Radiobiology FRCR part 1 Flashcards
How is a dose of radiation measured?
1J/Kg = gray (Gy)
Ho is equivalent dose defined?
ED = different effectiveness of tissue x dose
Measured in Sieverts
What are the phases of radiobiological effects?
physical - energy deposition, ionisation
Chemical - free radical, chemical modification
Biological - cell effects and toxicity
Where is RT most effective in the cell?
Nucleus, where DNA is attached to the nuclear membrane
How are free radical formed.
1st -excitement of H2O produces ionised H2O
2nd - Ionised water produce hydroxide ion and H free radical
How does radiation indirectly interact with DNA?
Photon excites e- leading to free radical formation with H2O, leading to DNA damage
How does radiation directly interact with DNA?
Photon excitements e- which damages DNA without H2O intermediate
What is the fenton reaction?
Peroixide catalyses with Fe2+ to hydroxy ions when oxidised to FE3+
What types of enzyme induced double-strand breaks (dsb) are there?
Blunt-ended
Cohesive end - exposed ss
What type of DNA breaks is associated with cell kill?
dsb
How does dsb lead to cell death?
chromosomal abberations
How does O2 increase DNA damage due to RT?
O2 is fixed to Irradaited DNA leading to the damage
What is the oxygen enhancement ratio (OER)?
ratio of radiation dose in hypoxia to the dose in air to produce the same biological effects
How is linear energy transfer (LET) defined?
Energy deposited per unit length of track (of radiation)
How are the tracks different in low LET?
Many branching tracks, sparsely ionising. From gamma or X-rays
How are the tracks different in high LET?
Fewer branching tracks, densely ionising. From alpha or carbon ions
How does LET effect cell kill?
higher LET has higher cell kill due to increased dsb.
What is optimum LET?
the value of LET which has the highest RBE
What is relative biological effectiveness (RBE)?
Ratio of dose of reference compared to rest radiation to compare equal effect.
What is the significant of cluster damage?
multiple breaks within a small length of DNA. more complex and difficult to fix, specially with dsb. DNA repair is LET dependent.
What types of DNA repair are there?
Direct substitution of damaged base. BER -base excision repair NER - nucleotide excision repair MMR- mismatch repair HR - homologous recombination NHEJ - non homologous end joining
What repair mechanisms are there for dsb?
Homolous recombination and non-homologous end-rejoining
Does direct substitution work?
Direct reversal - methyl taken from guanine to the cytosine on O6MGT to preserve the guanine….
Does direct substitution occur in RT?
No
How does base excision repair work?
- base recognised and removed
- cleavage of phosphodiester backbone.
- re-polymerised using undamaged strand as template
- resealing gap
What pathways of Ssd are there?
short patch (PARP) and long patch
What detects ssb?
PARP, which then recruits SSB repair scaffold protein.
What is nucleotide excision repair?
remove helix distortions in the helix due to a patch of bases
Does nucleotide excision repair occur in RT?
Radiation-induced crosslinks under hypoxic conditions
When in the cell cycle is homologous repair used?
S and G2 phase
When is homologous repair used?
In responce to dsb
How does homologous repair work?
- dsb detected
- endonuclease produces single strands from dsb
- homologous strand inversion
- new DNA based on homologous DNA strand template
When does NHEJ work?
End of G1 though throughout cell cycle
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
How does NHEJ work?
- Ku binds to dsb
- DNA polymerase
- ligase 4 recruited, sticking helix back together
Which is more error prone HR or NHEJ?
NHEJ is error prone
What its the role of PARP, Ku and ATM?
dsb damage sensors
How is the majority of dsb repaired in RT?
NHEJ
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.
How are oxidised bases and ssb repaired?
Base excision repair
What is the survival fraction?
Colonies counted/ (cells seeded * plating efficiency%)
In the linear-quadratic model what is the alpha term?
Initial slope, the single-hit probability of inactivation target directly
In the linear-quadratic model what is the beta term?
probability of two independent formed single hits combining to form a lethal hit
What value of alpha/beta ration in dicates a radiosensitive tumour?
high a/b ratio
What does a large shoulder of the linear-quadratic curve represent?
