TY - JOUR A1 - Schürmann, Robin Mathis A1 - Vogel, Stefanie A1 - Ebel, Kenny A1 - Bald, Ilko T1 - The physico-chemical basis of DNA radiosensitization BT - implications for cancer radiation therapy JF - Chemistry - a European journal N2 - High-energy radiation is used in combination with radiosensitizing therapeutics to treat cancer. The most common radiosensitizers are halogenated nucleosides and cisplatin derivatives, and recently also metal nanoparticles have been suggested as potential radiosensitizing agents. The radiosensitizing action of these compounds can at least partly be ascribed to an enhanced reactivity towards secondary low-energy electrons generated along the radiation track of the high-energy primary radiation, or to an additional emission of secondary reactive electrons close to the tumor tissue. This is referred to as physico-chemical radiosensitization. In this Concept article we present current experimental methods used to study fundamental processes of physico-chemical radiosensitization and discuss the most relevant classes of radiosensitizers. Open questions in the current discussions are identified and future directions outlined, which can lead to optimized treatment protocols or even novel therapeutic concepts. KW - cancer KW - dissociative electron attachment KW - low-energy electrons KW - radiation therapy KW - radiosensitizers Y1 - 2018 U6 - https://doi.org/10.1002/chem.201800804 SN - 0947-6539 SN - 1521-3765 VL - 24 IS - 41 SP - 10271 EP - 10279 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Vogel, Stefanie A1 - Ebel, Kenny A1 - Schürmann, Robin Mathis A1 - Heck, Christian A1 - Meiling, Till A1 - Milosavljevic, Aleksandar R. A1 - Giuliani, Alexandre A1 - Bald, Ilko T1 - Vacuum-UV and Low-Energy Electron-Induced DNA Strand Breaks BT - Influence of the DNA Sequence and Substrate JF - ChemPhysChem : a European journal of chemical physics and physical chemistry N2 - DNA is effectively damaged by radiation, which can on the one hand lead to cancer and is on the other hand directly exploited in the treatment of tumor tissue. DNA strand breaks are already induced by photons having an energy below the ionization energy of DNA. At high photon energies, most of the DNA strand breaks are induced by low-energy secondary electrons. In the present study we quantified photon and electron induced DNA strand breaks in four different 12mer oligonucleotides. They are irradiated directly with 8.44 eV vacuum ultraviolet (VUV) photons and 8.8 eV low energy electrons (LEE). By using Si instead of VUV transparent CaF2 as a substrate the VUV exposure leads to an additional release of LEEs, which have a maximum energy of 3.6 eV and can significantly enhance strand break cross sections. Atomic force microscopy is used to visualize strand breaks on DNA origami platforms and to determine absolute values for the strand break cross sections. Upon irradiation with 8.44 eV photons all the investigated sequences show very similar strand break cross sections in the range of 1.7-2.3x10(-16) cm(2). The strand break cross sections for LEE irradiation at 8.8 eV are one to two orders of magnitude larger than the ones for VUV photons, and a slight sequence dependence is observed. The sequence dependence is even more pronounced for LEEs with energies <3.6 eV. The present results help to assess DNA damage by photons and electrons close to the ionization threshold. KW - DNA origami KW - DNA radiation damage KW - DNA strand breaks KW - low-energy electrons KW - vacuum-UV radiation Y1 - 2019 U6 - https://doi.org/10.1002/cphc.201801152 SN - 1439-4235 SN - 1439-7641 VL - 20 IS - 6 SP - 823 EP - 830 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Ebel, Kenny A1 - Bald, Ilko T1 - Length and Energy Dependence of Low-Energy Electron-Induced Strand Breaks in Poly(A) DNA JF - International Journal of Molecular Sciences N2 - The DNA in living cells can be effectively damaged by high-energy radiation, which can lead to cell death. Through the ionization of water molecules, highly reactive secondary species such as low-energy electrons (LEEs) with the most probable energy around 10 eV are generated, which are able to induce DNA strand breaks via dissociative electron attachment. Absolute DNA strand break cross sections of specific DNA sequences can be efficiently determined using DNA origami nanostructures as platforms exposing the target sequences towards LEEs. In this paper, we systematically study the effect of the oligonucleotide length on the strand break cross section at various irradiation energies. The present work focuses on poly-adenine sequences (d(A₄), d(A₈), d(A₁₂), d(A₁₆), and d(A₂₀)) irradiated with 5.0, 7.0, 8.4, and 10 eV electrons. Independent of the DNA length, the strand break cross section shows a maximum around 7.0 eV electron energy for all investigated oligonucleotides confirming that strand breakage occurs through the initial formation of negative ion resonances. When going from d(A₄) to d(A₁₆), the strand break cross section increases with oligonucleotide length, but only at 7.0 and 8.4 eV, i.e., close to the maximum of the negative ion resonance, the increase in the strand break cross section with the length is similar to the increase of an estimated geometrical cross section. For d(A₂₀), a markedly lower DNA strand break cross section is observed for all electron energies, which is tentatively ascribed to a conformational change of the dA₂₀ sequence. The results indicate that, although there is a general length dependence of strand break cross sections, individual nucleotides do not contribute independently of the absolute strand break cross section of the whole DNA strand. The absolute quantification of sequence specific strand breaks will help develop a more accurate molecular level understanding of radiation induced DNA damage, which can then be used for optimized risk estimates in cancer radiation therapy. KW - DNA origami KW - DNA radiation damage KW - DNA strand breaks KW - low-energy electrons KW - sequence dependence Y1 - 2019 U6 - https://doi.org/10.3390/ijms21010111 SN - 1422-0067 VL - 21 IS - 1 PB - Molecular Diversity Preservation International CY - Basel ER - TY - JOUR A1 - Bald, Ilko A1 - Keller, Adrian A1 - Kopyra, Janina T1 - On the role of fluoro-substituted nucleosides in DNA radiosensitization for tumor radiation therapy JF - RSC Advances : an international journal to further the chemical sciences N2 - 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. KW - low-energy electrons KW - single-strand breaks KW - gas-phase KW - chemoradiation therapy KW - molecular-mechanisms KW - resonant formation KW - damage KW - attachment KW - drugs Y1 - 2014 U6 - https://doi.org/10.1039/C3RA46735J SN - 2046-2069 VL - 4 IS - 13 SP - 6825 EP - 6829 PB - Royal Society of Chemistry ER -