On the role of fluoro-substituted nucleosides in DNA radiosensitization for tumor radiation therapy

J Kopyra,I Bald,A Keller

doi:10.1039/c3ra46735j

Abstract

Gemcitabine (2′,2′-difluorocytidine) is a well-known radiosensitizer routinely applied in concomitant chemoradiotherapy. During irradiation of biological media with high-energy radiation secondary low-energy (<10 eV) electrons are produced that can directly induce chemical bond breakage in DNA by dissociative electron attachment (DEA). Here, we investigate and compare DEA to the three molecules 2′-deoxycytidine, 2′-deoxy-5-fluorocytidine, and gemcitabine. Fluorination at specific molecular sites, i.e., nucleobase or sugar moiety, is found to control electron attachment and subsequent dissociation pathways. The presence of two fluorine atoms at the sugar ring results in more efficient electron attachment to the sugar moiety and subsequent bond cleavage. For the formation of the dehydrogenated nucleobase anion, we obtain an enhancement factor of 2.8 upon fluorination of the sugar, whereas the enhancement factor is 5.5 when the nucleobase is fluorinated. The observed fragmentation reactions suggest enhanced DNA strand breakage induced by secondary electrons when gemcitabine is incorporated into DNA.

Highlights

The majority of patients diagnosed with cancer receive a radiation therapy treatment to reduce or remove the tumor tissue. 5- uorouracil, cisplatin (cis-diamminedichloroplatinum(II)) and 20,20-di uorocytidine belong to the most widely applied therapeutics in combined chemoradiotherapy, which are administered concomitantly with the high-energy radiation treatment to increase the effect of the radiation.[1]
The initial step in dissociative electron attachment (DEA) is the formation of a transient negative ion (TNI), which may decay by unimolecular dissociation into a negatively charged species and neutral counterparts
DEA to the three investigated compounds results in a multitude of fragment anions, but no parent anions have been observed indicating that their lifetimes with respect to dissociation are too short to be detected by the quadrupole mass spectrometer (QMS)

Summary

Introduction

The majority of patients diagnosed with cancer receive a radiation therapy treatment to reduce or remove the tumor tissue. 5- uorouracil, cisplatin (cis-diamminedichloroplatinum(II)) and 20,20-di uorocytidine (gemcitabine, Gem) belong to the most widely applied therapeutics in combined chemoradiotherapy, which are administered concomitantly with the high-energy radiation treatment to increase the effect of the radiation.[1]. We probe the competing pathways of electron attachment to either the nucleobase subunit or the sugar unit by studying DEA to the nucleoside dCyt and compare the DEA spectra with the ones obtained from 20-deoxy-5- uorocytidine (dFCyt) and Gem (Fig. 1).

Results

Conclusion