Radiation Biology

Front 1

Apoptosis

Back 1

Cell suicide pathway, initiated by cell when fault is detected (normally).

Front 2

Directly Ionizing Radiation

(examples of)

Back 2

Charged particles

(protons, electrons, alpha's etc)

Front 3

Indirectly Ionizing Radiation

(examples of)

Back 3

x-rays, gamma-rays, neutrons

(create fast moving charged secondary particles)

Front 4

3 effects of high energy (6-15MeV) beams

Back 4

-Compton scattering process dominates

-stopping potential largely independent of Z

-similar dose/g in tissue/bone/muscle

Front 5

Pair Production threshold energy and parent particles

Back 5

Threshold of 1.02MeV based on interaction between photon and nucleus

Front 6

High LET radiation

Back 6

direct action dominates

Front 7

Low LET radiation

Back 7

indirect action dominates

Front 8

Hydroxyl Radical

Back 8

OH

-contains 9 electrons (1 unpaired)

-can diffuse short distances (~4nm)

-~2/3 rad damage to mammalian cells from OH

-lifetime of 10-9 s

-biological response

cell kill (hours/days)

oncogenic (months/years)

hereditary (generations)

Front 9

Radiation protection drugs

Back 9

work by scavenging free radicals (OH)

less effective against high LET radiation due to directly ionizing characteristics

Front 10

DNA damage after 1Gy of dose

Back 10

Base damage >1k

SSB's ~1000

DSB's ~40

Front 11

SSB

Back 11

Single strand break,

readily repaired

Front 12

DSB

Back 12

Double strand break,

may cleave chromatin into two pieces.

many kinds of DSB depending on locations

Front 13

Process of malignant transformation results from mutations in what 3 groups of genes?

Back 13

Oncogenes (proliferation signal)

Tumor suppressors (growth inhibitory signal)

Genomic stability (DNA integrity)

Front 14

Radiation interaction with tissue at diagnostic energies (<1MV)

Back 14

photoelectric absorption begins to dominate

much higher dose/g in bone than other tissues

Front 15

pair production

Back 15

interaction between photon and nucleus

threshold 1.02MeV

probability increases with log(E) and Z^2

Front 16

Rayleigh scattering

Back 16

No energy lost, just scattered.

significant for E<10keV

Front 17

photo-electric energies / beam effect

Back 17

10keV to 1MeV

causes beam-hardening

Front 18

Compton scattering dominates at what energies?

Is this dependent upon Z?

Back 18

30keV to 10MeV and is independent of Z

Front 19

What does the photon energy for pair production become for high Z materials?

Back 19

for high Z, the pair production threshold is still 1.02MeV but probability of pair production is much higher

Front 20

Plot photon energy vs Z and fill in areas describing the pair production, photoelectric, and compton scattering.

Back 20

Front 21

describe Compton scattering

Back 21

an incident photon with sufficient energy collides with an orbital electron knocking it from the atom creating a fast electron. The residual energy of the incident photon continues as a scattered photon of reduced energy.

Note, the 'hole' is filled when electrons of outer shells notice it releasing characteristic x-rays

Front 22

Production of free radicals is by ______ action

Back 22

indirect action produces free radicals that damage DNA

Front 23

An estimate _______ (fraction) of radiation damage is caused by the hydroxyl radical.

Back 23

2/3

Front 24

List the chain of events that causes biological effects from radiation

Back 24

1. incident photon enters body

2. fast electron produced

3. Ion radical produced

4. Free radical created (decay)

5. bonds broken from reactivity of radical and DNA

6. biological effects

Front 25

In the LQ model what variables represent the repairable and non-repairable components

Back 25

alpha = non-repairable

beta = repairable

Front 26

Neutrons create what secondary charged particles

Back 26

recoil protons

Front 27

The hydroxyl radical has a diffuse/reactivity potential of approx _________

Back 27

4nm, DNA helix diameter = 2nm

double the width of the DNA molecule

Front 28

production of OH- radical. (chemical symbols)

Back 28

Note: OH- has one unpaired electron which makes its reactivity high

Front 29

Biological responses (3 and approx times)

Back 29

1. Cell kill ~hours/days

2. Oncogenic ~ months/years

3. Hereditary ~ generations

Front 30

Radiation chemist lingo:

'Spurs'-

'Blobs'-

Back 30

'spurs' -

up to 100eV of energy (3 ion pairs, ~4nm diameter) (up to 95% of x/g ray depositions are spurs.

