Radiobiology Flashcards
Ionization
The process by which a neutral atom acquires a positive or negative charge.
Excitation
Electrons raised to a higher energy level without actual ejection
Directly ionizing radiation
Charged particle such as electrons, protons, heavy ions, alpha and beta particles. Interact directly with atoms through coulombic forces and transfer kinetic energy directly.
Indirectly ionizing radiation
Photons (x-rays, gamma rays) and neutrons are charge less and therefore more penetrating. They have enough energy to fee an orbital electron which in turn is directly ionizing.
LET
Linear energy transfer is the average energy deposited per unit length.
As LET goes up so does the number of specific ionizations.
Specific ionizations
Number of ion pairs produced per unit length
Direct action
DNA damage caused directly by radiation
Indirect action
DNA damage due to chemical reactions caused by radiation. Radiation interacts with other atoms or molecules. Is the dominant process for low LET.
Stages of the cell cycle
Interphase: part of the cell cycle when cells are not actively dividing.
- G1: gap between telophase and DNA synthesis
- S phase: DNA synthesis
- G2: the gap between DNA synthesis and the first phase of mitosis
Mitosis
- prophase: centrioles move to opposite poles and start to form spindles. Chromosomes start to be seen as threads and be visible as they move to the equator.
- metaphase: centromere of a chromosome attached to spindle fibre at equator.
- anaphase: Centromeres have divided and single chromosomes are moving to opposite end of the cell.
- telophase: cell is divided.
Synchronous cell growth
All cells are at the same point of the cell cycle. Used for research purposes.
A synchronous cell growth
Cell are all in different stages of the cell cycle. Represents real life situations. Where the cells are in the cell cycle will impact how they respond to radiation.
3 fates of irradiated cells
Division delay: cells are prevented from entering mitosis. Can happen in both lethally and non-lethally damaged cells. Cells not in mitosis are delayed in G2.
- mitotic index: the ratio in cells in mitosis at any one time usually constant but radiation can impact the index.
- mitotic delay: due to radiation there is a reduced amount of cells in mitosis.
- mitotic overshoot: at lower doses cells recover from mitotic delay and add to the normal amount of cells in mitosis. Results in an increase in the mitotic index. Will return to normal after radiation.
Interphase death: occurs in cells that do not divide. The radiation breaks the DNA into pieces which causes apoptosis. Occurs at high doses and no mitotic overshoot occurs.
Reproductive failure: when cells are unable to divide due to break in chromosome.
Sub lethal damage
Smaller dose given over time allows healthy tissue time to repair themselves
Most sensitive phase of the cell cycle
G2 and M phases
Less sensitive in G1
At low doses progression into mitosis is delayed.
Least sensitive phase of the cell cycle
Late S
Early S is more sensitive
G1 is more sensitive
At higher doses all phases of the cell cycle can be effected (radiosenstive and radioresistent)
Intracellular repair
Cells ability to repair sub-lethal damage. Occurs when radiation is delivered in fractions. Each time the survival curve has the same D0, n and Dq therefore a higher total dose is needed for the same biological effect.
Factors that effect the response of cells and tissues to radiation
Biological factors: phase of cell cycle, intracellular repair
Physical factors: LET, RBE and dose rate
Chemical factors: sensitizers and protectors
High LET
Particles: - neutrons - alpha particles - electrons Characteristics - superficial - direct damage - Densely ionizing
Low LET
Particles: - x-rays - Gamma rays characteristics - Penetrating - Indirect damage - sparsely ionizing
RBE
Relative biological effectiveness. Equal doses of two different types of radiation do not produce the same biological effect. RBE relates radiation quality to biological response.
3 factors that contribute to the dose rate effect
Repair: reducing the dose rate makes the survival curve more shallow can causes the shoulder to disappear. At low dose rates the damage may be sublethal. The dose is not enough to kill the cell and the cell has a chance to recover.
Redistribution: with some cell line a reduction in dose rate results in a steeper cell curve. This is because lowering the dose of allows all cells to progress through the cell cycle and accumulate in G2 a radio sensitive phase.
Proliferation: further reduction in dose rate allows cells to pass through the G2 block and divide. Proliferation occurs during an exposure if the dose rate is low enough and time is long compared to the mitotic rate.
Two chemical factors that impact of the response of the cell to radiation
Sensitizers
Protectors
Chemical senstizers
Increase the killing effect of the given dose of radiation. Goal is to find an agent that shows a differential effect between tumor and normal tissue.
Oxygen is the universal enhance of radiation effects.
Oxygen enhancement ratio
OER, the ratio of hypoxic cells to aerobic doses needed to achieve the same result.
Not constant for the whole dose range. OER is lower for lower doses, due to cells in the cell cycle. Cells in G1 have lower OER and are more radio sensitive so they dominant at lower dose region of the survival curve.
With high LET radiation the amount of damage would not be repairable therefore the presence of oxygen would not further enhance response.
Why is there an oxygen effect?
Free radicals break chemical bonds which produce chemical changes initiating a chain of events resulting in biological damage.
