Radiation biology

from which threshold does the wavelength of radiation has ionising effect?

What is ionising effect?

Ionising radiation refers to energy that is powerful enough to remove tightly bound electrons from atoms or molecules which create ions

The lower the wavelength the higher the frequency the more significant it is

Wavelengths shorter than 124nm (12.4×10^-9m) are ionising

What is the difference between particulate radiation and electromagnetic radiation? What is the Compton effect?

Particulate radiation comes from actual particles such as alpha, beta, neutrons, needs a medium to travel through and are emitted during nuclear decay or fission (high LET)

Electromagnetic radiation is from energy waves (photons) that travels at a speed of light and can travel through a vacuum which are used in X rays or CT scans (low LET)

Ionisation mainly due to the Compton effect: when a photon strikes on electron which the electron absorbs the energy and the photo is deflected and loses energy, which increase in its wavelength (angle of scattering / Compton shift)

What is LET - Linear energy transfer?

Energy transferred to the medium per unit track length of the ionising particle

The denser the activity, the more likely that the target is hit.

Track structure of low LET radiation

Although low LET photons are sparsely ionising on average, they induce clusters of ionisation events due to ejection of an electron with sufficient energy to form a small track (delta ray)

= there is a high LET component event in low LET tracks

LET is the main determinant of radiation quality, or

Relative biological effectiveness. though RBE is highly dependent on the type of cell that is targeted

Dose equivalent (Sievert Sv) =

= Dose in Gray (Gy) * RBE

What is the difference between the stochastic effects and non-stochastic effects of ionising radiation?

Stochastic effect means that it is an one or all event which occurs at random , still increase approx, linarly with dose

Non-stochastic effect: that is non linear does response - characterised by threshold, reaching a threshold = radiation effect

What are the two distinct pathways of radiation-induced apoptosis

• intrinsic pathway: caspase mediated apoptosis: DNA damage - ATM/ATR - p53 - BAX, PUMA - caspase 9 - apoptosis

• via sphingomyelinase - ceramide pathway: this pathway is initiated at the plasma membrane, not the nucleus. Membrane damage leads to SMase activatio and via ceramide triggering apoptosis

Most important ionsing effect: post mitotic cell death

• Passage through mitosis with damaged chromosomes result in highly abnormal cells that are not able to proliferate indefinitly

• However this mechanism of killing is only of significant in proliferating cell populations

Mechanism of DNA damage: Direct effect and indirect effect

Direct effect

• The radiation acts directly on the DNA which induce the formation of DNA + radical ion +e-. The DNA losng 1e bcomes the free radical

Indirect effect: due to the radiolysis of water

Water - radiation induced → radical ion of h2o which then converted to hydroxyl free radical . the electron in the water can also cause the o2 to o2- superoxide

However the most important radical is OH*

OH*

OH* half lif is approx. 10-5 sec

the other man radical product, e-, reacts rapidly with o2 to form o2* which is not ractive towards DNA and can be detoxifide via SOD to mak h2o2 and catalase to make water or GSH

OH* is a powerful oxidant as it can add to doubl bonds and can abstract H atoms from any saturated carbon atoms

RH2 + oh* → rh* + h20

The most important reactions of OH* are

• Oxidation of lipids resulting in chain reactions with ROO* and RO*

• OH addition or H abstraction at thymine base whch blocks DNA replication

• Sugar damage (3x less frequently than base damage) but important as induce double strand break

What is the difference between DNA damage in normal vs hypoxic state?

In normal state, radiation induces DNA to becomes DNA radical DNA*, in the presence of oxygen, the DNA* becomes DNA-OO* and DNA+, which induces the fixation of the damage and leading to DNA strand break

In hypoxic condition, the DNA* after the first radiation step can becomes chemically repair quickly by GSH (reversible)

Clastogenesis

DNA double strand breaks results in chromosome breakage - clastogenesis

Some of these ds breaks are repaired with high fidelity HRR but many are repaired through error prone NHEJ or MHEJ

When >1ds break is present, misrepair by NHEJ can result in structurally abnormal chromosomes that can have 0 acentric or 2 - dicentric centromeres (damage and mirepair, not programmed recombination)

→ post mitotic catastrophy

However, chromosome translocation can cause radiation mutagenesis

Non-reciprocal translocation are usually lethal, but radiation can induce reciprocal translocation which allow mutant to survivce

Eg.

Philadelphia syndrome, chronic myeloid leukaemia Reciprocal translocation between chromosome 22 and 9 which leads to bcr-abl fusion gene codes for an oncoprotein, inhibted by imatinib