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Review
. 2013 Sep 26:8:223.
doi: 10.1186/1748-717X-8-223.

New insights into the synergism of nucleoside analogs with radiotherapy

Michael W Lee  1 , William B Parker, Bo Xu
Affiliations
Review

New insights into the synergism of nucleoside analogs with radiotherapy

Michael W Lee et al. Radiat Oncol. .

Abstract

Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells.

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Figures

Figure 1
Figure 1
Activation of dCK after radiation contributes to enhanced therapeutic effects of nucleoside analogs. Treatment with ionizing radiation causes double strand breaks in DNA and activates the serine/threonine kinase Ataxia-telangiectasia mutated (ATM) which, in turn, phosphorylates deoxycytidine kinase, leading to a synergistic effect with nucleoside analogs. For example, gemcitabine enters the cell via the hENT1 transporter and is rapidly phosphorylated to the monophosphate form by active, serine 74 phosphorylated dCK prior to incorporation into DNA.
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