Page 94 - 2014 Printable Abstract Book
P. 94
(S2602) Hole transfer in DNA: backbone-to-base and base-to-backbone. Amitava Adhikary; Anil Kumar,
PhD; David Becker, PhD; and Michael D. Sevilla, PhD, Oakland University, Rochester, MI
One electron oxidation (hole) of the sugar-phosphate backbone creates an electron loss center
(hole) which upon deprotonation forms a neutral sugar radical (for example, the C5′-sugar radical (C5′•)).
Sugar radicals are important initial damages as they are the immediate precursors of radiation-induced
frank DNA-strand breaks. Our recent work 1, 2 has shown that, for successful formation of a sugar radical,
-12
a very rapid (< 10 s) deprotonation must occur from the one-electron oxidized sugar-phosphate
1
backbone before a competitive backbone-to-base hole transfer can occur (scheme 1). .
Scheme 1. Competition between Backbone-to-base hole transfer (ht) and sugar radical formation (e.g.,
C5'•) via deprotonation of the one-electron oxidized sugar-phosphate. Our work has also shown that in
both ion-beam and γ-irradiated DNA, sugar radical formation is not scavengeable and this confirms that
fast deprotonation occurs at 77 K even though longer lived holes and electrons trapped on DNA bases are
successfully scavenged at 77 K. 1, 2 We also have shown that base to backbone hole transfer can be initiated
by photoexcitation of base cation radicals. Our experimental and theoretical works have established
excitation of base (purine and pyrimidine) cation radicals leads to excited states that couple the sugar and
base leading to hole transfer from base to sugar and formation of neutral sugar radicals. Thus, the rate
3
and extent of hole transfer from the sugar-phosphate backbone to the bases and from the bases to the
sugar-phosphate backbone are critical processes that determine the yield of sugar radicals and these
processes would be discussed using specific examples such as novel S-oligomers that stabilized holes on
the backbone. Supported by the NIH NCI under grant RO1 CA045424. 1. Adhikary, A.; Kumar, A.; Palmer,
1
B. J.; Todd, A. D.; Sevilla, M. D. (2013) J. Am. Chem. Soc., 2013, 135, 12827 - 12838. 2. Adhikary, A.; Becker,
D.; Palmer, B. J.; Heizer, A. N.; Sevilla, M. D. J. Phys. Chem. B, 2012, 116, 5900 - 5906. 3. Adhikary, A.;
Kumar, A.; Palmer, B. J.; Todd, A. D.; Heizer, A. N.; Sevilla, M. D. (2014) Int. J. Radiat. Biol., 2014, 90, 433 -
445.
(S2603) From low energy electron DNA damage to chemoradiation therapy. Leon Sanche, Sherbrook
University, Sherbrooke, Canada
Group in the Radiation Sciences, Faculty of Medicine, University of Sherbrooke, QC, CANADA J1H 5N4
When cells are irradiated with high energy particles, the immediate major products are ions and
secondary electrons; most of latter have very low energies (E < 30 e V). These low energy electrons (LEEs)
can interact with nuclear DNA and produce various damages, including base, phosphate and sugar
modifications, single strand break, base release and multiple lesions (e.g., double strand breaks and
crosslinks). Most of these are created via the formation of transient anions (TA), which dissociate or leave
the site in a dissociative excited state after autoionization. Thus, these TA can produce radicals or chain
scission, which can lead to further reactions and cell death or mutation. The major dissociation pathways
induced by LEEs in DNA alone and DNA modified by Pt-chemotherapeutic agents will be presented during
the conference. It will be shown that some of these pathways are considerably amplified by the binding
of Pt drugs to DNA and that this knowledge can be applied to improve chemoradiation therapy protocols,
more specifically, to determine the optimal timing between administration of a Pt chemotherapeutic
agent and tumor irradiation. Results from various analysis extending from DNA damages to animal studies
with nude mice, bearing human colorectal HCT116 tumors, will be presented.
