Radiobiology FRCR part 1 Flashcards
1
Q
How is a dose of radiation measured?
A
1J/Kg = gray (Gy)
2
Q
Ho is equivalent dose defined?
A
ED = different effectiveness of tissue x dose
Measured in Sieverts
3
Q
What are the phases of radiobiological effects?
A
physical - energy deposition, ionisation
Chemical - free radical, chemical modification
Biological - cell effects and toxicity
4
Q
Where is RT most effective in the cell?
A
Nucleus, where DNA is attached to the nuclear membrane
5
Q
How are free radical formed.
A
1st -excitement of H2O produces ionised H2O
2nd - Ionised water produce hydroxide ion and H free radical
6
Q
How does radiation indirectly interact with DNA?
A
Photon excites e- leading to free radical formation with H2O, leading to DNA damage
7
Q
How does radiation directly interact with DNA?
A
Photon excitements e- which damages DNA without H2O intermediate
8
Q
What is the fenton reaction?
A
Peroixide catalyses with Fe2+ to hydroxy ions when oxidised to FE3+
9
Q
What types of enzyme induced double-strand breaks (dsb) are there?
A
Blunt-ended
Cohesive end - exposed ss
10
Q
What type of DNA breaks is associated with cell kill?
A
dsb
11
Q
How does dsb lead to cell death?
A
chromosomal abberations
12
Q
How does O2 increase DNA damage due to RT?
A
O2 is fixed to Irradaited DNA leading to the damage
13
Q
What is the oxygen enhancement ratio (OER)?
A
ratio of radiation dose in hypoxia to the dose in air to produce the same biological effects
14
Q
How is linear energy transfer (LET) defined?
A
Energy deposited per unit length of track (of radiation)
15
Q
How are the tracks different in low LET?
A
Many branching tracks, sparsely ionising. From gamma or X-rays
16
Q
How are the tracks different in high LET?
A
Fewer branching tracks, densely ionising. From alpha or carbon ions
17
Q
How does LET effect cell kill?
A
higher LET has higher cell kill due to increased dsb.
18
Q
What is optimum LET?
A
the value of LET which has the highest RBE
19
Q
What is relative biological effectiveness (RBE)?
A
Ratio of dose of reference compared to rest radiation to compare equal effect.
20
Q
What is the significant of cluster damage?
A
multiple breaks within a small length of DNA. more complex and difficult to fix, specially with dsb. DNA repair is LET dependent.
21
Q
What types of DNA repair are there?
A
Direct substitution of damaged base. BER -base excision repair NER - nucleotide excision repair MMR- mismatch repair HR - homologous recombination NHEJ - non homologous end joining
22
Q
What repair mechanisms are there for dsb?
A
Homolous recombination and non-homologous end-rejoining
23
Q
Does direct substitution work?
A
Direct reversal - methyl taken from guanine to the cytosine on O6MGT to preserve the guanine….
24
Q
Does direct substitution occur in RT?
A
No
25
How does base excision repair work?
1. base recognised and removed
2. cleavage of phosphodiester backbone.
3. re-polymerised using undamaged strand as template
4. resealing gap
26
What pathways of Ssd are there?
short patch (PARP) and long patch
27
What detects ssb?
PARP, which then recruits SSB repair scaffold protein.
28
What is nucleotide excision repair?
remove helix distortions in the helix due to a patch of bases
29
Does nucleotide excision repair occur in RT?
Radiation-induced crosslinks under hypoxic conditions
30
When in the cell cycle is homologous repair used?
S and G2 phase
31
When is homologous repair used?
In responce to dsb
32
How does homologous repair work?
- dsb detected
- endonuclease produces single strands from dsb
- homologous strand inversion
- new DNA based on homologous DNA strand template
33
When does NHEJ work?
