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Medical and Biological Applications of Low Energy Accelerators
Published in Vlado Valković, Low Energy Particle Accelerator-Based Technologies and Their Applications, 2022
As it can be seen in Fig. 2.2, particle therapy exploits a favorable depth–dose curve. Charged particles deposit most of their initial energy when they slow down, close to the end of the range (Bragg peak) within the tumor target, while X-ray energy decreases exponentially with dose. Particles at high energy (entrance, normal tissue) have linear energy transfer (LET) similar to X-rays, while the LET becomes high when the ions slow down around the Bragg peak. This provides radiobiological advantages such as an increased relative biological effectiveness (RBE) and reduced oxygen enhancement ratio (OER) in the tumor.
Radiobiology of Tumours
Published in W. P. M. Mayles, A. E. Nahum, J.-C. Rosenwald, Handbook of Radiotherapy Physics, 2021
Gordon Steel, Catharine West, Alan Nahum
Another important radiobiological difference between radiations of differing LET concerns the effect of oxygen on cellular radiosensitivity. In Section 6.8, the concept of oxygen enhancement ratio (OER) was introduced in the context of the low-LET radiation qualities commonly employed in radiotherapy. As pointed out in Sections 6.8 and 6.9, OER values are sufficiently high in low-LET radiation (between ≈2 and ≈3) to make uncomplicated tumour control improbable in situations where the tumour contains an appreciable fraction of hypoxic clonogens. There is clinical evidence that this is, in fact, the case (Movsas et al. 2002; Nordsmark et al. 2005; Milosevic et al. 2012). With high-LET radiation, cell-survival curves obtained in vitro indicate that the OER is reduced below its low-LET value, with the degree of reduction being dependent on mean LET, as Figure 6.18 illustrates.
Modifications of Cellular Radiation Damage
Published in Kedar N. Prasad, Handbook of RADIOBIOLOGY, 2020
One of the most general and best-known modifying agents of radiation damage is molecular oxygen. Its ability to potentiate radiation response is called the oxygen effect, which is expressed in terms of the oxygen enhancement ratio (OER):
Inhibition of Wnt signalling pathway by XAV939 enhances radiosensitivity in human cervical cancer HeLa cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Jinhua Zhang, Jing Si, Lu Gan, Menghuan Guo, Junfang Yan, Yuhong Chen, Fang Wang, Yi Xie, Yupei Wang, Hong Zhang
Recently, 12C6+ radiotherapy, as a highly intensive local therapy, has become one of the most used therapeutic strategies for various malignancies. Compared to conventional photon and proton irradiation, 12C6+ radiotherapy induces a stronger lethal effect on cancer cells due to the unique physical and biological effects, including superior physical dose distribution (spread-out Bragg peak) [5], smaller volume of irradiated normal tissue [6], higher relative biological effectiveness, lower oxygen enhancement ratio, unrepaired DNA damage and nearly unchanged radio-sensitivity within the cell cycle [7–9]. This results in a cell-killing effect that is two to three times greater than that of X-rays [5,10]. Accumulating evidence suggests that 12C6+ irradiation has been widely used in the treatment of a variety of cancers, such as pancreatic cancer [11], non-small cell lung cancer [12], locally advanced cervical cancer, prostate carcinoma [13] and breast cancer [14]. What is more, in the stage IVA patients of cervical carcinoma, 12C6+ beam radiotherapy has respectively shown a 3-year local control and overall survival rate of 66% and 47%, indicating that it can be applied to locally advanced cervical cancer [15]. Thus far, it is estimated that more than 16,000 patients have received 12C6+ treatment. In spite of the fact that 12C6+ radiotherapy can be applied for cervical cancer treatment, there are still some limitations for haematological diseases, tumours around vital organs and patients with distant metastases [16,17]. Therefore, the identification of high-efficiency and low-toxic radiation sensitizers for cancer to improve the radio-sensitivity is required.
