A new action for topoisomerase inhibitors.
Topoisomerases are known to aid DNA replication by breaking and resealing supercoiled DNA. Consequently, cells exposed to topoisomerase inhibitors before or during the S (DNA synthetic) phase of the cell cycle undergo abnormal DNA replication and become irreversibly blocked in the G2 (pre-mitosis) phase. We report that following a 4-h exposure to topoisomerase II inhibitors, murine erythroleukemic cells (MELC) do not form mitotic figures but exhibit a time-dependent progression into G2 (4N DNA) and greater than G2 (up to 8N DNA) stages of the cell cycle. Following exposure to the topoisomerase I inhibitor camptothecin, recovering MELC also exhibit greater than G2 polyploidy, but to a considerably lesser degree: mitotic figures are present and a subpopulation of cells resumes cycling. However, both topo I and topo II inhibitors induce maximal percentages of greater than G2 cells when synchronized MELC are in the G2/M phase at the time of exposure. This suggests that, in addition to their S-phase action, topoisomerase inhibitors can interfere with chromosome condensation during G2 and, in so doing, induce polyploidy.
Zucker
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RM
ManTech Environmental Technology, Inc., Triangle Park, NC 27709.
Elstein
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KH
D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002467:Cell Nucleus / Q000648:ultrastructure; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004915:Leukemia, Erythroblastic, Acute; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D011123:Polyploidy; D013713:Teniposide / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin; D013713:Teniposide; D002166:Camptothecin