Effect of Dose Rate on the Survival of Irradiated Human Skin Fibroblasts

Nagasawa, Hiromichi; Little, John B.; Tsang, Ngan‐Ming; Saunders, Eric L.; Tesmer, Judith G.; Strniste, G.F.

doi:10.2307/3578247

Cited by 40 publications

(13 citation statements)

References 8 publications

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“…Taken together, these data strongly argue that the increased cell killing (inverse dose rate effects) and reduced ␥-H2AX levels following LDR IR exposures are primarily a consequence of reduced ATM activation. This hypothesis is in accordance with the finding that cells lacking ATM do not show inverse dose rate effects (34).…”

Section: Low Level Dna Damage Results In Reduced Signaling Across a Rsupporting

confidence: 93%

“…1 and 4A). This inverse dose rate effect on cell survival has been known to exist for many cell types, although a complete explanation for its cause has been lacking (21,24,(33)(34)(35). A similar inverse dose rate effect is also known to exist in the production of genomic mutations following radiation exposure (6), which may be a consequence of the ineffective activation of repair mechanisms, as shown by the data presented here.…”

Section: Low Level Dna Damage Results In Reduced Signaling Across a Rsupporting

confidence: 51%

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Evasion of Early Cellular Response Mechanisms following Low Level Radiation-induced DNA Damage

Collis

Schwaninger²,

Ntambi³

et al. 2004

Journal of Biological Chemistry

133

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DNA damage that is not repaired with high fidelity can lead to chromosomal aberrations or mitotic cell death. To date, it is unclear what factors control the ultimate fate of a cell receiving low levels of DNA damage (i.e. survival at the risk of increased mutation or cell death). We investigated whether DNA damage could be introduced into human cells at a level and frequency that could evade detection by cellular sensors of DNA damage. To achieve this, we exposed cells to equivalent doses of ionizing radiation delivered at either a high dose rate (HDR) or a continuous low dose rate (LDR). We observed reduced activation of the DNA damage sensor ataxia-telangiectasia mutated (ATM) and its downstream target histone H2A variant (H2AX) following LDR compared with HDR exposures in both cancerous and normal human cells. This lack of DNA damage signaling was associated with increased amounts of cell killing following LDR exposures. Increased killing by LDR radiation has been previously termed the "inverse dose rate effect," an effect for which no clear molecular processes have been described. These LDR effects could be abrogated by the preactivation of ATM or simulated in HDR-treated cells by inhibiting ATM function. These data are the first to demonstrate that DNA damage introduced at a reduced rate does not activate the DNA damage sensor ATM and that failure to activate ATMassociated repair pathways contributes to the increased lethality of continuous LDR radiation exposures. This inactivation may reflect one strategy by which cells avoid accumulating mutations as a result of error-prone DNA repair and may have a broad range of implications for carcinogenesis and, potentially, the clinical treatment of solid tumors.

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Section: Low Level Dna Damage Results In Reduced Signaling Across a Rsupporting

confidence: 93%

Section: Low Level Dna Damage Results In Reduced Signaling Across a Rsupporting

confidence: 51%

Evasion of Early Cellular Response Mechanisms following Low Level Radiation-induced DNA Damage

Collis

Schwaninger²,

Ntambi³

et al. 2004

Journal of Biological Chemistry

133

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“…Radiation dose-rate is an important determinant of biological outcome, with reduced biological effectiveness of radiation exposure at low dose-rate in normal cells. In contrast, ATM null human fibroblast cells are equally sensitive to low and high dose-rate irradiation (Nagasawa et al 1992, Nakamura et al 2006. Whether A-T heterozygotes are also equally sensitive to low and high dose-rate irradiation is unknown.…”

Section: Discussionmentioning

confidence: 99%

Low dose X-radiation adaptive response in spleen and prostate ofAtmknockout heterozygous mice

Day

Hooker

Zeng

et al. 2007

International Journal of Radiation Biology

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“…The bystander effect was first reported by Nagasawa et al (1992), who observed chromosome damage in 30% of cells following exposure to a broad field of a-particles such that only 1% of cell nuclei are actually hit. Since then, the bystander effect has become one of the most widely studied of the non-targeted effects, which also include genomic instability, adaptive responses, low-dose hypersensitivity, the inverse dose-rate effect and the regulation of genes at low-doses (Morgan, 2003a(Morgan, , 2003b.…”

Section: Bystander Effectmentioning

confidence: 91%

Microbeam radiation therapy: a review

Wang¹,

Qian

2015

IJCBDD

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The radiation effects in tissue depend not only on dose but also on volume exposed, for example, the smaller the volume, the greater the tolerance. Microbeam radiation therapy (MRT), which exploits this effect, can only be achieved with synchrotron X-rays owing to their extraordinarily slight divergence. MRT research over the past 20 years has yielded many results from preclinical trials based on different animal models, including mice, rats, piglets and rabbits. Typically, targets are exposed to multiple quasi-parallel slices of radiation some tens of micrometres wide with on-centre separations of several hundred micrometres. The microplanar beams are produced by a multi-slit collimator, which cuts horizontally microscopic beam sectors from a wigglergenerated fan beam. Peak entrance doses of several hundreds of Gy are surprisingly well tolerated by normal tissues and at the same time show a preferential damage of malignant tumour tissues.

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Effect of Dose Rate on the Survival of Irradiated Human Skin Fibroblasts

Cited by 40 publications

References 8 publications

Evasion of Early Cellular Response Mechanisms following Low Level Radiation-induced DNA Damage

Evasion of Early Cellular Response Mechanisms following Low Level Radiation-induced DNA Damage

Low dose X-radiation adaptive response in spleen and prostate ofAtmknockout heterozygous mice

Microbeam radiation therapy: a review

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