell lines formed colonies in soft agar. Similar concentration
s of flubendazole and harringtonine induced chromosome damage in CHL c
ells and cytotoxicity and morphological transformation in 10T1/2 cells
. The ability of flubendazole to induce polyploidy may be part of the
mechanism by which this compound induces morphological transformation.
Similarly, the ability of harringtonine to induce chromosomal aberrat
ions may be part of the mechanism by which this compound induces morph
ological transformation. Therefore, flubendazole and harringtonine ind
uce cytotoxicity and morphological and anchorage-independent transform
ation, harringtonine induces chromosome aberrations (breakage, translo
cation, and rings), and flubendazole induces polyploidy in cultured ma
mmalian cells. The clastogenic and cell transformation-inducing proper
ties of these compounds suggest that these drugs may have carcinogenic
potential. This should be investigated rigorously in animal carcinoge
nesis bioassays. The genotoxicity of these drugs should be considered
during their development as antiparasitic and antineoplastic agents. (
C) 1994 Society of Toxicology.