Life, death and genomic change in perturbed cell cycles.

HeLaS3 cells undergo apoptosis after 18-24 h of cell cycle stasis irrespective of the agent employed (colcemid, aphidicolin, cis-platin). At high drug concentrations apoptosis occurs in cells arrested in the cell cycle in which the drug is applied and at a cell cycle position dependent on the mechanism of drug action. At low concentrations (or short exposure times) cells undergo apoptosis after progressing through an aberrant mitosis and only after 18 h of cell cycle stasis in a 'pseudo G1/S' cell cycle position. Aberrent mitoses result in multipolar mitoses, chromosomal breakage and interchromosomal concatenation events. We propose that the ability of cells to delay progression into aberrent mitosis, as well as their propensity to undergo apoptosis, are important determinants of clinical cytotoxicity. We also suggest that apoptosis plays an important role in preventing the generation of aneuploidy and recombination and rearrangement events commonly associated with cancer.

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