Origin of aneuploidy in relation to disturbances of cell-cycle progression. I. Effects of vinblastine on mouse bone marrow cells.

Vinblastine (VBL) was tested in the mouse for induction of chromosome malsegregation in bone marrow cells. The occurrence of aneuploidy and polyploidy was correlated with cell-cycle kinetics measured by DNA labelling with bromodeoxyuridine (BrdUrd). Sister-chromatid exchanges (SCE) were also detected. A dose-dependent lengthening of the cell cycle was induced in the dose range of 0.9-4.5 mg/kg body weight, up to a complete inhibition of cell-cycle progression (100% of metaphases were arrested before completion of the first mitotic division following a recovery time of 18 h, compared with 8% in the controls). Both aneuploidy and polyploidy were induced. Aneuploid metaphases were grouped into 2 classes, those with no more than 2 extra chromosomes and those with 3-10 extra chromosomes. The frequencies of cells with severe aneuploidy and polyploidy increased considerably when second-generation cells were sampled at a recovery time of 24 h. This observation suggested that gross chromosome imbalances occur preferentially after a period of mitotic arrest, probably as a consequence of multipolar spindles or failure of proper spindle assembly. Non-disjunction of single chromosomes arises independently of the mitotic block. A slight increase in SCE frequency was observed only at a recovery time of 18 h. This study may provide information on the kinetics and mechanisms of origin of VBL-induced numerical aberrations in vivo.