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A role for MAP kinase in the antitumor activity of a nucleoside analog

Cancer Gene Therapy volume 9, pages 37–43 (2002)Cite this article

Abstract

Nucleoside analogs (NAs) have been used extensively in both antitumor and antiviral therapies. Their general mechanism of action has been postulated to result from incorporation into DNA, leading to disruption of DNA synthesis and DNA polymerase inhibition. To further explore the antitumor mechanisms of NAs we have evaluated ganciclovir (GCV), an NA antiviral agent, in herpes simplex virus thymidine kinase (HSV-TK) gene–modified tumor cells. This system allows specific evaluation of the antitumor effects of NAs because the antitumor effect is directly related to the phosphorylation of the prodrug GCV by the HSV-TK enzyme in the gene-modified tumor cells. We demonstrated that GCV incorporates into DNA and inhibits DNA polymerase, as has been observed in HSV–infected cells and with other antitumor NAs in tumor cells. A novel observation is that GCV activates MAP kinase within 1 hour of GCV exposure. This activation directly correlates with cytotoxicity, because inhibition of the MAP kinase extracellular regulated kinase (Erk) by PD98059, reversed GCV-mediated cytotoxicity. This effect appears to be specific to the Erk pathway, because inhibition of the p38 kinase with SB203580 had no effect on cytotoxicity. Further, GCV does not act as a DNA-damaging agent or activate general DNA-repair mechanisms, but does produce a number of metabolic disruptions, including a reversible decrease in NAD levels. These effects appear to be downstream of the earlier activation of Erk in this system, which may be a novel mechanism of action for GCV cytotoxicity in HSV-TK gene–modified tumor cells, and thus, needs to be further evaluated as the mechanism of tumor cell killing by other antitumor NAs.

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Acknowledgements

This work was supported by the TJ Martell Foundation and Rhode Island Hospital. The authors thank Ed Filardo, Jeff Quinn, Misty Saracino, and Fred Goulette for assistance.

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Author notes

  1. Scott M Freeman

    Present address: Onyx Pharmaceuticals, Richmond, CA, USA

Authors and Affiliations

  1. Department of Medicine, Brown University and Rhode Island Hospital, Providence, Rhode Island, USA

    Katharine A Whartenby, James W Darnowski & Paul Calabresi

  2. Schering Plough Research Institute, Kenilworth, New Jersey, USA

    Scott M Freeman

Authors
  1. Katharine A Whartenby
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  2. James W Darnowski
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  3. Scott M Freeman
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  4. Paul Calabresi
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Correspondence to Katharine A Whartenby.

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Whartenby, K., Darnowski, J., Freeman, S. et al. A role for MAP kinase in the antitumor activity of a nucleoside analog. Cancer Gene Ther 9, 37–43 (2002). https://doi.org/10.1038/sj.cgt.7700406

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