INDUCTION OF CHROMOSOMAL-ABERRATIONS, CYTOTOXICITY, AND MORPHOLOGICALTRANSFORMATION IN MAMMALIAN-CELLS BY THE ANTIPARASITIC DRUG FLUBENDAZOLE AND THE ANTINEOPLASTIC DRUG HARRINGTONINE

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.