Glossary of terms in radiation biology

α/β ratio The ratio of the parameters α and β in the linear-quadratic model; often used to quantify the fractionation sensitivity of tissues.

Abortive cell division The limited number of divisions of cells that are radiation damaged (so-called doomed cells). The residual proliferative capacity of these cells contributes significantly to overall cell production during radiation-induced repopulation in normal tissues.

Accelerated fractionation Intensification of radiation therapy by increasing the average rate of dose delivery, typically by increasing the dose per fraction, by delivering multiple fractions per day, or by increasing the number of treatment days per week; a schedule in which the average rate of dose delivery exceeds the equivalent of 10 Gy per week in 2-Gy fractions.

Accelerated proliferation Increase in the stem cell (clonogen) proliferation rate after radiation or cytotoxic chemotherapy relative to its pretreatment value.

Acute hypoxia Low oxygen concentrations associated with changes in blood flow through vessels (e.g. by transient closing of blood vessels). Also called transient or perfusion limited hypoxia.

Analogue A chemical compound structurally similar to another but differing by a single functional group.

Angiogenesis The process of formation of new blood vessels.

Anoxia The absence of oxygen.

Apoptosis A mode of rapid cell death after irradiation characterized by chromatin condensation, fragmentation and compartmentalization, often visualized by densely-staining nuclear globules. Sometimes postulated to be ‘programmed’ and therefore a potentially controllable process.

ARCON therapy The use of Accelerated Radiotherapy with CarbOgen and Nicotinamide.

Asymmetrical divisions Divisions of stem cells into, on average, one new stem cell and one transit or differentiating cell. These divisions are called asymmetrical, as two ‘different’ cells are generated.

Asymmetry loss Switch of stem cell divisions from an asymmetrical to a symmetrical pattern during radia- tion-induced repopulation in normal tissues.

Autophagy A process in which cellular components are self-digested through the lysosome pathway. This process can extend cell survival during starvation conditions and remove damaged organelles, but can also lead to cell death.

Autoradiography Use of a photographic emulsion to detect the distribution of a radioactive label in a tissue specimen.

BER Base excision repair – DNA repair pathway for repairing damage to DNA bases.

Biologically effective dose (BED) In fractionated radiotherapy, the total dose that would be required in very small dose fractions to produce a particular effect, as indicated by the linear-quadratic equation. Otherwise known as extrapolated total dose (ETD). BED values calculated for different α/βratios are not directly comparable. For time–dose calculations, EQD2 is preferred.

BNCT Boron neutron capture therapy.

Brachytherapy Radiotherapy using sealed radioactive sources placed next to the skin, or inserted into a body cavity or through needles into tissues.

Bragg peak Region of maximum dose deposition near the end of the tracks of protons, α-particles and

heavier ions. This phenomenon enables very precise spatial definition of dose in radiotherapy using ion beams.

Cancer stem cell A cell within a tumour that possesses the capacity to self-renew and to generate the heterogeneous lineages of cancer cells that comprise the tumour. In the context of cancer therapy, this definition translates into a cell which can cause a tumour recurrence.

CDK Cyclin-dependent kinase. These proteins are responsible for movement through the cell cycle and are inactivated by various mechanisms during the DNA damage response, to cause cell-cycle checkpoints.

Cell-cycle checkpoint Cellular control mechanism to verify whether each phase of the cell cycle has been accurately completed before progression to the next phase. An important function is to continually assess DNA damage detected by sensors.

Cell-cycle time The time between one mitosis and the next.

Cell death In the context of radiobiology, cell death is generally equated with any process that leads to the permanent loss of clonogenic capacity.

Cell loss factor The rate of cell loss from a tumour, as a proportion of the rate at which cells are being added to the tumour by mitosis. Sometimes designated by the symbol φ. Cell loss factor 1 Tpot/Td, where Tpot is potential doubling time and Td is the cell population doubling time.

Chronic hypoxia Persistent low oxygen concentrations such as those existing in viable tumour cells close to regions of necrosis. Also called diffusion limited hypoxia since it arises at distances greater than approximately 150 μm from blood vessels.

