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.

5-Selenocyanato and 5-trifluoromethanesulfonyl derivatives of 2′-deoxyuridine: synthesis, radiation and computational chemistry as well as cytotoxicity

“…4 Hence, in order to increase the efficiency of this modality and to minimize dangerous side effects of irradiation, including secondary cancer, 5 radiosensitizers -molecules that are selectively transported to cancer cells and make them susceptible to ionizing radiation (IR) -have to be employed in radiotherapy. 6 Hall and Giaccia 7,8 distinguished only two categories of radiosensitizers that might be employed in clinical treatment. According to their classication these two groups comprise the substances, which increase the sensitivity of hypoxic tumour cells toward ionizing radiation and the modied nucleosides that are incorporated into DNA during its biosynthesis.…”

Gas-Phase Oxidation of the Protonated Uracil-5-yl Radical Cation

“…3,4 To elucidate the underlying mechanisms, studies have examined the reactivity of these uracil-5-yl σ-radicals within nucleosides and DNA strands. [4][5][6] Recently, further insights have been reported on the photophysics of 5-iodouracil 7 as well as the negative-ion states (made from electron attachment) of 5-bromo and 5-iodouracil thought to be involved in the dissociative electron capture mechanism. 8 A key process, that ultimately results in DNA strand-cleavage, involves uracil-5-yl radicals abstracting H atoms from nearby functional groups.…”

Advances in computational photochemistry and chemiluminescence of biological and nanotechnological molecules

“…Modified NBs also play a central role in the design of potential photosensitizers (PSs) for photodynamic therapy. 56 This technique is used in the Fig. 10 Structures of the modified NBs reviewed in the present chapter.…”