New insights into the mechanism underlying the synergistic action of ionizing radiation with platinum chemotherapeutic drugs: the role of low-energy electrons

Abstract

Purpose: To investigate the efficiencies of platinum chemotherapeutic drugs (Pt-drugs) in the sensitization of DNA to the direct effects of ionizing radiation and to determine the role of low-energy electrons (LEEs) in this process.

Methods and materials: Complexes of supercoiled plasmid DNA covalently bound to either cisplatin, carboplatin, or oxaliplatin were prepared in different molar ratios. Solid films of DNA and DNA modified by Pt-drugs were irradiated with either 10-KeV or 10-eV electrons. Damages to DNA were quantified by gel electrophoresis, and the yields for damage formation were obtained from exposure-response curves.

Results: The presence of an average of 2 Pt-drug-DNA adducts (Pt-adducts) in 3199-bp plasmid DNA increases the probability of a double-strand break by factors of 3.1, 2.5, and 2.4 for carboplatin, cisplatin, and oxaliplatin, respectively. Electrons with energies of 10 eV and 10 KeV interact with Pt-adducts to preferentially enhance the formation of cluster lesions. The maximum increase in radiosensitivity per Pt-adduct is found at ratios up to 3.1×10(-4) Pt-adducts per nucleotide, which is equivalent to an average of 2 adducts per plasmid. Carboplatin and oxaliplatin show higher efficiencies than cisplatin in the radiosensitization of DNA. Because carboplatin and cisplatin give rise to identical reactive species that attach to DNA, carboplatin must be considered as a better radiosensitizer for equal numbers of Pt-adducts.

Conclusion: Platinum chemotherapeutic drugs preferentially enhance the formation of cluster damage to DNA induced by the direct effect of ionizing radiation, and LEEs are the main species responsible for such an enhancement via the formation of electron resonances.

Fig. 1

Enhancement factors in the yields of SSB, DSB and interduplex CL induced by 10-KeV (a) and 10-eV (b) electrons in the presence of cisplatin, carboplatin and oxaliplatin. * indicates a P-value < 0.05, when the different Pt-drug-DNA complexes are compared to unmodified DNA. † denotes a P-value < 0.05, when the different Pt-drug-DNA complexes are compared to each other.

Fig. 2

Exposure-response curve for the formation of DSB (a, b) and interduplex CL (c, d) by either 10-eV or 10-KeV electrons in DNA modified by cisplatin, carboplatin and oxaliplatin. Data are means ± standard deviation from five measurements. They have been fitted by employing a least-squares regression analysis.

Fig. 3

Enhancement factors in the yields of SSB, DSB and interduplex CL as a function of the number of Pt-adducts per nucleotide for DNA modified by cisplatin (a), carboplatin (b) and oxaliplatin (c) irradiated with 10-eV electrons. The fitted lines are based on a least-square regression analysis.