4.6 Article

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

Journal

RSC ADVANCES
Volume 4, Issue 13, Pages 6825-6829

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/c3ra46735j

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Funding

  1. Polish Ministry of Science and Higher Education
  2. European Union via the COST Action [MP1002]
  3. Deutsche Forschungsgemeinscha. (DFG) support through a Marie Curie FP7 Integration Grant within the 7th European Union Framework Programme
  4. University of Potsdam
  5. Alexander von Humboldt foundation

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Gemcitabine (20',20'-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 20'-deoxycytidine, 20'-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.

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