Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries–Part C: Oxygen effect and its implications on high- and low-LET dose

Richardson, Richard B.

doi:10.1080/09553000802389686

Cited by 14 publications

(13 citation statements)

References 34 publications

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“…The reciprocal of the half-maximal O 2 concentration is an important parameter, as it is an index for the O 2 affinity of the respiratory system. Before radiation exposure, it is assumed that the coupled half-maximal O 2 value is 0.55% [32] and the maximum O 2 flow is 40 pmol/s/10 6 cells. On the basis that a 2 Gy exposure causes total uncoupling, with no change in the respiratory capacity, the half-maximal O 2 concentration drops to 0.20%, based on data for human endothelial cells [31].…”

Section: Resultsmentioning

confidence: 99%

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Mitochondrial stress controls the radiosensitivity of the oxygen effect: Implications for radiotherapy

Richardson

Harper

2016

Oncotarget

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It has been more than 60 years since the discovery of the oxygen effect that empirically demonstrates the direct association between cell radiosensitivity and oxygen tension, important parameters in radiotherapy. Yet the mechanisms underlying this principal tenet of radiobiology are poorly understood. Better understanding of the oxygen effect may explain difficulty in eliminating hypoxic tumor cells, a major cause of regrowth after therapy. Our analysis utilizes the Howard-Flanders and Alper formula, which describes the relationship of radiosensitivity with oxygen tension. Here, we assign and qualitatively assess the relative contributions of two important mechanisms. The first mechanism involves the emission of reactive oxygen species from the mitochondrial electron transport chain, which increases with oxygen tension. The second mechanism is related to an energy and repair deficit, which increases with hypoxia. Following a radiation exposure, the uncoupling of the oxidative phosphorylation system (proton leak) in mitochondria lowers the emission of reactive oxygen species which has implications for fractionated radiotherapy, particularly of hypoxic tumors. Our analysis shows that, in oxygenated tumor and normal cells, mitochondria, rather than the nucleus, are the primary loci of radiotherapy effects, especially for low linear energy transfer radiation. Therefore, the oxygen effect can be explained by radiation-induced effects in mitochondria that generate reactive oxygen species, which in turn indirectly target nuclear DNA.

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Section: Resultsmentioning

confidence: 99%

“…Half-maximal O 2 concentration (

C_{O E R_{50}}^{R}

) is the percentage O 2 for which the cellular radiosensitivity is midway between the anoxic and fully oxygenated responses. A value of 0.55% O 2 was assumed for both low- and high-LET radiation; to our knowledge there is no discernible trend in

C_{O E R_{50}}^{R}

with LET [32]. …”

Section: Methodsmentioning

confidence: 99%

Mitochondrial stress controls the radiosensitivity of the oxygen effect: Implications for radiotherapy

Richardson

Harper

2016

Oncotarget

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“…This has been modelled by Richardson [43]–[45], who has highlighted the pronounced variations with oxygen concentration across the intima, which also varies with age as a result of modifications in arterial geometry [44]. It is well known that with decreasing oxygenation the effective dose reduces [45], and this implies that biologically effective dose per unit exposure reduces by 8–12% from age 0.5 to 70 years, whether for high linear energy transfer (LET) ( 222 Rn, 218 Po, 214 Po) or for low LET radiation [45]. This needs to be addressed in the dosimetry of any study; assuming that, as we argue above, intimal dose is of the most relevance to cardiovascular risk, not doing so would imply a modest negative bias in modifications of the radiation response by age at exposure.…”

Section: Discussionmentioning

confidence: 99%

A Model of Cardiovascular Disease Giving a Plausible Mechanism for the Effect of Fractionated Low-Dose Ionizing Radiation Exposure

2009

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Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally exposed groups receiving small daily radiation doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and cancer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapolation would be appropriate for this endpoint.

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“…The generation of oxidative stress, somatic DNA mutations and genetic instability has been strongly implicated in the pathogenesis of atherosclerosis, lending credence to potential inductance by IR [49]. Some protection is afforded against the detrimental effects of IR by the "oxygen effect" which increases radio-resistance in diseased and hypoxic artery walls (see Section 5) [50]. …”

Section: Comparison Of Aging and Radiation Effectsmentioning

confidence: 99%

Ionizing radiation and aging: rejuvenating an old idea

Richardson

2009

Aging

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118

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This paper reviews the contemporary evidence that radiation can accelerate aging, degenerative health effects and mortality. Around the 1960s, the idea that ionizing radiation caused premature aging was dismissed as the radiation-induced health effects appeared to be virtually confined to neoplasms. More recently, radiation has become associated with a much wider spectrum of age-related diseases, including cardiovascular disease; although some diseases of old age, such as diabetes, are notably absent as a radiation risk. On the basis of recent research, is there a stronger case today to be made linking radiation and aging? Comparison is made between the now-known biological mechanisms of aging and those of radiation, including oxidative stress, chromosomal damage, apoptosis, stem cell exhaustion and inflammation. The association between radiation effects and the free-radical theory of aging as the causative hypothesis seems to be more compelling than that between radiation and the nutrient-sensing TOR pathway. Premature aging has been assessed by biomarkers in calorie restriction studies; yet, biomarkers such as telomere erosion and p16INK4a are ambiguous for radiation-induced aging. Some animal studies suggest low dose radiation may even demonstrate hormesis health benefits. Regardless, there is virtually no support for a life span extending hypothesis for A-bomb survivors and other exposed subjects.

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Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries–Part C: Oxygen effect and its implications on high- and low-LET dose

Abstract: These results imply that the oxygen effect, and other radiation biological factors, have a significant influence on radiation biological effects and risk of cardiovascular disease (CVD) to Japanese atomic bomb (A-bomb) survivors and patients receiving radiotherapy of the mediastinum.

Cited by 14 publications

References 34 publications

Mitochondrial stress controls the radiosensitivity of the oxygen effect: Implications for radiotherapy

Mitochondrial stress controls the radiosensitivity of the oxygen effect: Implications for radiotherapy

A Model of Cardiovascular Disease Giving a Plausible Mechanism for the Effect of Fractionated Low-Dose Ionizing Radiation Exposure

Ionizing radiation and aging: rejuvenating an old idea

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