title: New insights into the mechanism underlying the synergistic action of ionizing radiation with platinum chemotherapeutic drugs: the role of low-energy electrons.
abstract: OBJECTIVE
  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
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Département de Médecine Nucléaire et Radiobiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, QC, Canada. Electronic address: Mohammad.Rezaee@USherbrooke.ca.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Rezaee
authors.forename: Darel John
authors.initials: DJ
authors.lastname: Hunting
authors.forename: Léon
authors.initials: L
authors.lastname: Sanche
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D018736:DNA Adducts; D004249:DNA Damage; D004278:DNA, Superhelical / Q000187:drug effects* / Q000528:radiation effects; D004583:Electrons / Q000627:therapeutic use*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010957:Plasmids / Q000187:drug effects / Q000235:genetics; D011836:Radiation Tolerance / Q000187:drug effects* / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D004278:DNA, Superhelical; D009944:Organoplatinum Compounds; D011838:Radiation-Sensitizing Agents; C096276:carboplatin-DNA adduct; C057270:cisplatin-DNA adduct; D000077150:Oxaliplatin; D016190:Carboplatin; D002945:Cisplatin
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