Clonogenic cells Cells that have the capacity to produce an expanding family of descendents (usually at least 50). Also called ‘colony-forming cells’ or ‘clonogens’.

Clonogenic survival Defined as the fraction of cells that survive following exposure to, or treatment with an agent that causes cell death. Only cells that are able to form colonies (clonogenic cells) are considered to have survived the treatment (see Cell death).

Colony The family of cells derived from a single clonogenic cell.

Complementation Identification of whether a (radiosensitive) phenotype in different mutants is caused by the same gene. Studied by means of cell fusion.

Consequential late effects Late normal-tissue complications which are influenced by the extent (i.e. severity and/or duration) of the early response in the same tissue or organ.

DDR The DNA damage response. A network of biological responses to DNA damage.

Direct action Ionization or excitation of atoms within DNA leading to free radicals, as distinct from the reaction with DNA of free radicals formed in nearby water molecules.

CGH Comparative genomic hybridization – a largescale method to detect amplifications and deletions in different regions of the genome by comparison with a reference cell or tissue using microarray technology (arrayCGH).

CHART Continuous hyperfractionated accelerated radiation therapy; a schedule delivering 54 Gy in 36 fractions, with three fractions per day on 12 consecutive days (i.e. including a weekend).

Chromatin The complex of DNA and proteins comprising the chromosomes.

Chromosomal instability An effect of irradiation in which new stable and unstable chromosomal aberrations continue to appear through many cell generations.

D0 A parameter in the multitarget equation: the radiation dose that reduces survival to e 1 (i.e. 0.37) of its previous value on the exponential portion of the survival curve.

Dose-modifying factor (DMF) When a chemical or other agent acts as if to change the dose of radiation, the DMF indicates the ratio of dose without to dose with the agent for the same level of effect.

used with different meanings, depending on context. For example, in low dose-rate exposures, has been used to indicate the percentage or fraction reduction in dose to achieve the same effect, if the dose rate is raised (gives

DRF values 1). Alternatively, has been used in studies of radioprotection as the ratio of dose with to dose without the protecting agent for the same level of effect (gives DRF values 1).

Double trouble A hot-spot within a treated volume receives not only a higher dose but also a higher dose per fraction, which means that the biological effectiveness of the dose is also greater.

Doubling time Time for a cell population or tumour volume to double its size.

Early endpoint Clinical manifestation of an early normal-tissue response to radiation therapy.

Early normal-tissue responses Radiation-induced normal-tissue damage that is expressed in weeks to a few months after exposure (per definition within 90 days after onset of radiotherapy). α/β ratio tends to be large ( 6 Gy).

Radiation dose that is estimated to produce a specified (normal tissue) effect in 50 per cent of subjects irradiated (‘effect-dose–50 per cent’).

Effectors Proteins with the specific task of effecting (carrying out) the response to damage, e.g. apoptosis, cell-cycle arrest, or DNA repair.

Elkind repair Recovery of the ‘shoulder’ on a radiation dose cell-survival curve when irradiation follows several hours after a priming dose.

Equivalent total dose in 2-Gy fractions. Note that the EQD2 depends on the endpoint considered.

Equivalent dose in 2-Gy fractions but adjusted for a possible difference in overall treatment time by using a reference overall time, T.

EUD Equivalent uniform dose. Conversion of a nonuniform dose distribution within a organ to a uniform dose, which would result in the same biological effect. This is a model-dependent quantity.

Exponential growth Growth according to an exponential equation: V V0 exp(kt). The volume or population doubling time is constant and equal to (loge2)/k.

Extrapolated total dose (ETD) Calculated isoeffective dose, at an infinitely low dose rate or fraction size (see Biologically effective dose).

Extrapolation number A parameter in the multitarget equation for cell survival versus dose: the point on

the surviving fraction axis to which the straight part of the curve back-extrapolates.

Field-size effect The dependence of normaltissue damage on the size of the irradiated area (particularly in skin); in modern literature typically referred to as the ‘volume effect’.

