Page 18 - 2014 Printable Abstract Book
P. 18
SRS are effective due to enhanced anti-tumor immunity. It is conceivable that the initial extensive cell
death caused directly and indirectly through vascular damage by high dose per fraction radiation leads to
massive release of antigens, thereby enhancing the anti-tumor immune response. The potential role of
vascular damage and immune response together with the role of 4 Rs and the limitation of LQ model in
the response of tumors to SBRT/SRS will be discussed. (Supported by grants from Elekta and Minnesota
Foundation).
TR7. MECHANISMS OF RADIATION DAMAGE TO DNA: FROM IONIZATION TO RADICAL INTERMEDIATES
TO PRODUCTS
(TR701) Mechanisms of radiation damage to DNA: From ionization to radical intermediates to
products. Michael D. Sevilla, Oakland University, Rochester, MI
Owing to the high radical scavenging capacity of the various components of cell nucleus, cellular
DNA is largely protected from radiation produced species in its surroundings. Thus, free radicals produced
via radiolysis of surrounding water are largely scavenged by proteins, glutathione and biomolecules other
than DNA. As a result, direct-type effects account for up to 50% of the damage to DNA which results in
various diamagnetic products and strand breaks. Direct ionization of DNA produces DNA-cation radicals
(holes) and DNA-anion radicals (excess electrons) within DNA and its immediate microenvironments (e.g.,
hydration layer) in addition to low energy electrons (LEE) and excitation events. LEEs, before
thermalization, have been shown to lead to frank DNA strand breaks via dissociative electron attachment.
In addition, recent efforts have established that excitation of the base cation radical, results in charge and
spin transfer to the sugar-phosphate backbone. Subsequent kinetically controlled deprotonation within
the lifetime of the excited cation radical leads to the formation of neutral sugar radicals which are known
strand break precursors. An increased understanding of the mechanisms of radiation damage to DNA have
resulted from various radiation chemical and experimental techniques including pulse radiolysis, ESR,
theoretical calculations, and mimetic approaches based on generating radicals site-specifically in DNA. An
example of the latter is radical formation via a Norrish-type photoexcitation. These and other mechanisms
of direct-type effect-induced DNA-radical formation that lead to production of DNA damage, such as, base
damage and strand breaks will be the focus of this talk. Supported by the NIH NCI under grant
R01CA045424.
TR8. A NOVEL METABOLIC MECHANISM OF THE RADIO-ADAPTIVE RESPONSE
(TR801) A novel metabolic mechanism of the radio-adaptive response. Zhi-Min Yuan, Harvard School of
Public Health, Boston, MA
The radio-adaptive response is a widely observed phenomenon in which a low (priming) dose of
ionizing radiation (IR) can induce a defense mechanism to protect cells and organisms against the harmful
effects of a subsequent higher (challenging) dose. Although the concept of the radio-adaptive response is
well recognized, the molecular mechanism involved remains largely unclear. We demonstrate a novel
metabolic mechanism of radio-adaptive response. Treatment of normal human cells with low-dose
radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis resulting in
increased radiation resistance. This metabolic change is highlighted by upregulation of genes encoding
16 | P a g e
death caused directly and indirectly through vascular damage by high dose per fraction radiation leads to
massive release of antigens, thereby enhancing the anti-tumor immune response. The potential role of
vascular damage and immune response together with the role of 4 Rs and the limitation of LQ model in
the response of tumors to SBRT/SRS will be discussed. (Supported by grants from Elekta and Minnesota
Foundation).
TR7. MECHANISMS OF RADIATION DAMAGE TO DNA: FROM IONIZATION TO RADICAL INTERMEDIATES
TO PRODUCTS
(TR701) Mechanisms of radiation damage to DNA: From ionization to radical intermediates to
products. Michael D. Sevilla, Oakland University, Rochester, MI
Owing to the high radical scavenging capacity of the various components of cell nucleus, cellular
DNA is largely protected from radiation produced species in its surroundings. Thus, free radicals produced
via radiolysis of surrounding water are largely scavenged by proteins, glutathione and biomolecules other
than DNA. As a result, direct-type effects account for up to 50% of the damage to DNA which results in
various diamagnetic products and strand breaks. Direct ionization of DNA produces DNA-cation radicals
(holes) and DNA-anion radicals (excess electrons) within DNA and its immediate microenvironments (e.g.,
hydration layer) in addition to low energy electrons (LEE) and excitation events. LEEs, before
thermalization, have been shown to lead to frank DNA strand breaks via dissociative electron attachment.
In addition, recent efforts have established that excitation of the base cation radical, results in charge and
spin transfer to the sugar-phosphate backbone. Subsequent kinetically controlled deprotonation within
the lifetime of the excited cation radical leads to the formation of neutral sugar radicals which are known
strand break precursors. An increased understanding of the mechanisms of radiation damage to DNA have
resulted from various radiation chemical and experimental techniques including pulse radiolysis, ESR,
theoretical calculations, and mimetic approaches based on generating radicals site-specifically in DNA. An
example of the latter is radical formation via a Norrish-type photoexcitation. These and other mechanisms
of direct-type effect-induced DNA-radical formation that lead to production of DNA damage, such as, base
damage and strand breaks will be the focus of this talk. Supported by the NIH NCI under grant
R01CA045424.
TR8. A NOVEL METABOLIC MECHANISM OF THE RADIO-ADAPTIVE RESPONSE
(TR801) A novel metabolic mechanism of the radio-adaptive response. Zhi-Min Yuan, Harvard School of
Public Health, Boston, MA
The radio-adaptive response is a widely observed phenomenon in which a low (priming) dose of
ionizing radiation (IR) can induce a defense mechanism to protect cells and organisms against the harmful
effects of a subsequent higher (challenging) dose. Although the concept of the radio-adaptive response is
well recognized, the molecular mechanism involved remains largely unclear. We demonstrate a novel
metabolic mechanism of radio-adaptive response. Treatment of normal human cells with low-dose
radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis resulting in
increased radiation resistance. This metabolic change is highlighted by upregulation of genes encoding
16 | P a g e
