DNA fragmentation as a consequence of cell cycle traverse in doxorubicin- and idarubicin-treated human lymphoma cells.
We have studied some of the factors involved in the cytotoxic actions of the anticancer anthracycline antibiotics doxorubicin (DOX) and idarubicin (IDA) towards human B-cell lymphoma cells in vitro. IDA was found to accumulate within cells to a greater degree than the related drug DOX for both short (1 h) and long-term (24 h) exposures. Both agents showed a similar capacity for trapping topoisomerase II in intact cells, but cross-linking activity was significantly lower than that induced by the specific poison VP16. IDA was four- to eight fold more potent for the induction of cytostasis and cell cycle arrest and for the instigation of DNA breakdown as a prelude to the full expression of apoptosis. Inhibition of DNA fragmentation at higher drug doses was linked closely with the inhibition of S-phase traverse. The findings suggest that DOX and IDA act in a similar fashion, the latter agent being more effective due to enhanced intracellular accumulation. We conclude that the presence of drug and topoisomerase II-associated DNA damage is not sufficient to induce DNA fragmentation; rather, unregulated commitment to S-phase traverse is an important factor in the activation of programmed cell death.
Smith
P J
PJ
MRC Clinical Oncology and Radiotherapeutics Unit, MRC Centre, GB-Cambridge, England.
Rackstraw
C
C
Cotter
F
F
D017209:Apoptosis; D002453:Cell Cycle; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015255:Idarubicin / Q000378:metabolism / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; D015255:Idarubicin