Contribution of Base Damages to the Molecular Radiosensitization Mechanism of Platinum Chemotherapeutic Drugs

Abstract

The measurement of clustered damages in Pt‐chemotherapeutic‐drugs‐DNA complexes induced by low‐energy (0‐30 eV) electrons (LEEs) may provide further understanding of the synergy mechanism in cancer treatment with concomitant chemoradiation therapy (CRT). Five‐monolayer films of Pt‐DNA complexes, containing cisplatin, carboplatin and oxaliplatin with ratio 5:1 were irradiated with mono‐energetic electrons of 10 eV, the most prominent energy for bond dissociation by LEE impact. Damages to plasmid DNA including crosslinks, SSBs, DSBs and the loss of the supercoiled configuration were analyzed by the electrophoresis. Base damages (BDs) occurring within two turns of DNA helix were detected by the treatment of E. coli base excision repair endonuclease (Nth and Fpg). The total DNA damages to Pt‐DNA complexes was found to be 350 ± 42, 296 ± 45 and 434 ± 46 ×10−15 electron−1molecule−1, respectively, while the percentages of BDs in this total were 56%, 54% and 60%, respectively. Compared to unmodified DNA, binding of Pt‐drugs to DNA increased BDs by factors of 1.9, 1.6 and 2.6, respectively, which partly resulted in significant enhancements of potentially lethal lesions (i. e., crosslinks, double strand breaks (DSBs) and non‐DSB cluster damages). These results reveal the significant role that LEEs play in the formation of clustered DNA damages related to BDs, which are expected to contribute to the higher efficacy of cancer treatment by CRT with the Pt‐drugs investigated.

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

“…When comparison is possible, the result is consistent with the previous studies. 14,15,32,33,47 Interestingly, in the range of 1−20 eV M EF for DSB and non-DSB clustered damages are 2.1 and 1.8, respectively, while those of isolated BD and SSBs are 1.7 and 1.4, respectively, indicating that cisplatin renders DNA particularly sensitive to LEE-induced clustered damage. Previously, no DSB have been seen in unmodified DNA bombarded with electrons of energies below 4 eV.…”

DNA radiosensitization by terpyridine-platinum: damage induced by 5 and 10 eV transient anions

“…The numerical values of these yields are listed in Table 1S of the ESI, † where they are compared to the results previously obtained under identical conditions, with cisplatin, carboplatin and oxaliplatin bound to DNA. 59,72,101,103…”

“…The detailed comparison of purine-and pyrimidine-related damage induced by 10 eV electrons in Pt-drug-DNA complexes is shown in Fig. 3, 72,103 where the yields of purine-related damage are found to be larger than those related to pyrimi-dine. However, the enhancement varies for different Pt-compounds and DNA damage.…”

“…The EF is defined as the yield of a given damage in the Pt-DNA complex divided by that in nonmodified DNA under identical conditions. The EFs of Tpy-Pt-DNA induced by 5 eV electrons are listed in order of increasing values from left to right in the first line 2.0 ± 0.5 2.3 ± 0.8 1.9 ± 0.6 Cisplatin-DNA 60 2.2 ± 0.9 2.5 ± 0.4 1.4 ± 0.4 Carboplatin-DNA 60 3.1 ± 1.0 3.1 ± 0.5 1.5 ± 0.4 Oxaliplatin-DNA 60 4.1 ± 1.8 2.4 ± 0.4 1.5 ± 0.4 Cisplatin-DNA 72 1.4 ± 1.0 1.4 ± 0.5 1.4 ± 0.7 1.4 ± 0.4 1.7 ± 0.4 1.4 ± 0.9 1.7 ± 0.5 1.9 ± 0.4 1.8 ± 0.3 Cisplatin-DNA 103 2.4 ± 0.8 1.4 ± 0.5 1.5 ± 0.3 1.5 ± 0.2 1.5 ± 0.2 1.7 ± 1.1 1.4 ± 0.8 1.9 ± 0.9 1.7 ± 0.4 Carboplatin-DNA 103 1.7 ± 0.4 1.1 ± 0.4…”

“…1.9 ± 0.4 1.3 ± 0.2 1.3 ± 0.2 1.6 ± 0.7 1.3 ± 0.6 1.6 ± 0.6 1.4 ± 0.3 Oxaliplatin-DNA 103 1.8 ± 0.4 1.4 ± 0.5 1.4 ± 0.3 1.7 ± 0.2 1.7 ± 0.2 1.5 ± 0.6 2.3 ± 0.7 2.6 ± 0.9 2.1 ± 0.5…”