New insights into the synergism of nucleoside analogs with radiotherapy

Michael W Lee,William B Parker,Bo Xu

doi:10.1186/1748-717x-8-223

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.

Highlights

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
Purine based analogs Fludarabine Originally synthesized by John Montgomery and Kathleen Hewson in 1969, the fluorinated arabinosyl nucleoside analog fludarabine is a prodrug that incorporates a number of structural features that extend its half-life by protecting it from degradative enzymes [1]
Incorporation of cladribine into DNA leads to inhibition of DNA synthesis and, importantly, inhibition of DNA repair which in turn leads to formation of single strand breaks in DNA, poly(ADP-ribose) polymerase (PARP) activation and apoptosis via p53 dependent and independent pathways [31,32,33]

Summary

Conclusions

A number of prominent nucleoside analogs have been shown to have a synergistic effect when used in combination with radiation. Many of the currently used nucleoside analogs that have exhibited synergistic activity with radiotherapy are activated by dCK. By leveraging recent developments in our understanding of dCK function and activation it may be possible to develop pharmacologic or genetic therapeutic approaches to increase the susceptibility of these tumors to radiation and antimetabolite combination therapy. New insight on the function of dCK and mechanism of activation has applicability to nucleoside analogs in the pipeline currently such as thiarabine and sapacitabine. ML, WBP and BX wrote the manuscript. All authors read and approved the final manuscript

39. Cheson BD

77. Seidman AD

84. Moore M