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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Phosphorylation of 4′-thio-β-d-Arabinofuranosylcytosine and Its Analogs by Human Deoxycytidine Kinase

Hitoshi Someya, Sue C. Shaddix, Kamal N. Tiwari, John A. Secrist III and William B. Parker
Journal of Pharmacology and Experimental Therapeutics March 2003, 304 (3) 1314-1322; DOI: https://doi.org/10.1124/jpet.102.045435
Hitoshi Someya
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Sue C. Shaddix
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Kamal N. Tiwari
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John A. Secrist III
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William B. Parker
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Abstract

4′-thio-β-d-Arabinofuranosylcytosine (T-araC) exhibits excellent in vivo antitumor activity against a variety of solid tumors despite its structural similarity to β-d-arabinofuranosylcytosine (araC), an agent which is poorly active against solid tumors in vivo. It is of great interest to elucidate why these compounds show a profound difference in antitumor activity. Because deoxycytidine kinase (dCK) is the critical enzyme in the activation of both compounds, here we report the differences in the substrate characteristics with human dCK between these compounds. The catalytic efficiency (Vmax/Km) of araC was 100-fold higher than that of T-araC using either ATP or UTP as the phosphate donor. However, Vmax values of araC and T-araC were similar when UTP was the phosphate donor. Since UTP is believed to be the true phosphate donor for dCK in intact cells, these data indicated that the rates of phosphorylation of these two compounds at high pharmacologically relevant concentrations would be similar. This prediction was confirmed in intact cell experiments, which supported the hypothesis that UTP is the physiological phosphate donor for dCK phosphorylation in cells. The relative lack of importance of phosphate donor to the phosphorylation of T-araC by dCK revealed important insights into the activation of this compound in human cells at pharmacological doses. These studies indicated that replacement of the 4′-oxygen with sulfur significantly reduced the substrate activity of nucleoside analogs with dCK and that the superior activity of T-araC with respect to araC against solid tumors was not due to superior activity with dCK.

Footnotes

  • This work was supported by a grant from the National Cancer Institute, P01 CA 34200. A preliminary report of this work was presented at the 2002 annual meeting of the American Association for Cancer Research (Someya et al., 2002).

  • DOI: 10.1124/jpet.102.045435

  • Abbreviations:
    T-araC
    4′-thio-β-d-arabinofuranosylcytosine
    araC
    β-d-arabinofuranosylcytosine
    araCMP
    5′-monophosphate of araC
    araCTP
    5′-triphosphate of araC
    Br-dCyd
    5-bromo-2′-deoxycytidine
    Br-T-araC
    5-bromo-4′-thio-β-d-arabinofuranosylcytosine
    CH3-dCyd
    5-methyl-2′-deoxycytidine
    CH3-T-araC
    5-methyl-4′-thio-β-d-arabinofuranosylcytosine
    Cl-dCyd
    5-chloro-2′-deoxycytidine
    Cl-T-araC
    5-chloro-4′-thio-β-d-arabinofuranosylcytosine
    dCK
    deoxycytidine kinase
    dCyd
    2′-deoxycytidine
    dThd
    thymidine
    F-araC
    5-fluoro-β-d-arabinofuranosylcytosine
    F-dCyd
    5-fluoro-2′-deoxycytidine
    F-T-araC
    5-fluoro-4′-thio-β-d-arabinofuranosylcytosine
    HPLC
    high pressure liquid chromatography
    MS
    mass spectrometry
    SAX
    strong anion exchange
    T-araCMP
    5′-monophosphate of T-araC
    T-araCTP
    5′-triphosphate of T-araC
    T-dCyd
    4′-thio-2′-deoxycytidine
    • Received October 9, 2002.
    • Accepted December 6, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 3
1 Mar 2003
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Phosphorylation of 4′-thio-β-d-Arabinofuranosylcytosine and Its Analogs by Human Deoxycytidine Kinase

Hitoshi Someya, Sue C. Shaddix, Kamal N. Tiwari, John A. Secrist and William B. Parker
Journal of Pharmacology and Experimental Therapeutics March 1, 2003, 304 (3) 1314-1322; DOI: https://doi.org/10.1124/jpet.102.045435

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Phosphorylation of 4′-thio-β-d-Arabinofuranosylcytosine and Its Analogs by Human Deoxycytidine Kinase

Hitoshi Someya, Sue C. Shaddix, Kamal N. Tiwari, John A. Secrist and William B. Parker
Journal of Pharmacology and Experimental Therapeutics March 1, 2003, 304 (3) 1314-1322; DOI: https://doi.org/10.1124/jpet.102.045435
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