(S2604) Small molecule inhibitors of DNA repair - potential clinical uses. Michael Weinfeld, University of
Alberta, Edmonton, Canada
92 | P a g e
PhD; David Becker, PhD; and Michael D. Sevilla, PhD, Oakland University, Rochester, MI
One electron oxidation (hole) of the sugar-phosphate backbone creates an electron loss center
(hole) which upon deprotonation forms a neutral sugar radical (for example, the C5′-sugar radical (C5′•)).
Sugar radicals are important initial damages as they are the immediate precursors of radiation-induced
frank DNA-strand breaks. Our recent work 1, 2 has shown that, for successful formation of a sugar radical,
-12
a very rapid (< 10 s) deprotonation must occur from the one-electron oxidized sugar-phosphate
1
backbone before a competitive backbone-to-base hole transfer can occur (scheme 1). .
Scheme 1. Competition between Backbone-to-base hole transfer (ht) and sugar radical formation (e.g.,
C5'•) via deprotonation of the one-electron oxidized sugar-phosphate. Our work has also shown that in
both ion-beam and γ-irradiated DNA, sugar radical formation is not scavengeable and this confirms that
fast deprotonation occurs at 77 K even though longer lived holes and electrons trapped on DNA bases are
successfully scavenged at 77 K. 1, 2 We also have shown that base to backbone hole transfer can be initiated
by photoexcitation of base cation radicals. Our experimental and theoretical works have established
excitation of base (purine and pyrimidine) cation radicals leads to excited states that couple the sugar and
base leading to hole transfer from base to sugar and formation of neutral sugar radicals. Thus, the rate
3
and extent of hole transfer from the sugar-phosphate backbone to the bases and from the bases to the
sugar-phosphate backbone are critical processes that determine the yield of sugar radicals and these
processes would be discussed using specific examples such as novel S-oligomers that stabilized holes on
the backbone. Supported by the NIH NCI under grant RO1 CA045424. 1. Adhikary, A.; Kumar, A.; Palmer,
1
B. J.; Todd, A. D.; Sevilla, M. D. (2013) J. Am. Chem. Soc., 2013, 135, 12827 - 12838. 2. Adhikary, A.; Becker,
D.; Palmer, B. J.; Heizer, A. N.; Sevilla, M. D. J. Phys. Chem. B, 2012, 116, 5900 - 5906. 3. Adhikary, A.;
Kumar, A.; Palmer, B. J.; Todd, A. D.; Heizer, A. N.; Sevilla, M. D. (2014) Int. J. Radiat. Biol., 2014, 90, 433 -
445.
(S2603) From low energy electron DNA damage to chemoradiation therapy. Leon Sanche, Sherbrook
University, Sherbrooke, Canada
Group in the Radiation Sciences, Faculty of Medicine, University of Sherbrooke, QC, CANADA J1H 5N4
When cells are irradiated with high energy particles, the immediate major products are ions and
secondary electrons; most of latter have very low energies (E < 30 e V). These low energy electrons (LEEs)
can interact with nuclear DNA and produce various damages, including base, phosphate and sugar
modifications, single strand break, base release and multiple lesions (e.g., double strand breaks and
crosslinks). Most of these are created via the formation of transient anions (TA), which dissociate or leave
the site in a dissociative excited state after autoionization. Thus, these TA can produce radicals or chain
scission, which can lead to further reactions and cell death or mutation. The major dissociation pathways
induced by LEEs in DNA alone and DNA modified by Pt-chemotherapeutic agents will be presented during
the conference. It will be shown that some of these pathways are considerably amplified by the binding
of Pt drugs to DNA and that this knowledge can be applied to improve chemoradiation therapy protocols,
more specifically, to determine the optimal timing between administration of a Pt chemotherapeutic
agent and tumor irradiation. Results from various analysis extending from DNA damages to animal studies
with nude mice, bearing human colorectal HCT116 tumors, will be presented.
(S2604) Small molecule inhibitors of DNA repair - potential clinical uses. Michael Weinfeld, University of
Alberta, Edmonton, Canada
92 | P a g e