FISH Fluorescence in situ hybridization. Fluorescent dyes are attached to specific regions of the genome, thus aiding the identification of chromosomal damage.

Flow cytometry Analysis of cell suspensions in which a dilute stream of cells is passed through a laser beam. DNA content and other properties are measured by light scattering and fluorescence following staining with dyes or labelled antibodies.

Fractionation sensitivity The dependence of the isoeffective radiation dose on the dose per fraction. Usually quantified by the α/β ratio – a high fractionation sensitivity is characterized by a low α/β ratio (see α/β ratio).

Free radical A fragment of a molecule containing an unpaired electron, therefore very reactive.

Functional imaging Imaging methods aimed at detecting physiological changes, for example metabolism or blood flow, in a tissue (in contrast to structural or anatomical imaging). Examples are glucose metabolism (detected by 18F-labelled FDG-PET) or oxygen consumption [blood oxygen level dependency (BOLD) MRI], or vascular function detected by dynamic contrast enhanced (DCE) CT (see Molecular imaging).

Functional subunits (FSUs) A concept of a (minimal) functional tissue structure (such as the alveolus in the lung). Their radiation-induced inactivation results in the reduced tissue function responses that can be seen after radiotherapy. Alternatively called tissue rescuing units (TRUs).

Genomic or genetic instability The failure to pass an accurate copy of the whole genome from a cell to its daughter cells, for example seen after irradiation.

Genomics Study of selected genes or the entire genome of the cell (DNA level).

Gray (Gy) 1 Gy is the SI unit equivalent to 1 J of energy per 1 kg of mass. The gray is most commonly used to refer to absorbed radiation dose and has replaced the previous unit, the rad (1 Gy 100 rad).

Gray equivalents (GyE) or cobalt gray equivalents (CGE): GyE or CGE for densely ionizing radiation is

equal to the measured physical dose in gray multiplied by the RBE factor.

Growth delay Extra time required for an irradiated versus an unirradiated tumour to reach a given size.

Growth fraction The proportion of cells in a population that are cycling.

Hierarchical tissues Tissues comprising a lineage of stem cells, transit cells, and postmitotic (differentiating or mature) cells.

HR Homologous recombination – DNA repair pathway for double-strand DNA breaks by using an undamaged homologous (identical) DNA sequence, usually from the sister chromatid.

Hyperbaric oxygen (HBO) The use of high oxygen pressures (2–3 atm) to enhance oxygen availability in radiotherapy.

Hyperfractionation Reduction in dose per fraction below a conventional level of 1.8–2.0 Gy.

Hyperthermia The heating of tumours above normal physiological temperatures, to treat cancer.

Hypofractionation The use of dose fractions larger than the conventional 2 Gy per fraction.

Hypoplasia Reduction in cell numbers in a tissue (e.g. owing to radiation-induced impairment of proliferation in early-responding tissues).

Hypoxia Low oxygen tension; usually refers to the very low levels that are required to make cells maximally radioresistant.

Hypoxic cell cytotoxins Any agents, typically bioreductive drugs, that preferentially kill hypoxic cells.

Hypoxic fraction The fraction of hypoxic cells within a tumour. This term is used in different contexts. Historically, it refers to the fraction of viable radioresistant hypoxic cells in a tumour. More recently it has been used to represent the frequency of oxygen measurements below some arbitrary threshold of oxygen tension (e.g. 5 mmHg).

Image segmentation The process of separating out mutually exclusive (i.e. non-overlapping) regions of interest in an image, for example outlining the lungs on a computed tomography (CT) scan.

IMRT Intensity-modulated radiation therapy – irradiation technique using non-uniform radiation beam intensities for delivering radiation therapy. This allows

high conformality treatment plans often with considerable sparing of critical organs at risk. Sometimes a distinction is made between IMXT (intensity-modulated X-ray therapy) and IMPT (intensity-modulated proton therapy).

Incomplete repair Increased damage from fractionated radiotherapy when the time interval between doses is too short to allow complete recovery.

