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

Abstract

The molecular mechanism of platinum-based drugs in concomitant chemoradiation therapy relies on enhancement of DNA damage in cancer cells, particularly that of detrimental clustered lesions and cross-links induced by the abundant low-energy electrons (LEEs) generated by ionizing radiation. We provide the complete 1-20 eV electron-energy dependence of the yields of all conformational LEE-induced lesions to biological DNA, when it binds to five molecules of the chemotherapeutic drug cisplatin. Recording at 1 eV intervals clearly show that the enhancement of all lesions is particularly intense at the energies of core-excited transient molecular anions (i.e., TMAs at 5, 6, and 10 eV). New TMAs are observed at 14 and 18 eV, only in yield functions of cisplatin-DNA complexes. Enhancements of all lesions by cisplatin are quantified over the 1-20 eV range, where maxima appear at 14 and 18 eV. The most detrimental lesions to cell survival exhibit the highest enhancements by factors of 2-3. Whereas no cluster lesions are induced by electrons of energy <5 eV in DNA, LEEs of any energy cause clustered damages in the complex. These results confirm the current notion that LEEs and TMAs play a dominant role in the molecular mechanism of platinum-drug chemoradiation therapy.