End of G1 though throughout cell cycle
34
How does HR work with key involved protiens
o ATM - sensitisation and phosphorylated in DBS
o Recruitment of BRCA-1
o Stripped and then stabilised by RPA
o Damaged and duplicate strands approximate due to cohesin
o RAD51 – stabilises the homologuos (Holliday) structure
o DNA polymerase then repaures the homologous strands
35
How does NHEJ work?
1. Ku binds to dsb
2. DNA polymerase
3. ligase 4 recruited, sticking helix back together
36
Which is more error prone HR or NHEJ?
NHEJ is error prone
37
What its the role of PARP, Ku and ATM?
dsb damage sensors
38
How is the majority of dsb repaired in RT?
NHEJ
39
What is the concept of synthetic lethality?
Normal cell have to methods of DNA repair, HR using BRCA and BER using PARP. therefore give PARPi to BRACA mt.
40
How are oxidised bases and ssb repaired?
Base excision repair
41
What is the survival fraction?
Colonies counted/ (cells seeded * plating efficiency%)
42
In the linear-quadratic model what is the alpha term?
Initial slope, the single-hit probability of inactivation target directly
43
In the linear-quadratic model what is the beta term?
probability of two independent formed single hits combining to form a lethal hit
44
What value of alpha/beta ration in dicates a radiosensitive tumour?
high a/b ratio
45
What does a large shoulder of the linear-quadratic curve represent?
A radio resistant tumour, low a.b ratio
46
what checkpoint is induced by RT in the cell cycle?
cell cycle checkpoint at G2
47
What is the most radio-resistant phase of the cell cycle?
Late S phase
48
What is the most radio-sensitive phase of the cell cycle?
G2 or M phase
49
What is potentially lethal damage repair?
cellular damage that is repaired between the treatment and analysis via assay.
50
What is sublethal damage repair?
increase in survival if a dose is split between two fractions in time.
51
How does fractionation affect cell kill?
- Increased sublethal damage repair.
| - RBE increases RBE
52
How does dose rate effect cell kill?
Similar to fractionation.
| lower rate = SLDR
53
What happens between two exposure of radiation
- initial increase in survival (SLD)
- decrease due redistribution/resortment
- Increase due to repopulation from 6 hours
54
What happens in resortment in radioteherapy?
Initial radiotherapy dose pushes cell into G2 cell cycle check, a radiosensitive phase of the cell cycle. => incereased cell kill
55
What happens in resortment in radioteherapy?
Initial radiotherapy dose pushes cell into G2 cell cycle check, a radiosensitive phase of the cell cycle. => increased cell kill
56
What is the bystander effect in RT?
Increased cell kill as a response to neighbour cells being irradiated
57
What is hyper-radiosensitivity?
cell are radio-sensitive due to low dose RT but become radio resistant at higher Gy RT.
58
What two models are there for measuring radiotherapy and cell survival?
Linear-quadratic and muilti-target model
59
What part of the cell cycle is stained by proliferation markers?
S phase
60
How can cell kinetics be measured?
Percentage-labelled mitosis (PLM) = proportion of labelled cell as a function of time.
61
What is the growth fraction?
Same as labelling index?
proliferative cell/ total cells.
62
What is Tpot?
potential doubling time of a tumour and is proportional to the duration of S phase/ labelling index.
63
How is cell loss measured?
Cell lose factor - cells loss as proportion to cell created by mitosis (1 - (Tpot/Td) (1 - potential vs actual tumour doubling time)
64
How is Cell loss fracture calculated?
1- (the ratio in potential and actual doubling time)
65
What is the repopulation paradox?
When tumours are treated, there is a decrease in tumour doubling time. This leads to a smaller tumour which has an aggressive growth rate.
66
Impact of hypoxia on tumour biology?
- angiogenesis
- apoptosis
- motility
- genomic stability
- invasion
67
Impact of hypoxia entreatment response?
lots
68
Why are hypoxic cell less radio-sensitive?
Less fixing of oxygen for DNA damage
69
What factors have a decreased OER between hypoxic and normal tumours?
