Absolute cross sections for chemoradiation therapy: Damages to cisplatin-DNA complexes induced by 10 eV electrons

Abstract

In chemoradiation therapy, the synergy between the radiation and the chemotherapeutic agent (CA) can result in a super-additive treatment. A priori, this increased effectiveness could be estimated from model calculations, if absolute cross sections (ACSs) involved in cellular damage are substantially higher, when the CA binds to DNA. We measure ACSs for damages induced by 10 eV electrons, when DNA binds to the CA cisplatin as in chemotherapy. At this energy, DNA is damaged essentially by the decay of core-excited transient anions into bond-breaking channels. Films of cisplatin-DNA complexes of ratio 5:1 with thicknesses 10, 15, and 20 nm were irradiated in vacuum during 5–30 s. Conformation changes were quantified by electrophoresis and yields extrapolated from exposure-response curves. Base damages (BDs) were revealed and quantified by enzymatic treatment. The ACSs were generated from these yields by two mathematical models. For 3197 base-pair plasmid DNA, ACS for single strand breaks, double strand breaks (DSBs), crosslinks, non-DSB cluster damages, and total BDs is 71 ± 2, 9.3 ± 0.4, 10.1 ± 0.3, 8.2 ± 0.3, and 115 ± 2 ×10−15 cm2, respectively. These ACSs are higher than those of nonmodified DNA by factors of 1.6 ± 0.1, 2.2 ± 0.1, 1.3 ± 0.1, 1.3 ± 0.3, and 2.1 ± 0.4, respectively. Since LEEs are produced in large quantities by radiolysis and strongly interact with biomolecules, we expect such enhancements to produce substantial additional damages in the DNA of the nucleus of cancer cells during concomitant chemoradiation therapy. The increase damage appears sufficiently large to justify more elaborate simulations, which could provide a quantitative evaluation of molecular sensitization by Pt-CAs.

Clustered DNA Damages induced by 0.5 to 30 eV Electrons

“…The enhancement of non-DSB clustered damages induced by 10-eV electrons was also observed in Pt–CA–DNA complexes [105,111]. EFs of 1.4–1.7, 1.1, and 1.4 caused by the respective binding of cisplatin, carboplatin, and oxaliplatin to DNA show that the physicochemical radiosensitization mechanism of cisplatin and its analogues could be universal; i.e., the Pt–drug covalently bound to DNA weakens the DNA structure [106], and could favor the initial formation of core-excited resonances, leading to the enhancement of C–O bond scissions (strand breaks) and/or base lesion simultaneously, and hence the formation of clustered lesions.…”

“…Figure 2C shows the measured absolute CSs of DSB (open points) and the energy dependence (solid points) estimated from effective yields, assuming a constant electron penetration factor ( f ) of 0.29 ± 0.14 for all energies [103]. The measured absolute CSs for DSBs and non-DSB clustered damages induced by 10-eV electrons are 4.3 ± 0.2 and 6.5 ± 1.6 × 10 −15 cm 2 , respectively [103,105]. In comparison, the CS of DSBs induced by 50-eV electrons were deduced from an effective yield with f = 0.45 ± 0.21 to be 2.7 ± 1.5 × 10 −15 cm 2 [101].…”

“…Furthermore, binding a chemotherapeutic agent to DNA can also increase LEE CSs. For example, when cisplatin is chemically bound to DNA in a ratio of 5:1, the CSs of DSBs and non-DSB clustered damages at 10 eV increase to 9.3 ± 0.4 and 8.2 ± 0.3 × 10 −15 cm 2 , respectively; i.e., they increase by factors of 2.2 and 1.3 compared to unmodified DNA [105].…”

Role of Transient Anions in Chemoradiation Therapy: Base Modifications, Cross-Links, and Cluster Damages Induced to Cisplatin-DNA Complexes by 1–20 eV Electrons

“…In a number of in vacuo and in vivo experiments, LEEs ( E < 20 eV) were found to play a pivotal role in the radiosensitization mechanism of Pt chemotherapeutic drugs. ,,,,− Bao et al recorded yield functions by measuring the energy dependence of the magnitude of DNA damages resulting from a 2 to 20 eV electron impact on freeze-dried films of cisplatin-DNA complexes in vacuum . By comparison to the results of identical experiments with unmodified DNA, the complex yield functions revealed considerable enhancement of CLs and DSBs, when DNA binds to cisplatin, oxaliplatin, and carboplatin, with the latter providing the highest DNA sensitization to LEEs.…”

DNA Protection against Damages Induced by Low-Energy Electrons: Absolute Cross Sections for Arginine–DNA Complexes

“…We report ACSs for damaging the plasmids in Arg–DNA with 5 and 10 eV electrons and in Dap–DNA with 10 eV electrons. Detailed explanations of the experimental procedure are available from previous publications. ,, ACSs allow for the adequate quantitation of modifications in the damaging efficiency of SEs introduced by molecules bound to DNA . Since Dap and Arg self-assemble layers of DNA in the same manner, the ACSs from Dap–DNA films serve as a different reference than ACSs previously determined for films constructed uniquely of DNA molecules, hereafter referred to as “DNA.” Furthermore, ACSs provide input parameters and experimental checkpoints in modeling calculations ,− and photoelectron experiments performed in water and with live cells, , in which genomic DNA damage induced by LEEs is simulated mathematically.…”