Indirect action Damage to DNA by free radicals formed through the ionization of nearby water molecules.

Initial slope The steepness of the initial part of the cell survival curve, usually indicated by the value of αin the linear-quadratic model.

Interphase death The death of irradiated cells before they reach mitosis. Sometimes used as a synonym for apoptosis.

Ionization The process of removing electrons from (or adding electrons to) atoms or molecules, thereby creating ions.

IRIF Ionizing radiation-induced foci. Used to describe the accumulation of DNA damage-response proteins that localize to sites of DNA damage after irradiation.

Isoeffect plots Graphs of the total dose for a given effect (e.g. ED50) plotted, for example, against dose per fraction or dose rate.

Labelling index Proportion or percentage of cells positive for a certain signal (e.g. fraction of cells within the S phase, labelled by 3H-thymidine or other precursors such as bromodeoxyuridine).

Late endpoints Clinical expression of late normal-tissue responses.

Late normal-tissue responses Radiation-induced normal-tissue damage that in humans is expressed months to years after exposure (per definition later than 90 days after the onset of radiotherapy). The α/β ratio tends to be small ( 5 Gy).

Latent time/period or latency interval Time between (onset of) irradiation and clinical manifestation of radiation effects.

Radiation dose to produce lethality in 50 per cent of a population of individuals within 30 days; similarly LD50/7, etc.

Linear energy transfer (LET) The rate of energy loss along the track of an ionizing particle. Usually expressed in keV/μm.

Linear-quadratic (LQ) model Model in which the effect (E) is a linear-quadratic function of dose (d): E αd βd2. For cell survival: S exp( αd βd2).

Local tumour control The complete regression of a tumour without later regrowth during follow-up; this requires that all cancer stem cells have been permanently inactivated.

Log-phase culture A cell culture growing exponentially.

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or D) An estimate of the average radiation dose to inactivate a cell. It is calculated as the area under the survival curve, plotted on linear coordinates.

Microarray An array of DNA spots of known sequence, usually on a glass slide, used to quantify amounts of genomic DNA or cDNA (made from mRNA) in cells or tissue. Can hold up to 50 000 spots, capable of monitoring expression of all known genes and their variants. Also, referred to as gene expression microarrays or ‘chips’.

MiRNA MicroRNAs – small 19–22 nucleotide singlestranded non-coding RNAs expressed in cells which can regulate expression of genes by interacting with mRNAs.

Mitigation Interventions to reduce the severity or risk of radiation side-effects, applied during or shortly after exposure and before clinically manifest symptoms occur (i.e. during the latent time).

Mitotic catastrophe Improper completion of cell division because of unrepaired or misrepaired DNA damage. Mitotic catastrophe occurs frequently after irradiation and is a major cause of cell death.

Mitotic delay Delay of entry into mitosis, resulting in an accumulation of cells in G2, as a result of treatment.

Mitotic index Proportion or percentage of cells in mitosis at any given time.

MMR Mismatch repair – DNA repair pathway for repairing mismatched bases in DNA, usually occurring through misincorporation by DNA polymerases.

Molecular imaging (Medical) imaging visualizing the spatial distribution of molecular targets, signalling pathways or cellular phenotypes. This is in contrast to traditional structural or anatomical imaging. Examples

could be PET or SPECT with an appropriately labelled tracer, MR spectroscopy or optical imaging (see Functional imaging).

Molecular-targeted drugs See Targeted agents.

Multitarget equation Model that assumes the presence of a number of critical targets in a cell, all of which require inactivation to kill the cell. Surviving fraction of a cell population is given by the formula 1 [1 exp(D/D0]n.

Necrosis Cell death associated with loss of cellular membrane integrity. Occurs in anoxic areas of tumours and is also a cause of cell death after irradiation.

NER Nucleotide excision repair – DNA repair pathway for repairing bulky DNA lesions such as thymine dimers or cisplatin adducts.

NHEJ Non-homologous end-joining DNA repair pathway for repairing double-strand DNA breaks without using any homologous sequence as template.

