In an effort to shed light upon the processes of antitumor drug-induced cell death, we have carried out a systematic study of the effects of the anti-topoisomerase II agent, etoposide, on Chinese hamster ovary cells. Treatment of Chinese hamster ovary cells for 1 h with a 2-log cell-killing concentration of etoposide induces a high incidence of DNA single-strand breaks which are rapidly repaired upon drug removal. p34cdc2 kinase activity is inhibited within 1 h of addition of etoposide. Following removal of drug, cells accumulate transiently in G2. Upon recovery of p34cdc2 kinase activity (between 12 and 24 h posttreatment), approximately 50% of cells progress through mitosis which results in micronucleation. Examination of mitotic figures at various posttreatment incubation times indicates that micronucleation of daughter cells could be attributed to abnormal segregation of chromosomes during mitosis. Unexpectedly, p34cdc2 kinase activity remains elevated relative to untreated controls until 36 h post-etoposide treatment, a point where no further cell division takes place. This activity decreases by 48 h posttreatment, concomitant with a decrease in cell viability as estimated by the ability to exclude trypan blue. These results indicate that etoposide may induce cytotoxicity via gross chromosomal fragmentation, and that p34cdc2 kinase may be involved in this process.

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This work was supported by funds from the NIH (USPHS Grant CA-24586).

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