A radio resistant tumour, low a.b ratio
what checkpoint is induced by RT in the cell cycle?
cell cycle checkpoint at G2
What is the most radio-resistant phase of the cell cycle?
Late S phase
What is the most radio-sensitive phase of the cell cycle?
G2 or M phase
What is potentially lethal damage repair?
cellular damage that is repaired between the treatment and analysis via assay.
What is sublethal damage repair?
increase in survival if a dose is split between two fractions in time.
How does fractionation affect cell kill?
- Increased sublethal damage repair.
- RBE increases RBE
How does dose rate effect cell kill?
Similar to fractionation.
lower rate = SLDR
What happens between two exposure of radiation
- initial increase in survival (SLD)
- decrease due redistribution/resortment
- Increase due to repopulation from 6 hours
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
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
What is the bystander effect in RT?
Increased cell kill as a response to neighbour cells being irradiated
What is hyper-radiosensitivity?
cell are radio-sensitive due to low dose RT but become radio resistant at higher Gy RT.
What two models are there for measuring radiotherapy and cell survival?
Linear-quadratic and muilti-target model
What part of the cell cycle is stained by proliferation markers?
S phase
How can cell kinetics be measured?
Percentage-labelled mitosis (PLM) = proportion of labelled cell as a function of time.
What is the growth fraction?
Same as labelling index?
proliferative cell/ total cells.
What is Tpot?
potential doubling time of a tumour and is proportional to the duration of S phase/ labelling index.
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)
How is Cell loss fracture calculated?
1- (the ratio in potential and actual doubling time)
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.
Impact of hypoxia on tumour biology?
- angiogenesis
- apoptosis
- motility
- genomic stability
- invasion
Impact of hypoxia entreatment response?
lots
Why are hypoxic cell less radio-sensitive?
Less fixing of oxygen for DNA damage
What factors have a decreased OER between hypoxic and normal tumours?
Lower RT doses
Higher LET
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.
Makers of tumour cell hypoxia?
Pimidazole and EF5.
Problem with pimanidazole?
Injected prior to biopsy.
What is a a prognostic factor for radio-responce with hypoxia modification medication?
F-FMISO from CT-PET
Methods for increasing O2?
- treat aneamia
- ## hyperbaric oxygen
what hypoxic medication has proven benefit in bladder cancer?
nicotinamide
What markers are there of hypoxia (association)?
HIF1a
CA9
Glut1
What cancers are RT +platinum ChT used for?
H+N
Cervix
NSCLC
What cancers are temozolamide and RT used for?
Glioblastoma
What Cht agents target DNA repair when used along side RT?
- Cisplatin
- Bleomycin
- Doxorubicin
- Nucleoside analogues (gemcitabine)
- PARPi
How can VEGF inhibitors assist RT?
- blocks VEGF as a survival factor
- promotes normal vasculisation
What are gefitinib and erlotinib?
intra-cellular kinase inhibitors for EGFR
What therapeutic strategies may be feasible in treating hypoxic tumours?
PI3K inhibits
Malarone (atorvaquine)
EGFR-i
What featured of normal tissue are predisposed to early toxicity?
Highly proliferative tissues. Hypoplasia induced.
What featured of normal tissue are predisposed to early toxicity?
slowly proliferative cells. depletion of functional cells
What a-b ratio predisposes to early toxicity?
Higher a/b.
How can tissue be organised in the ‘model system’.
Hierachical - stem cells>precursors>functional cells.
Flexible - proliferative and functional ability of cells
In the ‘model system’ of normal tissue, what type of tissue are predisposed to acute toxicity?
hierarchic tissue - bone marrow, intestines, mucosa, gonads
In the ‘model system’ of normal tissue, what type of tissue are predisposed to Late toxicity?
Flexible - kidney, spinal cord, adrenal, pancrease, endocrine organs.
Does dose effect time of onset of toxicity?
