Oxygen effect

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In biochemistry, the oxygen effect refers to a tendency for increased radiosensitivity of free living cells and organisms in the presence of oxygen than in anoxic or hypoxic conditions, where the oxygen tension is less than 1% of atmospheric pressure (i.e., <1% of 101.3 kPa, 760 mmHg or 760 torr).

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Physiology and causes

Relative sensitivity. This figure illustrates the typical change in the relative radiosensitivity for a biological effect such as cell death when exposed to radiations of low ionizing density (e.g. x-rays). The hyperbolic relationship shown has a maximum OER of 2.70 for 100% oxygen (at 760 mmHg), with a half-range OER value at 4.2 mmHg or 0.55% of oxygen. Relative sensitivity.png
Relative sensitivity. This figure illustrates the typical change in the relative radiosensitivity for a biological effect such as cell death when exposed to radiations of low ionizing density (e.g. x-rays). The hyperbolic relationship shown has a maximum OER of 2.70 for 100% oxygen (at 760 mmHg), with a half-range OER value at 4.2 mmHg or 0.55% of oxygen.

Explanation of the oxygen effect and relevance to hypoxic tissues

The oxygen effect has particular importance in external beam radiation therapy where the killing of tumour cells with photon and electron beams in well oxygenated regions can be up to three times greater than in a poorly vasculated portion of the tumour.

Besides tumour hypoxia, the oxygen effect is also relevant to hypoxia conditions present in the normal physiology of stem cell niches such as the endosteum adjacent to bone in bone marrow [1] and the epithelium layer of the intestine. [2] In addition, there are non-malignant diseases where oxygenated tissues can become hypoxic such as in stenosed coronary arteries associated with cardiovascular disease. [3]

Change with ionizing density. This figure illustrates the trend in the relative radiosensitivity or OER with oxygen tension for radiations of different ionizing density or linear energy transfer (LET, keV/mm). The inhibition of clone-formation by cultured human cells was measured after exposure to alpha-particles, deuterons and 250 kVp x-rays by Barendsen et al. (1966). The range of the maximum OER for 100% oxygen (at 760 mmHg) was 2.7 for 250 kVp x-rays dropping to 1.0 for 2.5 MeV alpha-particles. In each case the OER curves shown assume a half-range OER value of 4.2 mmHg or 0.55% oxygen. Change with ionizing density.png
Change with ionizing density. This figure illustrates the trend in the relative radiosensitivity or OER with oxygen tension for radiations of different ionizing density or linear energy transfer (LET, keV/μm). The inhibition of clone-formation by cultured human cells was measured after exposure to alpha-particles, deuterons and 250 kVp x-rays by Barendsen et al. (1966). The range of the maximum OER for 100% oxygen (at 760 mmHg) was 2.7 for 250 kVp x-rays dropping to 1.0 for 2.5 MeV alpha-particles. In each case the OER curves shown assume a half-range OER value of 4.2 mmHg or 0.55% oxygen.

Historical research on the oxygen effect

Holthusen (1921) [4] first quantified the oxygen effect finding 2.5 to 3.0-fold less hatching eggs of the nematode Ascaris in oxygenated compared to anoxic conditions, which was incorrectly assigned to changes in cell division. However, two years later, Petry (1923) [5] first attributed oxygen tension as affecting ionizing radiation effects on vegetable seeds. Later, the implications of the effects of oxygen on radiotherapy were discussed by Mottram (1936). [6]

A key observation limiting hypotheses to explain the biological mechanisms of the oxygen effect is that the gas nitric oxide is a radiosensitizer with similar effects to oxygen observed in tumour cells. [7] Another important observation is that oxygen must be present at irradiation or within milliseconds afterward for the oxygen effect to take place. [8]

The best known explanation of the oxygen effect is the oxygen fixation hypothesis developed by Alexander in 1962, [9] which posited that radiation-induced non-restorable or "fixed" nuclear DNA lesions are lethal to cells in the presence of diatomic oxygen. [10] [11] Recent hypotheses include one based on oxygen-enhanced damage from first principles. [12] Another hypothesis posits that ionizing radiation provokes mitochondria to produce reactive oxygen (and nitrogen species), which are leakage during oxidative phosphorylation that varies with a hyperbolic saturation relationship observed with both the oxygen and nitric oxide effects. [13]

Cell survival. This figure is illustrative of the reduction in the OER from aerobic to anoxic conditions for lower compared to higher doses, which has a bearing on the choice of dose fractionation exposures for radiotherapy of tumours. Cell survival.png
Cell survival. This figure is illustrative of the reduction in the OER from aerobic to anoxic conditions for lower compared to higher doses, which has a bearing on the choice of dose fractionation exposures for radiotherapy of tumours.