Lower RT doses
| Higher LET
70
What is the principle of reoxygenation in RT?
RT kills aerobic cells rather than hypoxic. Some hypoxic tumour cell transition to aerobic Subsequent RT dose would be effective for a new group of aerobic cells.
71
Makers of tumour cell hypoxia?
Pimidazole and EF5.
72
Problem with pimanidazole?
Injected prior to biopsy.
73
What is a a prognostic factor for radio-responce with hypoxia modification medication?
F-FMISO from CT-PET
74
Methods for increasing O2?
- treat aneamia
- hyperbaric oxygen
-
75
what hypoxic medication has proven benefit in bladder cancer?
nicotinamide
76
What markers are there of hypoxia (association)?
HIF1a
CA9
Glut1
77
What cancers are RT +platinum ChT used for?
H+N
Cervix
NSCLC
78
What cancers are temozolamide and RT used for?
Glioblastoma
79
What Cht agents target DNA repair when used along side RT?
- Cisplatin
- Bleomycin
- Doxorubicin
- Nucleoside analogues (gemcitabine)
- PARPi
80
How can VEGF inhibitors assist RT?
- blocks VEGF as a survival factor
| - promotes normal vasculisation
81
What are gefitinib and erlotinib?
intra-cellular kinase inhibitors for EGFR
82
What therapeutic strategies may be feasible in treating hypoxic tumours?
PI3K inhibits
Malarone (atorvaquine)
EGFR-i
83
What featured of normal tissue are predisposed to early toxicity?
Highly proliferative tissues. Hypoplasia induced.
84
What featured of normal tissue are predisposed to early toxicity?
slowly proliferative cells. depletion of functional cells
85
What a-b ratio predisposes to early toxicity?
Higher a/b.
86
How can tissue be organised in the 'model system'.
Hierachical - stem cells>precursors>functional cells.
Flexible - proliferative and functional ability of cells
87
In the 'model system' of normal tissue, what type of tissue are predisposed to acute toxicity?
hierarchic tissue - bone marrow, intestines, mucosa, gonads
88
In the 'model system' of normal tissue, what type of tissue are predisposed to Late toxicity?
Flexible - kidney, spinal cord, adrenal, pancrease, endocrine organs.
89
Does dose effect time of onset of toxicity?
Not in early toxicity but in late toxicity effects.
90
What are consequential late effects?
Late effects which are influenced by the extent (duration and severity) of early effects
91
What are the 5 Rs for normal tissue tolerance?
```
Radiosensitivity
Recovery
Repopulation
?Irradiated volume
Retreatment
```
92
What classification of late effects (toxicity) on normal tissue are there?
LENT/SOMA
Late effects in normal tissue/ subjective objective management analytic
93
radiation responce in normal cell depends on?
- Cellular radio-sensitivity (CSC).
- Kinetics (proliferation)
- organisation (hierarchical, flexible or functional subunit)
94
What does ataxia talengesia have to do with RT?
abnormal DNA repair caused by ATM gene. ATM detects DSBs. These patient have more toxicity
95
What factors effect toxicity in RT?
Age, DM, IBD, connective tissue disease, etc.
96
What effect the latency (time of onset) for early toxicity?
Life span of functional cells.
GI sooner the bone marrow
97
What is meant by the structural tissue (per unit area) tolerance?
Reflected cellular radio-sensitivity and ability for clonogenic stem cell to maintain mature cell population
98
What is meant by the functional tissue tolerance?
Depends on wether an irradiated area contribute to whole organ function. Depends tissue organisation and its radio-sensitivity against its reserve capacity.
99
How can functional sub-units be organised in a tissue?
Parallel or in series
100
What is the definition of a functional sub unit?
the largest tissue volume by which a single surviving colonogenic cell can regenerate.
101
What examples are there of tissue which are arranged n a parallel FSU?
lung
liver
kidney
102
What examples are there of tissue which are arranged n a series FSU?
spinal cord, oesophagus, intestine
103
How does tissue with parrallel FSU deal with RT?