Not in early toxicity but in late toxicity effects.
What are consequential late effects?
Late effects which are influenced by the extent (duration and severity) of early effects
What are the 5 Rs for normal tissue tolerance?
Radiosensitivity Recovery Repopulation ?Irradiated volume Retreatment
What classification of late effects (toxicity) on normal tissue are there?
LENT/SOMA
Late effects in normal tissue/ subjective objective management analytic
radiation responce in normal cell depends on?
- Cellular radio-sensitivity (CSC).
- Kinetics (proliferation)
- organisation (hierarchical, flexible or functional subunit)
What does ataxia talengesia have to do with RT?
abnormal DNA repair caused by ATM gene. ATM detects DSBs. These patient have more toxicity
What factors effect toxicity in RT?
Age, DM, IBD, connective tissue disease, etc.
What effect the latency (time of onset) for early toxicity?
Life span of functional cells.
GI sooner the bone marrow
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
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.
How can functional sub-units be organised in a tissue?
Parallel or in series
What is the definition of a functional sub unit?
the largest tissue volume by which a single surviving colonogenic cell can regenerate.
What examples are there of tissue which are arranged n a parallel FSU?
lung
liver
kidney
What examples are there of tissue which are arranged n a series FSU?
spinal cord, oesophagus, intestine
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
How does tissue with series FSU deal with RT?
- Complication due to hot spots not total organ.
- low functional reserve
What is the equivalent uniform dose (EUD)?
Absorbed dose that if homogenously delivered causes the same response as the actual clinical absorber dose distribution.
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
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.
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.
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)
What is relative risk (RR)?
Ratio of overall to background risk
What is the excess absolute risk (EAR)?
difference in additional absolute risk compared to background. (Not a ratio) (increased - background risk)
Solid cancer have what type of relationship between incidence and radiation exposure?
Men - linear-quadratic
Women - linear dose
= both dose-
What type of cancer are susceptible to background radiation?
Solids, not CLL, Hopkins, malignant melanoma.
Factors affecting cancer development risk due to radiation?
Dose Dose rate Sex Age of exposure Time since Attained age
Hereditary cancer due to radiation exposure is an example of a deterministic or stochastic effect?
Stochastic
What methods can be used to direct/ focus proton beam therapy onto a patient’s tumour?
Scattering (filters, barriers)
Scanning (range shifter)
How does an x ray photon deliver radiation dose?
Photo-electric effect (e- only) Compton scattering (y and e-) Pair production (e- and e+)
How do protons deliver radiation dose?
Coloumb (Rutherford) scattering
Proton inelastic reactions (release of neutron and y with lesser p’)
How can a briggs peak be spread out?
Different depths producing a spread out braggs pack (SOBP)
How do dsb effect the rate of repair?
Depend on the slow repair component. This is prolonged with dsb. Therefore repair takes longer
What are the 3As of tissue repopulation?
loss of Asymetric cell division
Abortive decision
Accelerated stem cell differentiation
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.
What is the implications of accelerated stem cell proliferation on RT?
dictates the rate of dose compensation
What is the implication of ‘abortive decision’ for tumour repopulation?
Corresponds to cell loss
What is the RF2 in radiotherapy?
Survival fraction at 2 Gy. Predicts radio sensitivity
What is the Dar in radiotherapy?
Mean inactivation dose. Calculated from the area under the survival curve (AUC).
What features for hypoxia RT sensitisers have?
Not metabolised, electron- affinic (mimic O2)
What is a Hyopoxic RT sensitiser?
Nimorazole
Name examples of radio protectors
Amifostine
Pentoxifylline
Pravastatin
Stem cell therapy
What is the therapeutic index?
The therapeutic is the rumour response for a fixed level of normal tissue damage.
What is the therapeutic ratio?
The therapeutic ratio is the relationship between the probability of tumour control and the likelihood of normal tissue damage.
What factors influence chance of cure in RT?
- Clonogenic number one tumour
- Hypoxia
- Repopulation ability
- Radiosensitivity of tumour
- Radiosensitivity of patient
