Modifiers of cell survival: Linear Energy Transfer Lecture 8 Ahmed Group

Definition of RBE RBE as a function of LET Effect of LET on cell survival Endpoint dependence of RBE Effect of dose, dose rate, cell type

Effect of LET on cell survival Endpoint dependence of RBE Definition of RBE RBE as a function of LET Effect of LET on cell survival Endpoint dependence of RBE Effect of dose, dose rate, cell type

RBE Energy loss effects depends on nature and probability of interaction between radiation particle and body material. The amount or quantity of radiation is expressed in terms of the absorbed dose, a physical quantity with the unit of Gray or Rad. Dose is a measure of energy absorbed per unit mass of tissue Equal doses of different types of radiation do not produce equal biologic effects. One gray of neutrons produces a greater biologic effect than 1 Gy of X-rays. The key to the difference lies in the pattern of energy deposition.

Deposition of energy of different particles Photon The electrons set in motion if X-rays are absorbed are very light, negatively charged particles. X-rays are sparsely ionizing Neutron By contrast, the particles set in motion if neutrons are absorbed are heavy and densely ionizing. As the density of ionization increases, the probability of a direct interaction between the particle track and the target molecule (possibly DNA) increases Alpha particle

RBE In comparing different radiations it is customary to use x-rays as the standard. To normalize these effects as an empirical parameter the Relative Biological Effectiveness RBE of radiation for producing a given biological effect is introduced: dose in Gy from 250 keV X-rays / dose in Gy from another radiation source to produce the same biologic response RBE = The RBE for different kinds of radiation can be expressed in terms of energy loss effects LET.

Effect of LET on cell survival Endpoint dependence of RBE Definition of RBE RBE as a function of LET Effect of LET on cell survival Endpoint dependence of RBE Effect of dose, dose rate, cell type

Linear Energy Transfer (LET) is the rate at which energy is deposited as a charged particle travels through matter by a particular type of radiation Linear Energy Transfer (LET): the energy deposited per unit track. Unit is keV/m. It is determined by: quality of radiation quantity of radiation received dose of radiation exposure conditions (spatial distribution) The different kinds of radiation have different energy loss effects LET. The linear energy transfer (LET)of charged particles in the medium is the quotient of dE/dx, where dE is the average energy locally imparted to the medium by a charged particle of specified energy in traversing a distance of dx.

air tissue high LET (, n, ~) incident radiation low LET (, x, ~) On the following diagram, each dot represents a unit of energy deposited. As you will see from the diagram, alpha particles impart a large amount of energy in a short distance. Beta particles impart less energy than alpha, but are more penetrating. Gamma rays impart energy sparsely and are the most penetrating. Remember, gamma and x-rays vary widely in energy. The diagram shows a high energy gamma ray. dispersion of energy air tissue high LET (, n, ~) greater radiotoxicity incident radiation low LET (, x, ~) LET = linear energy transfer

Variation of ionization density associated with different types of radiation A 10-MeV proton, typical of the recoil protons produced by high-energy neutrons used for radiotherapy. The track is intermediate in ionization density. A 500-keV proton, produced by lower energy neutrons (e.g., from fission spectrum) or by higher- energy neutrons after multiple collisions. The ionizations form a dense column along the track of the particle. A 1-MeV electron, produced for example, by photons of cobalt-60- -rays. The particle is very sparsely ionizing. A 5-keV electron, typical of secondary electrons produced by x-rays of diagnostic quality. This particle is also sparsely ionizing but a little denser than the higher-energy electron.

Typical Linear Energy Transfer Values

The optimal LET LET of about 100 keV/μm is optimal in terms of producing a biologic effect. At this density of ionization, the average separation in ionizing events is equal to the diameter of DNA double helix which causes significant DSBs. DSBs are the basis of most biologic effects. The probability of causing DSBs is low in sparsely ionizing radiation such as x-rays that has a low RBE.

For low LET radiation,  RBE  LET, for higher LET the RBE increases to a maximum, the subsequent drop is caused by the overkill effect. These high energies are sufficient to kill more cells than actually available! In the case of sparsely ionizing X-rays the probability of a single track causing a DSB is low, thus X-rays have a low RBE. At the other extreme, densely ionizing radiations (ex. LET of 200 keV/ μm) readily produce DSB, but energy is “wasted” because the ionizing events are too close together. Thus, RBE is lower than optimal LET radiation.

Effect of LET on cell survival Survival curves for cultured cells of human origin exposed to 250-kV X-rays, 15-MeV neutrons, and 4-MeV alpha-particles. As the LET of the radiation increases, the survival curve changes: the slope of the survival curves gets steeper and the size of the initial shoulder gets smaller. A more common way to represent these data is on the next slide.

