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Molecular Basis for G₂ Arrest Induced by 2'-C-Cyano-2'-Deoxy-1-ß-D-Arabino-Pentofuranosylcytosine and Consequences of Checkpoint Abrogation

¹ Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center and ² The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas and ³ Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan

Requests for reprints: William Plunkett, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Box 71, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3335; Fax: 713-794-4316; E-mail: wplunket{at}mdanderson.org.

2'-C-cyano-2'-deoxy-1-ß-D-arabino-pentofuranosylcytosine (CNDAC) is a nucleoside analogue with a novel mechanism of action that is currently being evaluated in clinical trials. Incorporation of CNDAC triphosphate into DNA and extension during replication leads to single-strand breaks directly caused by ß-elimination. These breaks, or the lesions that arise from further processing, cause cells to arrest in G₂. The purpose of this investigation was to define the molecular basis for G₂ checkpoint activation and to delineate the sequelae of its abrogation. Cell lines derived from diverse human tissues underwent G₂ arrest after CNDAC treatment, suggesting a common mechanism of response to the damage created. CNDAC-induced G₂ arrest was instituted by activation of the Chk1-Cdc25C-Cdk1/cyclin B checkpoint pathway. Neither Chk2, p38, nor p53 was required for checkpoint activation. Inhibition of Chk1 kinase with 7-hydroxystaurosporine (UCN-01) abrogated the checkpoint pathway as indicated by dephosphorylation of checkpoint proteins and progression of cells through mitosis and into G₁. Cell death was first evident in hematologic cell lines after G₁ entry. As indicated by histone H2AX phosphorylation, DNA damage initiated by CNDAC incorporation was transformed into double-strand breaks when ML-1 cells arrested in G₂. Some breaks were manifested as chromosomal aberrations when the G₂ checkpoint of CNDAC-arrested cells was abrogated by UCN-01 but also in a minor population of cells that escaped to mitosis during treatment with CNDAC alone. These findings provide a mechanistic rationale for the design of new strategies, combining CNDAC with inhibitors of cell cycle checkpoint regulation in the therapy of hematologic malignancies.

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