Oxygen Enhancement Ratio and the effect of radiation LET

The oxygen effect is quantified by measuring the radiation sensitivity or Oxygen Enhancement Ratio (OER) of a particular biological effect (e.g., cell death or DNA damage), [14] which is the ratio of doses under pure oxygen and anoxic conditions. Consequently, OER varies from unity in anoxia to a maximum value for 100% oxygen of typically up to three for low ionizing-density-radiation (beta-, gamma-, or x-rays), or so-called low linear energy transfer (LET) radiations.

Radiosensitivity varies most rapidly for oxygen partial pressures below ~1% atmospheric (Fig. 1). Howard-Flanders and Alper (1957) [15] developed a formula for the hyperbolic function of OER and its variation with oxygen concentration, or oxygen pressure in air.

Radiobiologists identified additional characteristics of the oxygen effect that influence radiotherapy practices. They found that the maximum OER value diminishes as the ionizing-density of the radiation increases (Fig. 2), from low-LET to high-LET radiations. [16] The OER is unity irrespective of the oxygen tension for alpha-particles of high-LET around 200 keV/μm. The OER is reduced for low doses as evaluated for cultured mammalian cells exposed to x-rays under aerobic (21% O2, 159 mmHg) and anoxic (nitrogen) conditions. [17] Typical fractionation treatments are daily 2 Gy exposures, as below this dose the so-called 'shoulder' or repair region of the cell survival curve is encroached upon reducing the OER (Fig. 3).

Related Research Articles

<span class="mw-page-title-main">Radiation therapy</span> Therapy using ionizing radiation, usually to treat cancer

Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a treatment using ionizing radiation, generally provided as part of cancer therapy to either kill or control the growth of malignant cells. It is normally delivered by a linear particle accelerator. Radiation therapy may be curative in a number of types of cancer if they are localized to one area of the body, and have not spread to other parts. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgery to remove a primary malignant tumor. Radiation therapy is synergistic with chemotherapy, and has been used before, during, and after chemotherapy in susceptible cancers. The subspecialty of oncology concerned with radiotherapy is called radiation oncology. A physician who practices in this subspecialty is a radiation oncologist.

The therapeutic index is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. The related terms therapeutic window or safety window refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

<span class="mw-page-title-main">Tumor hypoxia</span> Situation where tumor cells have been deprived of oxygen

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironements in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumour vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.

<span class="mw-page-title-main">Hormesis</span> Characteristic of biological processes

Hormesis is a characteristic of many biological processes, namely a biphasic or triphasic response to exposure to increasing amounts of a substance or condition. Within the hormetic zone, the biological response to low exposures to toxins and other stressors is generally favorable. The term "hormesis" comes from Greek hórmēsis "rapid motion, eagerness", itself from ancient Greek hormáein "to set in motion, impel, urge on", the same Greek root as the word hormone. The term 'hormetics' has been proposed for the study and science of hormesis.

<span class="mw-page-title-main">Radiation hormesis</span> Hypothesis regarding low doses of ionizing radiation on health

Radiation hormesis is the hypothesis that low doses of ionizing radiation are beneficial, stimulating the activation of repair mechanisms that protect against disease, that are not activated in absence of ionizing radiation. The reserve repair mechanisms are hypothesized to be sufficiently effective when stimulated as to not only cancel the detrimental effects of ionizing radiation but also inhibit disease not related to radiation exposure. It has been a mainstream concept since at least 2009.

Radioresistance is the level of ionizing radiation that organisms are able to withstand.

Radiosensitivity is the relative susceptibility of cells, tissues, organs or organisms to the harmful effect of ionizing radiation.

<span class="mw-page-title-main">Oxidative stress</span> Free radical toxicity

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O2− (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

<span class="mw-page-title-main">Tirapazamine</span> Chemical compound

Tirapazamine (SR-[[4233]]) is an experimental anticancer drug that is activated to a toxic radical only at very low levels of oxygen (hypoxia). Such levels are common in human solid tumors, a phenomenon known as tumor hypoxia. Thus, tirapazamine is activated to its toxic form preferentially in the hypoxic areas of solid tumors. Cells in these regions are resistant to killing by radiotherapy and most anticancer drugs. Thus the combination of tirapazamine with conventional anticancer treatments is particularly effective. As of 2006, tirapazamine is undergoing phase III testing in patients with head and neck cancer and gynecological cancer, and similar trials are being undertaken for other solid tumor types.

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The radiation-induced bystander effect is the phenomenon in which unirradiated cells exhibit irradiated effects as a result of signals received from nearby irradiated cells. In November 1992, Hatsumi Nagasawa and John B. Little first reported this radiobiological phenomenon.

The oxygen enhancement ratio (OER) or oxygen enhancement effect in radiobiology refers to the enhancement of therapeutic or detrimental effect of ionizing radiation due to the presence of oxygen. This so-called oxygen effect is most notable when cells are exposed to an ionizing radiation dose.

<span class="mw-page-title-main">18F-EF5</span> Chemical compound

EF5 is a nitroimidazole derivative used in oncology research. Due to its similarity in chemical structure to etanidazole, EF5 binds in cells displaying hypoxia.