The influence of ketogenic therapy on the 5 R’s of radiobiology
Published in International Journal of Radiation Biology, 2019
The oxygen enhancement ratio describes the enhancement of RT efficacy with increasing oxygen concentrations and can reach values between 2 and 3 when comparing normoxic cells (21% O2) to severely hypoxic cells (≤0.1% O2). Reoxygenation of hypoxic tumor areas is therefore one of the main reasons why RT is applied in a fractionated scheme. Reoxygenation has recently gained renewed attention due to findings that single-fraction stereotactic RT lacks a dose–response relationship and achieves lower tumor control rates than multifraction stereotactic RT even if the same biologically effective doses are applied (Guckenberger et al. 2013; Shuryak et al. 2015). This is consistent with a detrimental effect of missing reoxygenation in single-fraction RT (Lindblom et al. 2014). Among several strategies proposed to deliver oxygen to tumor cells, hyperbaric oxygen (HBO) before a RT session has shown some good clinical results in terms of improved local control rates and overall survival (Bennett et al. 2012; Stępień et al. 2016). The group of Dominic D’Agostino has shown that HBO therapy increased ROS production and inhibited the growth of highly aggressive VM-M3 mouse tumor cells; its efficacy in vivo was thereby enhanced by simultaneously applying a KD and/or exogenous ketones (Poff et al. 2013, 2015). Thus, it could be speculated that HBO prior to a RT session can be made even more effective when the patient is in a state of ketosis. A recent case report of a poly-metastasized breast cancer patient in which a combination of HBO, KD, STF, glucose deprivation, hyperthermia and chemotherapy was used over 6 months reported a complete clinical, radiological and pathological response and provides a proof-of-principle example for such integrative treatment concepts (İyikesici et al. 2017).
The cardiac toxicity of radiotherapy – a review of characteristics, mechanisms, diagnosis, and prevention
Published in International Journal of Radiation Biology, 2021
Moreover, oxidative stress is recognized as a critical common mechanism that contributes to endothelial cell injury. The sensitivity to radiation increases in well-oxygenated cells. Oxygen enhancement ratio (OER), which is regarded as an important concept in radiobiology, is the ratio of radiation doses administered under hypoxic to oxic conditions needed to achieve the same biological effect. In general, OER is related to the linear energy transfer (LET) of radiation. Oxygen presence enhanced the effect of low-LET radiation. But at the same time, oxygen can produce reactive oxygen species (ROS) in mitochondria. Another process starts with the radiolysis of water molecules into ROS (superoxide (O2−), hydroxyl radical (OH), and hydrogen peroxide (H2O2)). Meanwhile, inducible nitric oxide synthase (iNOS) which participants in nitric oxide (NO) production is up-regulated. NO (a vascular protectant) can react with O2− and generate reactive nitrogen species (RNS). In physiological conditions, ROS and RNS are involved in many beneficial cellular processes and they can be removed by antioxidants. However when the amount of ROS and RNS exceeds the capacity of intracellular antioxidants, molecular damage in DNA, proteins, and lipids occurs (Ping et al. 2020). ROS can trigger important mechanisms such as mitochondrial permeability transition (MPT) and calcium release which could result in apoptosis and necrosis of cells. Some mechanisms such as hypertrophy, proliferation, and fibrosis are also activated by ROS. The degranulation of mast cells induces the release of some cytokines such as TNF-α, TGF-β, IL-4. They participant in the late phase of RIHD (Wang et al. 2020). What’s more, signal pathways such as IL, TGF-β1, Insulin-like growth factor-1 (IGF-1), and nuclear factor-kappa B (NF-κB) are activated in oxidative stress (Ahamed and Laurence 2017; Kenchegowda et al. 2018; Baselet et al. 2019; Ping et al. 2020; Li et al. 2021). TGF-β1 acts as a pro-inflammatory and pro-fibrotic factor (Zeisberg et al. 2007) and IGF-1 can induce secretory clusterin protein (sCLU) expression. Secretory clusterin is an extracellular molecular chaperone which is implicated in the process of RIHD (Criswell et al. 2005; Klokov et al. 2013). NF-κB activation is essential for apoptosis and inflammatory reaction in radiation cardiotoxicity (Abd-ElRaouf et al. 2021). These cytokines above lead to inflammation and fibrosis in RIHD.