Law of Bergonie and Tribondeau

• Stem cells are radiosensitive, the more mature cells are more resistant

• The younger tissue and organs, the more radiosensitive

• When the metabolic activity is high, the radiosensitivity is high

• As the proliferation and the growth rate increase, the radiosensitivity increases

Physical factors affecting the radiosensitivity

• When a biological medium irradiated, the effect will depend on the amount of deposited energy (Gy) per unit of mass

Linear energy transfer (LET)

• The measure of the rate at which the energy transferred form the ionizing radiation to the soft tissue

• It expresses the quality of the radiation and determines the value of the quality factor used in radiation protection

• The unit is keV of the transferred energy per micrometer of track length in soft tissue (keV/µm)

• As the ability of radiation to produce a biological effect increases, the LET increases

• LET of diagnostic x-ray is the lower among all other radiations (3keV/ µm)

Relative biologic effectiveness (RBE)

Describes the biologic effect quantitatively

Dose of standard radiation necessary

to produce a given effect

RBE= ___________________________________

Dose of test radiation necessary

to produce the same effect

• The standard radiation is orthovoltage x-radiation in the range of 200-250 kVp

• The diagnostic x-ray has a RBE of 1

• The maxim RBE is 3 (Ex: heavy nuclei)

• As the LET increases, the RBE increase until a maximum value (3)

Fractionation and protraction

• When the irradiation time increases, a higher dose is required to produce the same effect

• If the dose delivered continuously but at lower dose rate, it is called protraction

• Protraction has lower rate and longer irradiation time

• Fractionation is giving the dose in equal fractions separated by certain time

• Fractionation is less effective because tissue repair and recovery occur between the doses, used for radiotherapy

Biological factors affecting radiosensitivity

• There are Biological factors affect the response of a specimen to the radiation such as sex, age and metabolic rate

• Oxygen effect

• The biological effect increases when a specimen is irradiated in the presence of the oxygen in more than anoxic (without oxygen) or hypoxic (low oxygen) condition

This effect can be described numerically by the

oxygen enhancement ratio

Dose necessary under anoxic condition

to produce a given effect

OER= __________________________

Dose necessary under aerobic condition

to produce the same effect

• The irradiation usually occurs under hyperparic (high pressure) oxygen in the radiation therapy to increase the sensitivity of the avascular tumours which has less sensitivity than supplied tumours with adequate blood

• The OER is dependent on the LET

• The maximum OER for the lowest LET is 3

• The minimum OER for the highest LET is 1

Age

• Humans are more sensitive before birth

• The sensitivity starts to decreases until maturity

• In old age, humans again become more sensitive

Sex

• The results of experiments are not all in agreement

• Female can sustain 5% to 10% more radiation than male

• Females are less radiosensitive than males

• Recovery

If a cell irradiated without sufficient dose to die before reaching the next division phase (interphase) and given sufficient time for repairing, the cell will sustain from the sub-lethal damage

• Repair mechanism is an inherent characteristic in the biochemistry of the cell

• If a cell irradiated with a certain dose, the cell will respond through shrinkage (atrophy)

• The recovery is a combination between repopulation and repairing

Chemical agentsCan increase the sensitivity to the radiation

Radiosensitizers

• Increase the sensitivity to the radiation

• Ex: halogenated pyrimidines, hydroxyurea, vitamin K

• The halogenated pyrimidines incorporate into the DNA and increase the sensitivity

• RBE equals 2

• If a cell requires 200 rad to die , 100 rad will be enough in the presence of the sensitizer

Radioprotectors

• Molecules include sulfhydryl group (sulphur and hydrogen bound together)

• Ex: cysteine and cysteamine

• Relative effectiveness is 2

• If a cell requires 200 rad to die, 400 rad will be required in the presence of the radioprotectors agents

• Agents must be administrated in toxic levels to the humans to be effective which can be worse than the radiation

Radiation dose-response relationship

There are 2 important things beyond radiobiology experiments:

• To design therapeutic treatment for malignant tumours

• To determine the effects of low irradiation

Linear dose response

• There is direct proportion between the dose and the response

• In A and B which intersect the dose axis at zero or below , the relationship is linear and non threshold

• Non threshold means that regardless the size of the dose, there is a response

• At dose zero, there is a response at A called ambient (natural response) means that There is a response even without radiation (non threshold)

• C and D have Linear and threshold relationship

• They intersect the dose axis at value more than zero (threshold)

• D is steeper than C, which means any increment in the dose will result in greater response for D

Non linear dose response

• A, B and C are non linear

• A, B are non linear and non threshold

• In A, each increment in the response results in the low dose range

• In B, the response increases in the high dose range

• C is non linear and threshold

• In C, any increment in the dose increases the response until the inflection point, after that the response will be less effective

• C is called S or sigmoid type

Irradiation of macromolecules

• Reduces the macromolecule in to smaller molecules

• The small molecules can attach to a different macromolecule or another segment in the same macromolecule (crosslinking)

• Finally disruption of a single chemical bond produces a molecular lesion or point lesion

• At low dose, point lesion is considered as cellular lesion causes late effects observed at the whole body level

• All macromolecules radiation effects are reversible

Macromolecules

• It called anabolism and the breakdown of large molecules is called catabolism

• Multiple copies of specific proteins occur in the cell more than nucleic acids, so less radiosensitive than nucleic acids

• RNA is available in more copies than DNA but less than proteins

• RNA is intermediate in radiosensitivitybetween the proteins and DNA

Radiation effect on DNA

• If the DNA irradiated severely, chromosome aberration could be detected

• DNA can be damaged and results in cell death without any visible damage to the chromosomes

• DNA can result in uncontrollable growth of the cells

Types of DNA damages

• Main chain scission with only one side

• Main chain scission with the 2 sides

• Main chain scission and crosslinking

• Breakage causes a separation of the bases

• Change or loss in base

• The first 4 damages could be reversible

• Any of the damages can result in changing the sequence of the bases leading to a genetic mutation

• The 5th type is not reversible

• Three effects of DNA irradiation: cell death, malignant disease and genetic damage

• The last 2 effects occur at the molecular level related to linear-non threshold relationship

Radiolysis of water

• The dissociate of water into other molecules products

• When the atom of the water is irradiated, it is ionized and 2 ions (pair) are produced

• H2O+ radiation HOH+ + e

• If the ion pair joined again to form water molecule, no damage happens

• HOH+ + e H2O

Free radicals

• The resulted free radical is uncharged molecule contains unpaired single e in the valance or the most outer shell which causes them to be highly reactive

• free radicals exist with less than 1 ms

222

22

23

2

22

OHHOOH

OOe

OHHOHe

HHH

OHOHOH

aq

aq

22

2

OH

H

e

H

OH

aq

Direct and indirect effect

• When radiation effect occurs on a target molecule, it is called direct effect

• If the radiation occurs on noncritical molecule and the energy transferred to the target molecule, it is called indirect effect like the free radicals (intermediate molecules) which transfer energy to the target molecule

• The majority of the interactions are indirect since 85% of the body is water

• The presence of the O2 increase the indirect effect because of the production of the new free radicals

Target theory

• For a cell to die, its target molecule must be inactivated (DNA)

• The interaction of the radiation with the cell components occurs randomly

Presence of O2 and LET

• When there is low LET, the distance between the ionization and the target will be large, so O2 will interact with the radiation and produces free radicals which will increase the propability of damaging the target via the indirect effect

• When there is high LET, the distance between the ionization and the target will be close, so the damages will occur directly to the target and the presence of the O2 will not result in significant effect