Micronuclei in mouse bone-marrow cells. A simple in vivo model for the evaluation of drug-induced chromosomal aberrations

Abstract

For studying, in vivo, chromosomal damage in bone-marrow cells of CD mice the following compounds were used: Trenimon®; Endoxanm® (cyclophosphamide); triethylenemelamine (TEM); methyl methanesulfonate (MMS); ethyl methanesulfonate (EMS); mitomycin C; colchicine; N-methyl- N′-nitro- N-nitrosoguanidine (MNNG) and caffeine. In a first set of experiments the compounds were given twice intraperitoneally with an interval of 24 h. In a second set, effects on bone marrow were studied after 2 i.v. or p.o. administrations of TEM or EMS. All compounds except MNNG and caffeine produced bone-marrow depression and micronuclei, depending on the dose. For the active compounds an interesting difference was revealed by a comparison of the lowest effective dose (as measured by micronuclei formation) with the lethal dose. Trenimon, TEM, cyclophosphamide and MMS (some of which are used in human chemotherapy in similar mg/kg doses) were active on mouse bone-marrow at very low doses compared with their lethal doses. On the other hand, colchicine, mitomycin C and EMS exhibited an effect only at doses very close to, or within, the toxic range. Different routes of administration of either TEM or EMS produced similar effects. The results indicate that the test is especially suitable for initial large-scale screening of suspected chromosomal mutagens and spindle poisons. In addition, the use of the relationship between doses required to induce micronuclei and lethal doses in mice provides a practical measure of the relative potencies of such compounds.