Non-stochastic effect An effect where the severity increases with increasing dose, perhaps after a threshold region; also called a deterministic effect.

NTCP Normal-tissue complication probability – generally a term used in modelling normal-tissue radiation response.

Oxygen enhancement ratio (OER) The ratio of dose given under anoxic conditions to the dose resulting in the same effect when given under some defined level of oxygen tension. If oxygen tensions 21 per cent are used, the OER measured is usually termed the ‘full OER’. An OER of about half the full OER is usually obtained when the oxygen tension is between 0.5 and 1 per cent.

PET Positron emission tomography.

Plateau-phase cultures Cell cultures grown to confluence so that proliferation is markedly reduced (also known as ‘stationary phase’).

Plating efficiency (PE) The proportion or percentage of in vitro plated cells that form colonies.

Potential doubling time (Tpot) The (theoretical) cell population doubling time in the assumed absence of cell loss.

Potentially lethal damage (PLD) repair Operational term to describe an increase in cell survival that may occur during an interval between treatment and assay, caused by

post-irradiation modification of cellular physiology or environment (e.g. suboptimal growth conditions).

Prodromal phase Signs and symptoms in the first 48 hours following irradiation as a part of the response to partial or total-body irradiation (‘radiation sickness’).

Programmed cell death Cell death that occurs as the result of an active process carried out by molecules in the cell. Examples include apoptosis, autophagy, senescence, and in some cases even necrosis.

Proteomics Study of the proteins expressed in cells, including structure and function.

Quasi-threshold dose (Dq) Dose point of extrapolation of the exponential portion of a multitarget survival curve back to the level of unity. Surviving fraction: Dq D0 ln(n).

Radiation modifier A substance (e.g. drug or gas) which in itself does not evoke an effect on cells or tissues, but which changes the effect of radiation.

Radioresponsiveness The clinical responsiveness to a course of radiation therapy. This depends on multiple factors, one of them hypothesized to be cellular radiosensitivity.

Radiosensitizer In general, any agent that increases the sensitivity of cells to radiation. Commonly applied to electron-affinic chemicals that mimic oxygen in fixing free-radical damage, although these should more correctly be referred to as hypoxic cell sensitizers .

Radiosensitivity, cellular The sensitivity of cells to ionizing radiation in vitro. Usually indicated by the surviving fraction at 2 Gy (i.e. SF2) or by the parameters of the linear-quadratic or multitarget equations.

Reassortment or Redistribution Return towards a more even cell-age distribution, following the selective killing of cells in certain phases of the cell cycle.

Recovery At the cellular level – an increase in cell survival as a function of time between dose fractions or during irradiation with low dose rates (see Repair). At the tissue level – an increase in tissue isoeffective total dose with a decrease in dose per fraction or for irradiation at low dose rates.

Regression rate The rate at which the tumour volume shrinks during or after treatment.

Relative biological effectiveness (RBE) Ratio of dose of a reference radiation quality (usually 60Co γ-rays or

250 keV X-rays) and dose of a test radiation that produce equal effect.

Reoxygenation The processes by which surviving hypoxic clonogenic cells become better oxygenated during the period after irradiation of a tumour.

Repair Restoration of the integrity of damaged macromolecules (see Recovery).

Repair saturation A proposed explanation of the shoulder on cell survival curves on the basis of the reduced effectiveness of repair after high radiation doses.

Repopulation Describes the proliferation of surviving clonogenic tumour cells during fractionated radiotherapy. Rapid repopulation of clonogenic tumour cells during therapy is an important factor in treatment resistance. Also describes the regeneration response of early-reacting tissues to fractionated irradiation, which results in an increase in radiation tolerance with increasing overall treatment time.

Reproductive integrity Ability of cells to divide many times and thus be ‘clonogenic’.

Senescence A permanent arrest of cell division associated with differentiation, aging, or cellular damage.

Sensitizer enhancement ratio (SER) The same as dose-modifying factor (DMF), but typically used to describe radiosensitizing agents so that SER 1.