- complication due to total dose, not hot spots.
- Tolerates small volumes of RT well.
- Good functional reserve capacity
104
How does tissue with series FSU deal with RT?
- Complication due to hot spots not total organ.
| - low functional reserve
105
What is the equivalent uniform dose (EUD)?
Absorbed dose that if homogenously delivered causes the same response as the actual clinical absorber dose distribution.
106
When does RT dose affect onset and when does it affect severity of toxicity?
Maximum severity is dose dependent in early toxicity effect
| Latency time is dose dependent in late toxicity effect
107
What is meant by deterministic effect in relation to radiation exposure?
Deterministic is the functional impairment of an organ or tissue due to radiation exposure.
Has threshold. Due to cell kill.
108
What is meant by Stochastic effect in relation to radiation exposure?
Probability of radiation exposure effect. Has no threshold. Due to non-lethal cell modification.
109
What is Excess relative risk (EER)?
Proportion increase in risk compared to background risk. (e.g; RR of 2.2 is an ERR of 1.2)
110
What is relative risk (RR)?
Ratio of overall to background risk
111
What is the excess absolute risk (EAR)?
difference in additional absolute risk compared to background. (Not a ratio) (increased - background risk)
112
Solid cancer have what type of relationship between incidence and radiation exposure?
Men - linear-quadratic
Women - linear dose
= both dose-
113
What type of cancer are susceptible to background radiation?
Solids, not CLL, Hopkins, malignant melanoma.
114
Factors affecting cancer development risk due to radiation?
```
Dose
Dose rate
Sex
Age of exposure
Time since
Attained age
```
115
Hereditary cancer due to radiation exposure is an example of a deterministic or stochastic effect?
Stochastic
116
What methods can be used to direct/ focus proton beam therapy onto a patient's tumour?
Scattering (filters, barriers)
| Scanning (range shifter)
117
How does an x ray photon deliver radiation dose?
```
Photo-electric effect (e- only)
Compton scattering (y and e-)
Pair production (e- and e+)
```
118
How do protons deliver radiation dose?
Coloumb (Rutherford) scattering
| Proton inelastic reactions (release of neutron and y with lesser p')
119
How can a briggs peak be spread out?
Different depths producing a spread out braggs pack (SOBP)
120
How do dsb effect the rate of repair?
Depend on the slow repair component. This is prolonged with dsb. Therefore repair takes longer
121
What are the 3As of tissue repopulation?
loss of Asymetric cell division
Abortive decision
Accelerated stem cell differentiation
122
What is asymmetric cell division and its implications on RT?
stem cells produce either differentiated or stem cells from mixed (asymtet-). This means that increased RT is needed for increased treatment time.
123
What is the implications of accelerated stem cell proliferation on RT?
dictates the rate of dose compensation
124
What is the implication of 'abortive decision' for tumour repopulation?
Corresponds to cell loss
125
What is the RF2 in radiotherapy?
Survival fraction at 2 Gy. Predicts radio sensitivity
126
What is the Dar in radiotherapy?
Mean inactivation dose. Calculated from the area under the survival curve (AUC).
127
What features for hypoxia RT sensitisers have?
Not metabolised, electron- affinic (mimic O2)
128
What is a Hyopoxic RT sensitiser?
Nimorazole
129
Name examples of radio protectors
Amifostine
Pentoxifylline
Pravastatin
Stem cell therapy
130
What is the therapeutic index?
The therapeutic is the rumour response for a fixed level of normal tissue damage.
131
What is the therapeutic ratio?
The therapeutic ratio is the relationship between the probability of tumour control and the likelihood of normal tissue damage.
132
What factors influence chance of cure in RT?
- Clonogenic number one tumour
- Hypoxia
- Repopulation ability
- Radiosensitivity of tumour
- Radiosensitivity of patient
