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Down-Regulation of DNA Topoisomerase II Leads to Prolonged Cell Cycle Transit in G₂ and Early M Phases and Increased Survival to Microtubule-Interacting Agents

Group of Molecular and Clinical Cancer Therapeutics, Institut National de la Santé et de la Recherche Médicale U673, Hôpital Saint-Antoine, Paris, France (A.S., M.-G.C., A.E.E., A.K.L.); and Laboratory of Molecular and Cellular Pharmacology, Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Gdansk, Poland (A.S., M.S.)

Microtubule binders are cell cycle-specific agents with preferential cytotoxicity toward mitotic cells. We have characterized vincristine-selected human leukemia cells to establish whether development of vincristine resistance was accompanied by changes in cell cycle kinetics and distribution. Our results indicate that vincristine resistance is accompanied by delayed G₂ transit and prolonged early mitosis in both the absence and the presence of the microtubule binder nocodazole. The altered G₂/M regulation is accompanied by resistance to short-term (12 h) but not continuous nocodazole exposure in agreement with the transient nature of the observed cell cycle alterations. Western blot analysis indicates that vincristine-selection is accompanied by down-regulation of topoisomerase II without detectable alterations of the other mitotic regulators studied, including Cdk1, p21, 14-3-3, and 14-3-3. This was associated with at least 7-fold less chromosome-associated topoisomerase II, decreased catalytic activity, and cross-resistance to topoisomerase II inhibitors. Characterization of isogenic cell lines expressing different levels of topoisomerase II proteins shows that cellular levels of topoisomerase II, but not the closely related topoisomerase II, directly influence the cell cycle kinetics in G₂ and early mitosis as well as the resistance to nocodazole. These results underline the importance of topoisomerase II in late G₂ and early M phases and provide evidence for an as-yet-unsuspected interaction between topoisomerase II and microtubule-directed agents.

Address correspondence to: Dr. Annette K. Larsen, Group of Molecular and Clinical Cancer Therapeutics, INSERM U673, Hôpital Saint-Antoine, 75571 Paris 12, France. E-mail: akraghlarsen{at}aol.com

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