'blobs'-

100-500eV of energy (12 ion pairs, ~7nm diameter)

Front 31

How can DSBs be quantified?

Back 31

Quantification of DSB is done through pulse-field-gel-electrophoresis (PFGE)

*sugar phosphate has a net neg. charge*

Front 32

List and briefly describe the cell stages/cycles

Back 32

M = mitosis

S= DNY syn. phase

G= gaps

Front 33

Which cell stage/cycle has a drastically different time for mammals vs other.

Back 33

G1 cycle

ie. hamster cells t(G1)=1

HeLa cells t(G1)=11

Front 34

What happens in the G1 and G2 phases

Back 34

G1 - 2 different pre-replication chromosomal strands not connected

G2 - post-replication chromosome in 'X' or 'Y' configuration

Front 35

Incorrect re-joining in which cell phase(s) is(are) responsible for chromosomal aberrations

Back 35

G1 and G2

Front 36

List the lethal and non-lethal chromosomal aberrations

Back 36

Lethal - dicentrics, rings, anaphase bridges

Non-lethal - translocations, small deletions

Front 37

List one bio-marker for human radiation exposure

Back 37

T-lymphocytes (can detect down to 25cGy)

Front 38

key DNA repair pathways for DSBs

Back 38

-Homologous recombination repair (HRR)

requires undamaged DNA strand as template

occurs in late S/G2 phases

Error free process

-Non-Homologous end joining (NHEJ)

occurs in G1 phase

prone to error, and source of oncogenic lesions

Front 39

Surviving fraction formula (LQ model)

Back 39

Front 40

LQ model DSB vs SSB

Back 40

Front 41

LQ model - at what does are the two components of cell kill equal

Back 41

Front 42

Fractionation - Dose to reduce S to 37% etc

Back 42

Front 43

Single acute dose, surviving fraction as a function of the BED

Back 43

Front 44

BED formula (excluding fractionation)

Back 44

Front 45

BED formula (including fractionation component)

Back 45

Front 46

The LQ model is based on the probability of ______.

Back 46

The LQ model is based on the probability of 'DSBs'.

Front 47

4 R's of Radiobiology

Back 47

1) Repair of sublethal damage

2) Re-assortment of surviving cells within the cell cycle

3) Re-population of surviving cells

4) Re-oxygenation

Front 48

LQ model limitations

Back 48

Front 49

Neutrons interact with ________.

Back 49

Nucleii

Front 50

Fast neutrons have a KE > _____. They gradually _______ through ______ collisions with hydrogen atoms dominant. They create ______ which deposit energy at 30KeV/um. The max energy deposition (______) deposited by thermalised neutrons.

Back 50

KE > ~1MeV

gradually thermalise through elastic collisions

create recoil protons

deposition (100keV/um) deposited

Front 51

Thermalized neutrons have a KE < ______. They have a _______ cross section for absorption with ____. They also release capture ______.

Back 51

KE < 1eV

have a high cross

absorption with H

capture gammas

Front 52

Surviving fraction formula including the probability of DSBs

Back 52

Note- The number of DSBs = Pdsb times D

Front 53

Two mechanisms responsible for DSBs

Back 53

Front 54

What ratio are tissues characterized by via the LQ model?

Back 54

Front 55

LQ model limitations

Back 55

Front 56

3 of the four R's of radiobiology as described by this graph

Back 56

Front 57

Cell cycle that varies drastically between HeLa cells and Hamster Cells.

Back 57

Time of the G1 phase!