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<span class="mw-page-title-main">Abscopal effect</span>

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References

  1. ↑ Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD (2007). "The oxygen fixation hypothesis: a reevaluation". Proceedings of the National Academy of Sciences. 104 (13): 5431–5436. doi: 10.1073/pnas.0701152104 . PMC   1838452 . PMID   17374716.
  2. ↑ Zheng L, Kelly CJ, Colgan SP (2015). "Physiologic hypoxia and oxygen homeostasis in the healthy intestine. A review in the theme: Cellular responses to hypoxia". Am J Physiol Cell Physiol. 309 (6): C350–C360. doi:10.1152/ajpcell.00191.2015. PMC   4572369 . PMID   26179603.
  3. ↑ Richardson, RB (2008). "Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries-Part B: modeling oxygen diffusion into vessel walls". Int J Radiat Biol. 84 (10): 849–857. doi:10.1080/09553000802389645. PMID   18979320. S2CID   24585967.
  4. ↑ Holthusen H (1921). "Beitrage zur Biologie der Strahlenwirkung". Pflügers Archiv. 187: 1–24. doi:10.1007/BF01722061. S2CID   26030155.
  5. ↑ Petry EJ (1923). "Kenntnis der Bedingungen der biologischen Wir kung der Rontgenstrahlen". Biochemische Zeitschrift: 135–353.
  6. ↑ Mottram JC (1936). "Factor of importance in radiosensitiity of tumours". Br J Radiol. 9: 606–614. doi:10.1259/0007-1285-9-105-606.
  7. ↑ Gray LH, Green FO, Hawes CA (1958). "Effect of nitric oxide on the radiosensitivity of tumour cells". Nature. 182 (4640): 952–953. Bibcode:1958Natur.182..952G. doi:10.1038/182952a0. PMID   13590191. S2CID   27573591.
  8. ↑ Howard-Flanders, P, Moore, D (1958). "The time interval after pulsed irradiation within which injury to bacteria can be modified by dissolved oxygen. I. A search for an effect of oxygen 0.02 second after pulsed irradiation". Radiat Res. 9 (4): 422–437. Bibcode:1958RadR....9..422H. doi:10.2307/3570768. JSTOR   3570768. PMID   13591515.
  9. ↑ Alexander P (1962). "On the mode of action of some treatments that influence the radiation sensitivity of cells". Trans N Y Acad Sci. 24: 966–978. doi:10.1111/j.2164-0947.1962.tb01456.x. PMID   14011969.
  10. ↑ Ewing D (1998). "The oxygen fixation hypothesis: a reevaluation". Am J Clin Oncol. 21 (4): 355–361. doi:10.1097/00000421-199808000-00008. PMID   9708633.
  11. ↑ Hall, EJ; Giaccia, AJ (2019). Radiobiology for the Radiologist. Philadelphia, PA: Wolters Kluwer. p. 597. ISBN   978-1-49-633541-8.
  12. ↑ Grimes DR, Partridge M (2015). "A mechanistic investigation of the oxygen fixation hypothesis and oxygen enhancement ratio". Biomedical Physics & Engineering Express. 1 (4): 045209. doi:10.1088/2057-1976/1/4/045209. PMC   4765087 . PMID   26925254.
  13. ↑ Richardson RB, Harper ME (2016). "Mitochondrial stress controls the radiosensitivity of the oxygen effect: Implications for radiotherapy". Oncotarget. 7 (16): 21469–21483. doi:10.18632/oncotarget.7412. PMC   5008299 . PMID   26894978.
  14. ↑ Thoday JM, Read J (1947). "Effect of oxygen on the frequency of chromosome aberrations produced by X-rays". Nature. 160 (4070): 608. Bibcode:1947Natur.160..608T. doi: 10.1038/160608a0 . PMID   20271559. S2CID   4068339.
  15. ↑ Howard-Flanders P, Alper T (1957). "The sensitivity of microorganisms to irradiation under controlled gas conditions". Radiat Res. 7 (5): 518–540. Bibcode:1957RadR....7..518H. doi:10.2307/3570400. JSTOR   3570400. PMID   13485393.
  16. ↑ Barendsen GW, Koot CJ, Van Kersen GR, Bewley DK, Field SB, Parnell CJ (1966). "The effect of oxygen on impairment of the proliferative capacity of human cells in culture by ionizing radiations of different LET". Int J Radiat Biol Relat Stud Phys Chem Med. 10 (4): 317–327. doi:10.1080/09553006614550421. PMID   5297012.
  17. ↑ Palcic B, Brosing JW, Skarsgard LD (1982). "Survival measurements at low doses: oxygen enhancement ratio". Br J Cancer. 46 (6): 980–984. doi:10.1038/bjc.1982.312. PMC   2011221 . PMID   7150493.
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