The synergistic interaction of cisplatin with ionizing radiation is the clinical rationale for the treatment of several cancers including head and neck, cervical and lung cancer. The underlying molecular mechanism of the synergy has not yet been identified, although both DNA damage and repair processes are likely involved. Here, we investigate the indirect effect of γ rays on strand break formation in a supercoiled plasmid DNA (pGEM–3Zf-) covalently modified by cisplatin. The yields of single- and double-strand breaks were determined by irradiation of DNA and cisplatin/DNA samples with 60Co γ rays under four different scavenging conditions to examine the involvement of hydrated electrons and hydroxyl radicals in inducing the DNA damage. At 5 mM tris in an N2 atmosphere, the presence of an average of two cisplatins per plasmid increased the yields of single- and double-strand breaks by factors of 1.9 and 2.2, respectively, relative to the irradiated unmodified DNA samples. Given that each plasmid of 3,200 base pairs contained an average of two cisplatins, this represents an increase in radiosensitivity of 3,200-fold on a per base pair basis. When hydrated electrons were scavenged by saturating the samples with N2O, these enhancement factors decreased to 1.5 and 1.2, respectively, for single- and double-strand breaks. When hydroxyl radicals were scavenged using 200 mM tris, the respective enhancement factors were 1.2 and 1.6 for single- and double-strand breaks, respectively. Furthermore, no enhancement in DNA damage by cisplatin was observed after scavenging both hydroxyl radicals and hydrated electrons. These findings show that hydrated electrons can induce both single- and double-strand breaks in the platinated DNA, but not in unmodified DNA. In addition, cisplatin modification is clearly an extremely efficient means of increasing the formation of both single- and double-strand breaks by the hydrated electrons and hydroxyl radicals created by ionizing radiation.
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1 March 2013
Research Articles|
January 31 2013
Cisplatin Enhances the Formation of DNA Single- and Double-Strand Breaks by Hydrated Electrons and Hydroxyl Radicals
Mohammad Rezaee;
Mohammad Rezaee
1
Groupe en Sciences des Radiations, Départment de Médecine Nucléaire et Radiobiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
1Address for correspondence: Groupe en Sciences des Radiations, Départment de Médecine Nucléaire et Radiobiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H5N4; e-mail: Mohammad.Rezaee@USherbrooke.ca.
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Léon Sanche;
Léon Sanche
Groupe en Sciences des Radiations, Départment de Médecine Nucléaire et Radiobiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
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Darel J. Hunting
Darel J. Hunting
Groupe en Sciences des Radiations, Départment de Médecine Nucléaire et Radiobiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
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Radiat Res (2013) 179 (3): 323–331.
Article history
Received:
September 05 2012
Accepted:
October 17 2012
Citation
Mohammad Rezaee, Léon Sanche, Darel J. Hunting; Cisplatin Enhances the Formation of DNA Single- and Double-Strand Breaks by Hydrated Electrons and Hydroxyl Radicals. Radiat Res 1 March 2013; 179 (3): 323–331. doi: https://doi.org/10.1667/RR3185.1
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