Cellular signal adaptation with damage control at low doses versus the predominance of DNA damage at high doses

Feinendegen, L. E.; Bond, V.P.; Sondhaus, C. A.; Altman, Kurt I.

doi:10.1016/s0764-4469(99)80051-1

Cited by 41 publications

(27 citation statements)

References 35 publications

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“…These responses, except for apoptosis, whenever examined as function of dose show dose-dependence in that they increasingly disappear with doses above about 200 mGy. 87 In fact, this particular response pattern is in principle very similar to that frequently seen in toxicology and pharmacology and typically expresses the ubiquitous characteristics of complex adaptive systems. As one of many examples: increasing concentrations of penicillin initially stimulate growth of Staphylococcus cultures to about 150% of control at about 0.015 units penicillin per mL broth; with higher penicillin concentrations bacterial growth falls steeply and linearly, as expected.…”

Section: Radiation-induced Versus Endogenous Dna Damage M Pollycove Amentioning

confidence: 72%

Radiation-induced versus endogenous DNA damage: possible effect of inducible protective responses in mitigating endogenous damage

2003

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Ionizing radiation (IR) causes damage to DNA that is apparently proportional to absorbed dose. The incidence of radiation-induced cancer in humans unequivocally rises with the value of absorbed doses above about 300 mGy, in a seemingly linear fashion. Extrapolation of this linear correlation down to zero-dose constitutes the linear-no-threshold (LNT) hypothesis of radiation-induced cancer incidence. The corresponding dose-risk correlation, however, is questionable at doses lower than 300 mGy. Non-radiation induced DNA damage and, in consequence, oncogenic transformation in non-irradiated cells arises from a variety of sources, mainly from weak endogenous carcinogens such as reactive oxygen species (ROS) as well as from micronutrient deficiencies and environmental toxins. In order to relate the low probability of radiation-induced cancer to the relatively high incidence of non-radiation carcinogenesis, especially at low-dose irradiation, the quantitative and qualitative differences between the DNA damages from non-radiation and radiation sources need to be addressed and put into context of physiological mechanisms of cellular protection. This paper summarizes a co-operative approach by the authors to answer the questions on the quantitative and qualitative DNA damages from non-radiation sources, largely endogenous ROS, and following exposure to low doses of IR. The analysis relies on published data and justified assumptions and considers the physiological capacity of mammalian cells to protect themselves constantly by preventing and repairing DNA damage. Furthermore, damaged cells are susceptible to removal by apoptosis or the immune system. The results suggest that the various forms of non-radiation DNA damage in tissues far outweigh corresponding DNA damage from low-dose radiation exposure at the level of, and well above, background radiation. These data are examined within the context of low-dose radiation induction of cellular signaling that may stimulate cellular protection systems over hours to weeks against accumulation of DNA damage. The particular focus is the hypothesis that these enhanced and persisting protective responses reduce the steady state level of nonradiation DNA damage, thereby reducing deleterious outcomes such as cancer and aging. The emerging model urgently needs rigorous experimental testing, since it suggests, importantly, that the LNT hypothesis is invalid for complex adaptive systems such as mammalian organisms.

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Section: Radiation-induced Versus Endogenous Dna Damage M Pollycove Amentioning

confidence: 72%

Radiation-induced versus endogenous DNA damage: possible effect of inducible protective responses in mitigating endogenous damage

2003

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“…The so-called ''linear-no threshold'' hypothesis [387] allows estimation of risk by extrapolation and rightly adopts a cautious stance towards safety. Nevertheless, this hypothesis has been questioned [388] and the explanation of risk may be more relevant and more meaningful to the lay person if expressed as multiples of the natural background radiation using the background-equivalent radiation time unit [389]. The risk/ benefit of using CT scanning in patients exposed to ionising radiation in the absence of a clinical indication underlies the need of standardising the use of low-radiation dose protocols in the context of COPD clinical trials [390].…”

Section: Outcomes For Copd Pharmacological Trialsmentioning

confidence: 99%

Outcomes for COPD pharmacological trials: from lung function to biomarkers

Cazzola¹,

MacNee²,

Martínez³

et al. 2008

European Respiratory Journal

744

566

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“…A popular hypothesis presented in Figure 1 postulates that the AR could be induced by reactive oxygen species (ROS) (Feinendegen et al, 1996(Feinendegen et al, , 1999Jones et al, 1999;de Saint-Georges, 2004;Shankar et al, 2006). ROS are generated in organisms during metabolism and/or formed after exposure to different biotic and abiotic stimuli (UVirradiation, ionizing radiation, ozone exposure, heavy metals), damaging some cell constituents and producing oxidative stress (Joiner et al, 1996Mendez-Alvarez et al, 1999;Bolwell et al, 2002;Neill et al, 2002;Vranová et al, 2002;Babu et al, 2003;Asad et al, 2004;Verschooten et al, 2006;Wang et al, 2006).…”

Section: The Adaptive Responsementioning

confidence: 99%

“…There is evidence that different stress conditions can activate similar defense mechanisms in various biological systems (Joiner et al, 1996Babu et al, 2003). The AR probably involves the transcription of many genes and the activation of numerous signaling pathways that trigger cell defenses (Figure 2): more efficient detoxification of free radicals, DNA repair systems, induction of new proteins in irradiated cells with a conditioning dose, and enhanced antioxidant production (Bryant, 1979;Wolff, 1998;Mendez-Alvarez et al, 1999;Pajovic et al, 2001;Assis et al, 2002;Chankova and Bryant, 2002;Neill et al, 2002;Sasiadek et al, 2002;Sedgwick and Lindahl, 2002;Dimova et al 397 Figure 1 -Scheme of a popular hypothesis for the induction of the adaptive response (AR) via reactive oxygen species (ROS) (Feinendegen et al, 1996(Feinendegen et al, , 1999.…”

Section: Molecular Mechanisms Of the Adaptive Responsementioning

confidence: 99%

Adaptive response: some underlying mechanisms and open questions

2008

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Organisms are affected by different DNA damaging agents naturally present in the environment or released as a result of human activity. Many defense mechanisms have evolved in organisms to minimize genotoxic damage. One of them is induced radioresistance or adaptive response. The adaptive response could be considered as a nonspecific phenomenon in which exposure to minimal stress could result in increased resistance to higher levels of the same or to other types of stress some hours later. A better understanding of the molecular mechanism underlying the adaptive response may lead to an improvement of cancer treatment, risk assessment and risk management strategies, radiation protection, e.g. of astronauts during long-term space flights. In this mini-review we discuss some open questions and the probable underlying mechanisms involved in adaptive response: the transcription of many genes and the activation of numerous signaling pathways that trigger cell defenses -DNA repair systems, induction of proteins synthesis, enhanced detoxification of free radicals and antioxidant production.

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Cellular signal adaptation with damage control at low doses versus the predominance of DNA damage at high doses

Cited by 41 publications

References 35 publications

Radiation-induced versus endogenous DNA damage: possible effect of inducible protective responses in mitigating endogenous damage

Radiation-induced versus endogenous DNA damage: possible effect of inducible protective responses in mitigating endogenous damage

Outcomes for COPD pharmacological trials: from lung function to biomarkers

Adaptive response: some underlying mechanisms and open questions

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