Front 58

Progression through phases of the cell cycle are regulated by periodic activation of _______

Back 58

The CDK family. Cyclin-dependent kinase. Various cyclin-dependent kinase-cyclin complexes are required to phosphylorate several protein substrates, which drive key events, including the initiation of DNA replication and the onset of mitosis.

Front 59

A group of cells' exposure to ___________ can cause their cycles to be made synchronous. This chemical does what???

Back 59

Hydroxy-urea

It kills cells in S and imposes a block at the end of G1 phase.

Front 60

Describe the molecular 'checkpoint' genes function and what the loss of this gene results in

Back 60

These genes stop the cell from cycling if it is damaged. Major checkpoint is in late G2.

Note:

- Chromosome check/repair prior to mitosis

- Loss of checkpoint leads to increased radio-sensitivity.

Front 61

DSBs can be repaired! But how?

Back 61

- Homologous recombination (S/G2)

requires an undamaged template strand

- Non-homologous end joining (G1)

error prone and may cause cancer mutations

Front 62

Back 62

Front 63

When are cells most sensitive?

When are cells most resistant?

Back 63

Sensitive: M phase, and often G2.

Resistant: slow cycling cells are resistant in early G1 and more sensitive in late G1. Greatest resistance in late S

Front 64

Effective repair of radiation damage mostly attributed by ___________

Back 64

homologous repair

(requires undamaged template strand)

Front 65

Sulfhydryls

Back 65

(natural radioprotectors)

Radiation resistance through the cell cycle correlates with the level of sulfhydryls.

Front 66

OER dependence on cell cycles

Back 66

The OER varies little with cell-cycle.

-Maybe slightly lower in G1 than S

Front 67

Hereditary syndromes and radiation sensitivity

Back 67

some syndromes can result in high radiation sensitivity due to missing 'checkpoints'.

ie ataxia telangiectasia

Front 68

Dose Rate Effect

Back 68

Note:

Low DR < 50cGy/h

Front 69

Inverse-DR effect (concept)

Back 69

Front 70

Inverse-DR effect (explanation)

Back 70

Front 71

Repair half-time for sub-lethal damage to mamnalian cells is ~ _____

Clinically at least _____ between fractions

Back 71

1 hr

6 hrs

Front 72

Back 72

Front 73

Oxygen enhancement ratio. Ratio of dose _______ / dose ___________ for same effect. OER can be as high as ____. OER goes _____ as LET goes up.

Back 73

Oxygen enhancement ratio. Ratio of dose hypoxic / does normoxic for same effect. OER can be as high a 3. OER goes down as LET goes up.

Front 74

OER vs LET

Back 74

OER goes up as LET goes down.

Front 75

OER mechanisms

Back 75

2/3 of DNA damage is indirect

- when molecular O2 is present, free radiacl damage is 'fixed' (made permanent)

-hypoxic cells, damage is repairable

-fixation requires only ~3 mmHg or 0.5% O2 (normal level is ~ 50 mmHg)

Front 76

Back 76

Front 77

How does hypoxia manifest clinically?

Back 77

Hypoxia can be

-Chronic - diffusion limited

-Acute - temporary vessel closure

Hypoxia is associated with

-increased risk of metastasis

-genomic instability-selection of cells with diminished apoptotic potential

Front 78

Cells >~ ______ from 'functioning' vessels can become severely hypoxic.

Back 78

100 microns

Front 79

Back 79

Front 80

Hypoxic fraction in human tumors varies _____ to _____ %. Typically _____%

Back 80

0-50% Typically 15%

Front 81

Illustration of re-oxygenation

Back 81

Front 82

RBE formula

RBE and LET proportionality

Back 82

RBE - Relative Biological Effect

Front 83

Highest RBE value that is still efficient at causing DSBs

Back 83

Highest RBE is 100 KeV/micron. Higher RBE values become inefficient at causing DSBs

Front 84

Back 84

Front 85

Does RBE vary with dose and fractionation

Back 85

Yes. RBE varies with dose and fractionation.

Front 86

RBE vs LET (plot)

Back 86

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Back 87