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

Abstract

Platinum chemotherapeutic agents, such as cisplatin (cis-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 doublestrand 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.

Transient Anions in Radiobiology and Radiotherapy: From Gaseous Biomolecules to Condensed Organic and Biomolecular Solids

“…More recently, the energy dependence of conformational damage induced to pure plasmid DNA [183] and cisplatin-plasmid DNA complexes [184] was investigated in the range 2-20 eV. In addition to the strong resonances (i.e., TMAs) in pure DNA around 5 and 10 eV, further TMA specific to cisplatin-modified DNA were observed in the yield function of SSBs at 13.6 and 17.6 eV.…”

“…In all cases, the measured yields were larger than those measured with nonmodified DNA. To reconcile all existing results starting from those obtained with hydrated electrons to those generated up to 20 eV, Bao et al [184] suggested a single mechanism that could apply to shape and core-excited resonances, depending or not if electronic excitation of the Pt or guanines was involved in TMA formation. This mechanism, previously proposed for shape resonances by Rezaee et al [178], can be explained with reference to Figure 6.…”

Evaluating experimental molecular physics studies of radiation damage in DNA*

“…effective yields of SSBs formed upon irradiation [71]. When plotting number of SSBs per DNA molecule against the radiation dose obtained from both methods that were our subjects of investigations, it is clearly seen, that the underestimation of the damage levels is already significant at very low doses of radiation (Fig.…”

Absolute cross-sections for DNA strand breaks and crosslinks induced by low energy electrons

“…The present comprehensive study suggests that a similar procedure could be adapted to obtain absolute CSs for electron-induced damage/reaction occurring in other molecular or biomolecular solids. Similar studies are presently underway with the chemotherapeutic agent cisplatin bound to plasmid DNA, to transform the LEE energy dependence of effective CSs for damage to the cisplatin-DNA complex 51 to absolute CSs. The latter are expected to be of considerable value to estimate the increase in the local dose distribution near the DNA of cancer cells in patients receiving concomitant radio-and chemo-therapy.…”