Effect of LET on cell survival Endpoint dependence of RBE Definition of RBE RBE as a function of LET Effect of LET on cell survival Endpoint dependence of RBE Effect of dose, dose rate, cell type

RBE as a function of LET Variation of RBE with LET for survival of mammalian cells of human origin The LET at which the RBE reaches a peak is much the same (about 100 keV/ μm) for a wide range of mammalian cells, from mouse to human, and is the same for mutation as an endpoint as for cell killing As the LET increases, the RBE increases slowly at first, and then more rapidly as the LET increases beyond 10 keV/ μm. Between 10 and 100 keV/ μm, the RBE increases rapidly with increasing LET and reaches the maximum at about 100 keV μm. Beyond this value for the LET, the RBE again falls to lower values. Curves 1, 2, and 3 refer to cell-survival levels of 0.8, 0.1, and 0.01, respectively, illustrating that the absolute value of the RBE is not unique but depends on the level of biological damage and therefore, on the dose level.

Effect of LET on cell survival Endpoint dependence of RBE Definition of RBE RBE as a function of LET Effect of LET on cell survival Endpoint dependence of RBE Effect of dose, dose rate, cell type

Factors that determine RBE Effects of dose, dose rate, cell type Biologic system or endpoint Radiation quality includes the type of radiation and its energy, whether electromagnetic or particulate and whether charged or uncharged. RBE depends on the dose level and the number of fractions. In general, the shape of the dose-response relationship varies for radiations that differ substantially in their LET. RBE can vary with the dose rate because the slope of the dose-response curve for sparsely ionizing radiations such as x- and g-rays, varies critically with a changing dose rate. For densely ionizing radiations, dose-rate is of little importance.

Factors that determine RBE Biologic system or endpoint The biologic system or endpoint that is chosen has a marked influence on the RBE values obtained. RBE varies according to the tissue or endpoint studied. RBE values are high for tissues that accumulate and repair a great deal of SLD and low for those that do not repair SLD.

To measure the RBE of some test radiation, one first chooses a biologic system in which the effect of radiations may be scored quantitatively. An example We need to measure the RBE of fast neutrons compared with 250-kV X-rays, using the lethality of plant seedlings as a test system. Groups of plants are exposed to a range of either X-rays or neutron doses. LD50 of X-rays (250-kV) in causing plant deaths is 6 Gy (600 rad) LD50 of neutrons in causing plant deaths is 4 Gy (400 rad) The RBE of neutrons compared with x-rays is then simply the ratio of 6:4 which is 1.5.

The RBE generally increases as the dose is decreased. The study of RBE is relatively straightforward so long as a test system with a single endpoint is used. It becomes more complicated if, instead, a test system such as the response of mammalian cells in culture is chosen. Figure shows survival curves obtained if mammalian cells in culture are exposed to a range of doses of either fast neutrons or 250-kV X-rays. The RBE may be calculated from these survival curves as the ratio of doses producing the same biologic effect. Because the X-rays and neutron survival curves have different shapes, the X-ray survival curve having an initial shoulder and the neutron curve being an exponential function of dose, the resultant RBE depends on the level of biological damage (and therefore the dose) chosen. The RBE generally increases as the dose is decreased.

RBE and fractionated doses Because the RBE of more densely ionizing radiations, such as neutrons, varies with the dose per fraction, the RBE for a fractionated regimen with neutrons is greater than for a single exposure, because a fractionated schedule consists of a number of small doses and the RBE is large for small doses. For a surviving fraction of 0.01 the RBE for neutrons relative to X-raysis 2.6 (was 1.5 at single exposure). This is a direct consequence of the larger shoulder for X-ray curve that is repeated for each fraction. The width of the shoulder represents a part of the dose that is “wasted”; the larger the number of fractions, the greater the extent of the wastage. Neutrons curve-almost no shoulder. Result: neutrons become progressively more efficient than X-rays as the dose per fraction is reduced and the number of fractions is increased. Further, the neutron RBE is larger at a low dose rate than for an acute exposure, because the effectiveness of neutrons decreases with dose rate to a much smaller extent than is the case for x- or -rays.

RBE as a function of dose fractionation Fractionation of radiation dose increases cell survival

RBE for different cells and tissues Even for a given total dose or dose per fraction, the RBE varies greatly according to the tissue or endpoint studied. Figure below illustrates the difference in intrinsic radiosensitivity among various types of cells. Survival curves for various types of clonogenic mammalian cells irradiated with 300 kV X-rays or 15-MeV neutrons. Note that the variations in radiosensitivity among different cell lines is markedly less for neutrons than for X-rays.

RBE as a function of dose rate The lower the dose rate, the higher the survival

Factors that determine RBE Radiation quality (LET). Includes the type of radiation and its energy. Radiation dose. Number of dose fractions (dose per fraction). The shape of the dose-response relationship varies for radiations that differ substantially in their LET. Dose rate. The slope of the dose-response curve for sparsely ionizing radiations such as X- or gamma-rays, varies critically with a changing dose rate. The biologic response to densely ionizing radiations depends little on the rate at which the radiation is delivered. Biologic system or endpoint. In general, RBE values are high for tissues that accumulate and repair sublethal damage and low for those that do not.