Radiation Biology

Question 1

What are the non-ionising forms of radiation?

Answer 1

Extremely low frequency radiation in electromagnetic fields and domestic power supplies this is at about 300 Hz with controversial health effects
Radiofrequency at .3-30MHz and microwave frequency (30 MHz-300GHz) the non-thermal health effects of these are controversial
Ultraviolet light at 200-300nm which leads to photochemical excitation of pyrimidine bases in DNA to form dimers this has a huge potential health risk with 45% of all skin cancers belived to be due to this

Question 2

What are the ionising forms of radiation?

Answer 2

This is radiation which causes indiscriminate ionization of atoms and molecules with 10eV of energy it includes particulate radiation which is Hi LET and electromagnetic radiation which is low LET

Question 3

What it LET with regards to radiation?

Answer 3

It is the energy transferred to a medium per unit track length of the ionizing particle

Question 4

What is the difference between HiLET and Low LET radiation?

Answer 4

High LET deposits a high amount of energy across a small distance while Low LET deposits a lower amount of energy across a larger distance
This makes LET the main determinant in radiation quality or relative biological effectiveness

Question 5

What is the Gray with respect to radiation?

Answer 5

This is the unit of the absorbed dose of radiation with 1 gray being equal to 1 joule of energy per Kg

Question 6

What are Sieverts with respect to radiation?

Answer 6

This is the unit of dose equivalent and corrects the gray for differences in relative biological effectiveness (determined by the gray*relativebiologicalequivalence)

Question 7

Is relative biological equivalence a constant value?

Answer 7

The RBE of high LET is always greater then low LET but RBE is not a constant for a particular type of radiation and instead depends on the biological end point

Question 8

How many Sv is the LD50 for humans?

Answer 8

Only 4 Sv delivered as photons this is an extremely low amount of energy (equivalent to a sip of hot coffee) and is due to the fact that ionising radiation deposit in small amounts of energy in large quanta

Question 9

What is the medical significance of ionizing radiation?

Answer 9

Background ionizing radiation is responsible for approximately 2% of all types cancers which results in a similar number of people seen with UV-induced malignant melanoma but this is spread across several types of cancers

Question 10

What are the cellular responses to ionising radiation?

Answer 10

Mutation which can result in cancer in somatic cells and heritable mutations in the germ line
Cell Killing
DNA damage response which is a set of signal transduction pathways initiated by DNA damage
Non-DNA targets can be affected like ROS causing membrane damage and redox signalling

Question 11

What normal tissues are most sensitive to radiation damage?

Answer 11

Haematopoietic stem cells and the GI tract

Question 12

What are the sensors of DNA damage response?

Answer 12

MRN complex (MRE11, Rad-50, NBS1) detects double strand breaks and signals to the protein kinase ATM
ATRIP(ATR interacting protein) detects single stranded DNA from processed DNA breaks at stalled replication forks and signals to ATR

Question 13

What are the transducers of the DNA damage response?

Answer 13

These are typically PI3 Kinase-related protein kinases (PIKK) such as ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3 related)
These phosphorylate SQ and TQ motifs in at least 700 targets

Question 14

What are the mediators and effectors that control the DNA damage response?

Answer 14

Cell cycle checkpoints
DNA Repair
Transcription
Apoptosis
Senescence (and more)

Question 15

How does ATM cause the cell to deal with DNA damage?

Answer 15

It can signal CHK1 and 2 which are checkpoint kinases

These will inhibit the activation of CDC2A=5AC which is a phosphatase required in cell cycle progression

Question 16

What are the methods of cell killing caused by radiation?

Answer 16

Mitotic catastrophe which is the post-reproductive cell death and the main mechanism of radiation induced cell death
Apoptosis which is important in some specific cell types like lymphomas but not with most cancer cell types
Autophagy which can be protective or a mechanism of cell death
Necrosis
Necroptosis

Question 17

What are the two distinct pathways of radiation induced apoptosis?

Answer 17

There is DNA damage which can lead to ATM/ATR activation followed by p53 activation causing apoptosis
Alternatively membrane damageanc activate sphingomyelinase leading to ceramide formation activating apoptosis

Question 18

What is Reproductive (Post-mitotic) cell death?

Answer 18

This is when having the cell passage through mitosis is necessary for killing
The cells may remain metabolically active for long periods of time but lose the ability to divide making them sterile, this is the most common method of tumour cell killing in radio therapy

Question 19

Why is the distinction between apoptosis and reproductive cell death pathways not clear, and how can this be accounted for?

Answer 19

In many cases postmitotic cell death will lead to apoptotic death eventually
This can be accounted for by considering prompt apoptosis (irrespective of cell cycle stage), delayed apoptosis subsequent to prolonged cell cycle arrest and post-mitotic apoptosis

Question 20

What is the key assay that sums up all cell death pathways?

Answer 20

Clonogenic cell killing where unirridatied plates are compared to irradiated plates and the assay will score the number of cells in the population capable of indefinite replication

Question 21

What are the two mechanisms of DNA damage induced by radiotherapy?

Answer 21

The direct effect where the DNA is directly affected by the radiation generating a DNA free radical ion which is the converted to a Hydrogen ion and DNA free radical
The indirect effect where H2O is hit by the radiation generating H2O radical ion which is converted to the hydroxyl free radical and hydrogen ion

Question 22

What are the features of the OH free radical?

Answer 22

It a powerful oxidant with a half life of 10^-5 seconds and a diffusion distance of 20 Amstrongs to increase the target zone around the DNA

Question 23

What are the two major radical products induced by ionizing radiation?

Answer 23

The major damaging species is the OH free radical while the other main product is the aquated electron which is relatively innocuous but will react rapidly with O2 to from superoxide (though this too is fairly unreactive)

Question 24

What are the two most important reactions of the OH free radicals?

Answer 24

Oxidation of lipids which causes a chain reaction which can damage cell membranes
Oxidation of DNA bases and sugars

Question 25

What can be the result of the hydroxyl radical interacting with DNA?

Answer 25

It can perform an OH addition or H abstraction at the thymine base to produce thymine glycol which blocks DNA replication
It can perform sugar damage (although this is 3 times less common) this is more significant biologically as it has the ability to make DNA strand breaks

Question 26

What occurs immediately following damage induced by ionizing radiation?

Answer 26

There is competition between the fast chemical repair mechanisms of the cell through use of thiols including glutathione and cysteine and damage fixation by oxygen?

Question 27

What is the oxygen effect in radiotherapy?

Answer 27

Cells with a greater supply of O2 suffer more damage in radiation therapy as the increased oxygen concentration promotes the damage fixation by O2 over the fast chemical repair mechanism
This can lead to problems with radiotherapy as cancers are typically hypoxic

Question 28

How much radiation is required to kill a mammalian cell and how can this be improved upon?

Answer 28

The typical mean lethal dose in mammalian cells is 2 Sv which is the equivalent of 400,000 ionisation events of which 4000 of these are likely to affect DNA and 1000 of those are likely to result in DNA strand breaks
However clustered ionisation events can lead to double strand breaks which are more difficult to repair accurately and can reduce the amount of radiation present

Question 29

What is clastogenesis?

Answer 29

DNA double strand breaks that result in chromosome damage

Question 30

How can chromosomal damage provide a mechanism for post-mitotic cell death?

Answer 30

The radiation may induce chromosome breaks which are misrepaired to form an acentric and dicentric chromosome leading to a failure to correctly segregate the genes after mitosis which can result in the cell being unable to proliferate after mitosis