Sensors Proteins with the specific task of sensing damage to DNA.

sievert (Sv) Dose-equivalent in radiation protection. Dose in grays multiplied by a radiation quality factor.

variations in DNA sequence between individuals at a single nucleotide that is the major source of genetic variation. Can affect protein function and expression, and thus response to damage.

Spatial cooperation The use of radiotherapy and chemotherapy to hit disease in different anatomical sites.

Spheroid Clump of cells grown together in tissueculture suspension.

Split-dose recovery Decrease in radiation effect when a single radiation dose is split into two fractions separated by times up to a few hours (also termed Elkind recovery, or recovery from sublethal damage).

SSBR Single-strand break repair – DNA repair pathway for repairing a break occurring in only one of the two DNA strands.

Stathmokinetic method Study of cell proliferation using agents that block cells in mitosis.

Stem cells Cells with an unlimited proliferative capacity, capable of self-renewal and of differentiation to produce all the various types of cells in a lineage.

Stochastic (non-deterministic) effect An effect where the incidence, but not the severity, increases with increasing dose (e.g. mutagenesis, carcinogenesis, teratogenesis).

Sublethal damage (SLD) Non-lethal cellular injury that can be repaired. Interaction between SLD in a cell can result in cytolethality. This process is described in the linear-quadratic model by the quadratic β term.

Supra-additivity or synergism A biological effect caused by a combination that is greater than would be expected from the addition of the effects of the component agents.

Symmetrical division Division of each stem cell into two stem cell daughters, occurring during radiationinduced repopulation in normal tissues.

Target cell A cell whose response to radiation is responsible for the clinical manifestation of a radiation response (e.g. in a normal tissue or tumour).

Targeted agents Small molecules or antibodies that inhibit cellular pathways that are specific to cancer cells or substantially overexpressed in malignant cells compared with normal cells.

Targeted radiotherapy Treatment of cancer by means of drugs that localize in tumours and carry therapeutic amounts of radioactivity.

Target theory The idea that the shoulder on cell-sur- vival curves results from the number of unrepaired lesions per cell.

TBI Total-body irradiation.

The radiation dose that gives a 50 per cent tumour control probability.

TCP Tumour control probability – generally a term used in modelling tumour radiation response.

Telangiectasia Pathologically dilated capillaries, observed in all irradiated tissues and organs in association with late radiation effects.

Theragnostics Use of molecular imaging to assist in prescribing the distribution of radiation dose in four dimensions (i.e. the three spatial dimensions plus time).

Therapeutic index or ratio Denotes the relationship between the probability for tumour cure and the likelihood for normal-tissue damage. An improved therapeutic ratio represents a more favourable ratio of efficacy to toxicity.

Time–dose relationships The dependence of isoeffective radiation dose on the overall treatment time and number of fractions (or fraction size) in radiotherapy.

Time factor Describes the change in isoeffective total dose for local tumour control or normal-tissue complications that follows a change in the overall treatment duration.

Tolerance dose The maximum radiation dose or intensity of fractionated radiotherapy that is associated with an acceptable complication probability (usually of 1–5 per cent). Actual values depend on treatment protocol, irradiated volume, concomitant therapies, etc., but also on the status of the organ/patient.

Transcriptomics Study of genes which are expressed in cells at the RNA level.

Transient hypoxia Low oxygen concentrations associated with the transient closing of blood vessels. Also called acute or perfusion limited hypoxia.

Tumour bed effect (TBE) Slower rate of tumour growth after irradiation owing to stromal injury in the irradiated ‘vascular bed’.

Tumour cord Sleeve of viable tumour growing around a blood capillary.

Vascular targeted therapies Treatments designed to specifically target tumour vasculature; includes angiogenesis inhibitors and vascular disrupting agents.

Volume doubling time Time for a tumour to double in volume.

Volume effect Dependence of radiation damage on the volume of tissue irradiated and the anatomical distribution of radiation dose to an organ.

Xenografts Transplants between species; usually applied to the transplantation of human tumours into immune-deficient mice and rats.