biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...

, the oxygen effect refers to a tendency for increased

radiosensitivity Radiosensitivity is the relative susceptibility of cells, tissues, organs or organisms to the harmful effect of ionizing radiation. Cells types affected Cells are least sensitive when in the S phase, then the G1 phase, then the G2 phase, and ...

of free

living cells The cell is the basic structural and functional unit of life forms. Every cell consists of a cytoplasm enclosed within a membrane, and contains many biomolecules such as proteins, DNA and RNA, as well as many small molecules of nutrients an ...

and organisms in the presence of

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...

than in anoxic or hypoxic conditions, where the

oxygen tension Blood gas tension refers to the partial pressure of gases in blood. There are several significant purposes for measuring gas tension. The most common gas tensions measured are oxygen tension (PxO2), carbon dioxide tension (PxCO2) and carbon monoxi ...

is less than 1% of

atmospheric pressure Atmospheric pressure, also known as barometric pressure (after the barometer), is the pressure within the atmosphere of Earth. The standard atmosphere (symbol: atm) is a unit of pressure defined as , which is equivalent to 1013.25 millibars, 7 ...

(i.e., <1% of 101.3 kPa, 760 mmHg or 760 torr).

Physiology and causes

Explanation of the oxygen effect and relevance to hypoxic tissues

The oxygen effect has particular importance in external beam

radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radia ...

where the killing of

tumour cells A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

with

photon A photon () is an elementary particle that is a quantum of the electromagnetic field, including electromagnetic radiation such as light and radio waves, and the force carrier for the electromagnetic force. Photons are massless, so they always ...

and

electron The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family, and are generally thought to be elementary particles because they have no kn ...

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 Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...

conditions present in the normal physiology of

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

niches such as the

endosteum The endosteum (plural endostea) is a thin vascular membrane of connective tissue that lines the inner surface of the bony tissue that forms the medullary cavity of long bones. This endosteal surface is usually resorbed during long periods of ma ...

adjacent to bone in

bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...

and the epithelium layer of the

intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...

. In addition, there are non-malignant diseases where oxygenated tissues can become hypoxic such as in stenosed

coronary arteries The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ of ...

associated with

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...

Historical research on the oxygen effect

Holthusen (1921) first quantified the oxygen effect finding 2.5 to 3.0-fold less hatching eggs of the

nematode The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-Parasitism, parasitic nematodes also known as eelworms. They are a diverse animal phylum inhab ...

Ascaris ''Ascaris'' is a genus of parasite, parasitic nematode worms known as the "small intestinal roundworms", which is a type of parasitic worm. One species, ''Ascaris lumbricoides'', affects humans and causes the disease ascariasis. Another species ...

in oxygenated compared to anoxic conditions, which was incorrectly assigned to changes in

cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...

. However, two years later, Petry (1923) first attributed oxygen tension as affecting

ionizing radiation Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...

effects on vegetable seeds. Later, the implications of the effects of oxygen on

radiotherapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radia ...

were discussed by Mottram (1936). A key observation limiting hypotheses to explain the biological mechanisms of the oxygen effect is that the gas

nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...

is a

radiosensitizer A radiosensitizer is an agent that makes tumor cells more sensitive to radiation therapy. It is sometimes also known as a radiation sensitizer or radio-enhancer. Mechanism of action Conventional chemotherapeutics are currently being used in con ...

with similar effects to oxygen observed in tumour cells. Another important observation is that oxygen must be present at irradiation or within milliseconds afterward for the oxygen effect to take place. The best known explanation of the oxygen effect is the oxygen fixation hypothesis developed by Alexander in 1962, which posited that radiation-induced non-restorable or "fixed" nuclear DNA lesions are lethal to cells in the presence of

diatomic oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly Chemical reaction, reactive nonmetal, and an oxidizing agent that readily forms oxides with mos ...

. Recent hypotheses include one based on oxygen-enhanced damage from first principles. Another hypothesis posits that ionizing radiation provokes

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

to produce reactive oxygen (and nitrogen species), which are leakage during

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...

that varies with a hyperbolic saturation relationship observed with both the oxygen and nitric oxide effects. Cell survival

Oxygen Enhancement Ratio and the effect of radiation LET

The oxygen effect is quantified by measuring the radiation sensitivity or

Oxygen Enhancement Ratio 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 ce ...

(OER) of a particular biological effect (e.g.,

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

), 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 Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labiod ...

gamma Gamma (uppercase , lowercase ; ''gámma'') is the third letter of the Greek alphabet. In the system of Greek numerals it has a value of 3. In Ancient Greek, the letter gamma represented a voiced velar stop . In Modern Greek, this letter re ...

-, or

x-ray An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...

s), or so-called low

linear energy transfer In dosimetry, linear energy transfer (LET) is the amount of energy that an ionizing particle transfers to the material traversed per unit distance. It describes the action of radiation into matter. It is identical to the retarding force acting on ...

(LET) radiations. Radiosensitivity varies most rapidly for oxygen partial pressures below ~1% atmospheric (Fig. 1). Howard-Flanders and Alper (1957) developed a formula for the

hyperbolic Hyperbolic is an adjective describing something that resembles or pertains to a hyperbola (a curve), to hyperbole (an overstatement or exaggeration), or to hyperbolic geometry. The following phenomena are described as ''hyperbolic'' because they ...

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 Ionization, or Ionisation is the process by which an atom or a molecule acquires a negative or positive charge by gaining or losing electrons, often in conjunction with other chemical changes. The resulting electrically charged atom or molecule i ...

-density of the radiation increases (Fig. 2), from low-LET to high-LET radiations. The OER is unity irrespective of the

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

s under aerobic (21% O2, 159 mmHg) and anoxic (nitrogen) conditions. Typical

fractionation Fractionation is a separation process in which a certain quantity of a mixture (of gases, solids, liquids, enzymes, or isotopes, or a suspension) is divided during a phase transition, into a number of smaller quantities (fractions) in which the ...

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).

References

{{reflist Biochemistry Ionizing radiation#Health effects Medical physics Oxygen Radiation therapy Radiobiology