Cisplatin Radiosensitization of DNA Irradiated with 2–20 eV Electrons: Role of Transient Anions

Platinum chemotherapeutic agents, such as cisplatin (<i>cis</i>-diamminedichloroplatinum­(II)), can act as radiosensitizers when bound covalently to nuclear DNA in cancer cells. This radiosensitization is largely due to an increase in DNA damage induced by low-energy secondary electrons, produced in large quantities by high-energy radiation. We report the yields of single- and double-strand breaks (SSB and DSB) and interduplex cross-links (CL) induced by electrons of 1.6–19.6 eV (i.e., the yield functions) incident on 5 monolayer (ML) films of cisplatin–DNA complexes. These yield functions are compared with those previously recorded with 5 ML films of unmodified plasmid DNA. Binding of five cisplatin molecules to plasmid DNA (3197 base pairs) enhances SSB, DSB, and CL by factors varying, from 1.2 to 2.8, 1.4 to 3.5, and 1.2 to 2.7, respectively, depending on electron energy. All yield functions exhibit structures around 5 and 10 eV that can be attributed to enhancement of bond scission, via the initial formation of core-excited resonances associated with π → π* transitions of the bases. This increase in damage is interpreted as arising from a modification of the parameters of the corresponding transient anions already present in nonmodified DNA, particularly those influencing molecular dissociation. Two additional resonances, specific to cisplatin-modified DNA, are formed at 13.6 and 17.6 eV in the yield function of SSB. Furthermore, cisplatin binding causes the induction of DSB by electrons of 1.6–3.6 eV, i.e., in an energy region where a DSB cannot be produced by a single electron in pure DNA. Breaking two bonds with a subexcitation-energy electron is tentatively explained by a charge delocalization mechanism, where a single electron occupies simultaneously two σ* bonds linking the Pt atom to guanine bases on opposite strands

Radiation Damage to DNA: The Indirect Effect of Low-Energy Electrons

We report the effect of the DNA hydration level on damage yields induced by soft X-rays and photoemitted low-energy electrons (LEEs) in thin films of plasmid DNA irradiated in N₂ at atmospheric pressure under different humidity levels. Contrary to a dilute solution of DNA, the number of H₂O molecules per nucleotide (Γ) in these films can be varied from Γ = 2.5 to ∼33, where Γ ≤ 20 corresponds to layers of hydration and Γ = 33 to an additional bulk-like water layer. Our results indicate that DNA damage induced by LEEs does not increase significantly until the second hydration shell is formed. However, this damage increases dramatically as DNA coverage approaches bulk-like hydration conditions. A number of phenomena are invoked to account for these behaviors, including dissociative electron transfer from water–interface electron traps to DNA bases, quenching of dissociative electron attachment to DNA, and quenching of dissociative electronically excited states of H₂O in contact with DNA

Radiation-Induced Formation of 2′,3′-Dideoxyribonucleosides in DNA: A Potential Signature of Low-Energy Electrons

We have identified a series of modifications of the 2′-deoxyribose moiety of DNA arising from the exposure of isolated and cellular DNA to ionizing radiation. The modifications consist of 2′,3′-dideoxyribonucleoside derivatives of T, C, A, and G, as identified by enzymatic digestion and LC-MS/MS. Under dry conditions, the yield of these products was 6- to 44-fold lower than the yield of 8-oxo-7,8-dihydroguanine. We propose that 2′,3′-dideoxyribonucleosides are generated from the reaction of low-energy electrons with DNA, leading to cleavage of the C3′–O bond and formation of the corresponding C3′-deoxyribose radical

Unified Mechanism for the Generation of Isolated and Clustered DNA Damages by a Single Low Energy (5–10 eV) Electron

Clustered DNA damages are the most detrimental modifications induced by ionizing radiation in cells and several mechanisms have been proposed for their formation. We report measurements of such damages induced by a single low energy electron via the formation of the two major core-excited resonances of DNA located at 4.6 and 9.6 eV. Cross-links and single and double strand breaks (SSBs and DSBs) are analyzed by gel electrophoresis. Treatment of irradiated samples with Esherichia coli base excision repair endonucleases reveals base damages (BDs). DSBs resulting from such treatments arise from clustered damages consisting of at least two BDs or one BD accompanied by a SSB. The total DNA damages induced by 4.6 and 9.6 eV electrons are 132 ± 32 and 201 ± 36 × 10^–15 electron^–1 molecule^–1, comprising 43% and 52% BDs, respectively. We propose a unifying mechanism to account for these clustered damages, DSBs, and single BDs, as well as all previously measured isolated lesions

Fundamental Mechanisms of DNA Radiosensitization: Damage Induced by Low-Energy Electrons in Brominated Oligonucleotide Trimers

The replacement of nucleobases with brominated analogs enhances DNA radiosensitivity. We examine the chemistry of low-energy electrons (LEEs) in this sensitization process by experiments with thin films of the oligonucleotide trimers TBrXT, where BrX = 5-BrU (5-bromouracil), 5-BrC (5-bromocytosine), 8-BrA (8-bromoadenine), or 8-BrG (8-bromoguanine). The products induced from irradiation of thin (∼ 2.5 nm) oligonucleotide films, with 10 eV electrons, under ultrahigh vacuum (UHV) are analyzed by HPLC-UV. The number of damaged brominated trimers ranges from about 12 to 15 × 10^–3 molecules per incident electron, whereas under the identical conditions, these numbers drop to 4–7 × 10^–3 for the same, but nonbrominated oligonucleotides. The results of HPLC analysis show that the main degradation pathway of trinucleotides containing brominated bases involve debromination (i.e., loss of the bromine atom and its replacement with a hydrogen atom). The electron-induced sum of products upon bromination increases by factors of 2.1 for the pyrimidines and 3.2 for the purines. Thus, substitution of any native nucleobase with a brominated one in simple models of DNA increases LEE-induced damage to DNA and hence its radiosensitivity. Furthermore, besides the brominated pyrimidines that have already been tested in clinical trials, brominated purines not only appear to be promising sensitizers for radiotherapy, but could provide a higher degree of radiosensitization