Hypoxic cell sensitizers
mimic oxygen, making hypoxic cells more sensitive. Increases the radio sensitivity of cells that are deficient of oxygen.
Chemical protectors
Agents that reduce the effect of radiation on the cells. It must be present at the time of radiation to have an effect.
Work as free radical scavengers.
Most efficient at low LET.
Response of tissue or organs depends on:
- inherent senstivity of cells in that organ or tissue
- turnover kinetics of different cells (whether dividing or not and if so what is the rate of division)
Parenchymal tissue
Tissues if made of cells characteristics of that tissue or organ and its functional cells.
Stromal tissue
Composed of connective tissue and vasculature that supports the organs parenchyma for its structure and function.
Acute responding tissue
Typically seen within 10 days of starting treatments. Typically happen in tissues with high rapid turnover rate. High alpha/beta ratio Examples: Skin Jejunum Colon Testis
Late responding tissue
Damage not evident until cells begin to divide. Occur in predominantly in slow proliferating tissues and appear after a delay of several months or years after radiation. Low alpha/beta ratio Examples: Spinal cord Kidney Lung Bladder
Functional subunits (FSU’s)
Concept used to model the radiation response of normal tissues. It is a compartment of an organ that performs part of the organ function. Can be arranged in serial, parallel or both.
Structurally defined FSU’s
Each FSU is independent of its neighbor. The survival of FSU is depending on one or more clonogenic cells surviving within it. If all FSU’s are irradiated and all clonogenic cells are killed the organ will no longer function. If only a small portion of the organ is irradiated to a high dose it will continue to function.
Ex. Kidneys
Structurally undefined FSU’s
Not independent of neighbor. Cologenic cells can migrate from one FSU to another if one is depleted another can migrate and repopulate a depleted FSU.
Ex. Skin
Serial organs
When FSU’s are arranged in a series, like links in the chain. If one link is broken the chain can no longer function.
If a single FSU fails than the organ experiences detrimental effects.
Examples:
- spinal cord
- GI tract
These organs are susceptible to high point doses. Death in any segment along the organ will result in failure of the organ.
Have a threshold dose any dose below normal function is maintained.
In the spinal cord myelopathy can increase with increased volume at lower doses most likely due to damage of the vasculature rather than damage to the nerve cells.
Parallel organs
The organ is not dependent on all FSU’s functioning. Only about 30% of FSU’s are required to maintain function.
Each FSU is able to function independently of each other. Loss of a single FSU leads to a slight decrease in function of the organ.
Are more sensitve to volume effects. Sensitive to the irradiation of the whole volume but small volumes can be treated with much higher doses.
Functional damage will not occur until a critical number of FSU’s are deactivated.
Ex. liver and kidneys
Example of organs that are a combination of serial and parallel
Lungs
Brain
General organ changes
Acute: inflammation, edema, loss of mucosal surfaces
Late: fibrosis, atrophy, ulceration, stricture, stenosis, obstruction
Necrosis is the ultimate result of failure to repair
Healing occurs by
Regeneration
Repair
Regeneration
Replacement of damaged cells by the same type of cell. Results in total or partial reversal of early radiation damage.
Acutely responding tissue will undergo regeneration at all dose levels unless target cells are destroyed than repair would take place.
Late responding tissues have minimal regeneration capabilities. therefore moderate to high doses will result in repair.
Repair
Replacement of the depleted original cell by a different type of cell. It does not restore the organ to the pre-radiation conditions. It can produce secondary chronic effects.
TD5/5
Minimum tolerance dose. The dose to which a given population of patients is exposed under standard treatment conditions resulting in no more than 5% severe complications within 5 years after treatment.
TD50/5
Maximum tolerance dose. The dose at which a given population of patients exposed under standard set of treatment conditions resulting in no more than 50% severe complications within 5 years of treatment.
5 R’s of radiobiology
Repair Regeneration/re population Re oxygenation Redistribution Radio sensitivity
Pros and cons of fractionation on normal tissues
Advantages:
- spares tissue by repair of sublethal damage
- reducing fraction size greatly reduces reactions in late responding tissues
- repopulation/regeneration if overall time is sufficiently long (acute responding tissue only)
Disadvantage:
- reassortment increases damage to cells by moving them into sensitive phases of the cell cycle
Pros and cons of fractionation on tumors
Advantages:
- reassortment increases damage to cells by moving cells into sensetive phases of the cell cycle
- reoxygenation increases damage
Disadvantages:
- of overall time is too long, tumour cells repopulate during treatment
Hyperfractionated
Delivering the dose in twice as many fractions in about the same overall time by giving two treatments per day. The overall dose is increased as each fraction is smaller.
Accelerated treatment
Delivering dose to the same total dose in a much shorter time by delivering more than one fraction per day.
Acute effects are the dose-limiting factor required reducing fraction size or to have a break during treatment.
Purpose is the reduce repopulation in rapidly proliferating tumors with little or no chance in late effects.
Hypofractionation
Smaller number of larger sized fractions.
IMRT has improved dose distributions lowering dose to normal tissues the possibility of fraction size could be increased without increasing late effects.
