title: Mechanisms of Damage to DNA Labeled with Electrophilic Nucleobases Induced by Ionizing or UV Radiation.
abstract: Hypoxia--a hallmark of solid tumors--makes hypoxic cells radioresistant. On the other hand, DNA, the main target of anticancer therapy, is not sensitive to the near UV photons and hydrated electrons, one of the major products of water radiolysis under hypoxic conditions. A possible way to overcome these obstacles to the efficient radio- and photodynamic therapy of cancer is to sensitize the cellular DNA to electrons and/or ultraviolet radiation. While incorporated into genomic DNA, modified nucleosides, 5-bromo-2'-deoxyuridine in particular, sensitize cells to both near-ultraviolet photons and γ rays. It is believed that, in both sensitization modes, the reactive nucleobase radical is formed as a primary product which swiftly stabilizes, leading to serious DNA damage, like strand breaks or cross-links. However, despite the apparent similarity, such radio- and photosensitization of DNA seems to be ruled by fundamentally different mechanisms. In this review, we demonstrate that the most important factors deciding on radiodamage to the labeled DNA are (i) the electron affinity (EA) of modified nucleoside (mNZ), (ii) the local surroundings of the label that significantly influences the EA of mNZ, and (iii) the strength of the chemical bond holding together the substituent and a nucleobase. On the other hand, we show that the UV damage to sensitized DNA is governed by long-range photoinduced electron transfer, the efficiency of which is controlled by local DNA sequences. A critical review of the literature mechanisms concerning both types of damage to the labeled biopolymer is presented. Ultimately, the perspectives of studies on DNA sensitization in the context of cancer therapy are discussed.
authors.affiliation: Faculty of Chemistry University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Rak
authors.affiliation: Faculty of Chemistry University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Lidia
authors.initials: L
authors.lastname: Chomicz
authors.affiliation: Faculty of Chemistry University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Wiczk
authors.affiliation: Faculty of Chemistry University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Westphal
authors.affiliation: Faculty of Chemistry University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zdrowowicz
authors.affiliation: Faculty of Chemistry University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Wityk
authors.affiliation: Faculty of Chemistry University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Żyndul
authors.affiliation: Faculty of Chemistry University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Samanta
authors.initials: S
authors.lastname: Makurat
authors.affiliation: Faculty of Chemistry University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Golon
mesh_terms: D001973:Bromodeoxyuridine; D004247:DNA / Q000737:chemistry*; D053960:DNA Breaks / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects*; D004583:Electrons; D005609:Free Radicals / Q000737:chemistry; D005720:Gamma Rays; D006801:Humans; D009705:Nucleosides / Q000737:chemistry*; D011839:Radiation, Ionizing; D014466:Ultraviolet Rays
chemical_list: D005609:Free Radicals; D009705:Nucleosides; D004247:DNA; D001973:Bromodeoxyuridine