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Molecular Pharmacology

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Research ArticleArticle

2′-C-Cyano-2′-deoxy-1-β-d-arabino-pentofuranosylcytosine: A Novel Anticancer Nucleoside Analog that Causes Both DNA Strand Breaks and G2 Arrest

Atsushi Azuma, Peng Huang, Akira Matsuda and William Plunkett
Molecular Pharmacology April 2001, 59 (4) 725-731; DOI: https://doi.org/10.1124/mol.59.4.725
Atsushi Azuma
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Peng Huang
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Akira Matsuda
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William Plunkett
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Abstract

The mechanism of 2′-C-cyano-2′-deoxy-1-β-d-arabino-pentofuranosylcytosine (CNDAC) action was investigated in human lymphoblastoid CEM cells and myeloblastic leukemia ML-1 cells. CNDAC was metabolized to its 5′-triphosphate and incorporated into DNA, which was associated with inhibition of DNA synthesis. After incubation of cells with [3H]CNDAC, metabolites were detected in 3′→5′ phosphodiester linkage and at the 3′ terminus of cellular DNA. Specific enzymatic hydrolysis of DNA demonstrated that the parent nucleoside and its 2′-epimer 2′-C-cyano-2′-deoxy-2-ribo-pentofuranosylcytosine accounted for approximately 65% of the total analogs incorporated into DNA and essentially all of the drug in the 3′→5′ phosphodiester linkage. In contrast, all detectable radioactivity at 3′ termini was associated with 2′-C-cyano-2′,3′-didehydro-2′,3′-dideoxycytidine. This de facto DNA chain-terminating nucleotide arises from an electronic characteristic and cleavage of the 3′-phosphodiester bond subsequent to the addition of a nucleotide to the incorporated CNDAC moiety by β-elimination, a process that generates a single strand break in DNA. Investigation of the biological consequences of these actions indicated that, after incubation with cytostatic concentrations of CNDAC, cell cycle progression was delayed during S phase, but that cells arrested predominantly in the G2 phase. This differed from the S phase-arresting actions of ara-C and gemcitabine, other deoxycytidine analogs that inhibit DNA replication but do not cause strand breaks. Thus, once incorporated into DNA, the CNDAC molecule appears to act by a dual mechanism that 1) delays the progress of further DNA replication, but 2) upon addition of a deoxynucleotide results in the conversion of the incorporated analog to a de facto DNA chain terminator at the 3′ terminus of a single strand break. It is likely that DNA strand breaks trigger cell cycle arrest in G2.

Footnotes

    • Received September 15, 2000.
    • Accepted December 15, 2000.
  • Send reprint requests to: William Plunkett, Ph.D., Department of Experimental Therapeutics, Box 71, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. E-mail: wplunket{at}mdanderson.org

  • This work was funded in part by Grant CA28596 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD, and by Sankyo Company Ltd., Tokyo, Japan.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (4)
Molecular Pharmacology
Vol. 59, Issue 4
1 Apr 2001
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Research ArticleArticle

2′-C-Cyano-2′-deoxy-1-β-d-arabino-pentofuranosylcytosine: A Novel Anticancer Nucleoside Analog that Causes Both DNA Strand Breaks and G2 Arrest

Atsushi Azuma, Peng Huang, Akira Matsuda and William Plunkett
Molecular Pharmacology April 1, 2001, 59 (4) 725-731; DOI: https://doi.org/10.1124/mol.59.4.725

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Research ArticleArticle

2′-C-Cyano-2′-deoxy-1-β-d-arabino-pentofuranosylcytosine: A Novel Anticancer Nucleoside Analog that Causes Both DNA Strand Breaks and G2 Arrest

Atsushi Azuma, Peng Huang, Akira Matsuda and William Plunkett
Molecular Pharmacology April 1, 2001, 59 (4) 725-731; DOI: https://doi.org/10.1124/mol.59.4.725
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