radio biology of low dose radiation
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8/6/2019 Radio Biology of Low Dose Radiation
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Radiobiology of low dose ionizingRadiobiology of low dose ionizing
RadiationRadiation
DrDr SaikatSaikat DasDas
MBBS, DMRT, MD, DNB, MNAMSMBBS, DMRT, MD, DNB, MNAMS Assistant Professor Assistant Professor
Department of Radiation Oncology Unit IIDepartment of Radiation Oncology Unit II
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Therapeutic application ofTherapeutic application of
ionizing radiationionizing radiation Radiation produces ionsRadiation produces ions
The target is nucleus and more specifically it is The target is nucleus and more specifically it is
DNA DNA
Can cause damage to DNA at various levelsCan cause damage to DNA at various levels
There is a effective DNA damage control There is a effective DNA damage control
system in placesystem in place The unit of absorbed dose of radiation per unit The unit of absorbed dose of radiation per unit
mass is Gray (Gy)mass is Gray (Gy)
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Clonogenic assayClonogenic assay
10
4
8
6
PE=0.6 PE=0.5
Surviving fraction= PE treated/PE control=0.5/0.6=0.83
Plating
Incubation
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Survival curve of cellsSurvival curve of cells
Linear Scale Logarithmic scale
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Factors affectingFactors affecting
RadiosensitivityRadiosensitivityPhysical factorsPhysical factors
Energy, Total dose, Dose rate, FractionEnergy, Total dose, Dose rate, Fraction
Chemical factorsChemical factors
Radio sensitizers, O2, Chemical modifiersRadio sensitizers, O2, Chemical modifiers
Biological factorsBiological factors
Type of cell, cell cycleType of cell, cell cycle
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ISOEFFECT LINEISOEFFECT LINE
0
10
20
30
40
50
60
70
80
90
1 2 4 8 16 32
Number of fractions
T o t a l D o s e (
G r a y )
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Low dose cell survivalLow dose cell survival
S = e-D-D2
S = e-r(1+( s/ r -1)e-D/Dc)D-D2
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Dose dependant responseDose dependant response
to Radiation at <1 Gyto Radiation at <1 Gy In the mammalian cell survival curve to radiationIn the mammalian cell survival curve to radiation
response there is an area of increased radiationresponse there is an area of increased radiation
sensitivity (HRS) which precedes a portion of sensitivity (HRS) which precedes a portion of increasedincreased radioresistanceradioresistance (IRR) with a finite zone(IRR) with a finite zone
of transition (HRS/IRR)of transition (HRS/IRR)
Underlying mechanism is complex and gradually Underlying mechanism is complex and gradually evolving as an area of translational researchevolving as an area of translational research
Flow Flow cytometriccytometric studies indicate an enriched cellstudies indicate an enriched cell
population inpopulation in G2 phaseG2 phase at HRS/IRR responseat HRS/IRR response
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HRS/IRR.some factsHRS/IRR.some facts
It appears that the HRS/IRR responseIs associated with cell cyclecheck points
Chemically inhibiting DNA repairmechanism eliminates IRR
IRR is also eliminated in
Ataxia Telangiectasia And Nijmegen breakage syndrome
This indicates that HRS and IRR is A dynamic process and is related to
DDR
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HRS HRS in vivo evidencein vivo evidence
HRS and IRR haveHRS and IRR havebeenbeen characterisedcharacterised inin
mammalian tumor andmammalian tumor andnormal cell linenormal cell line
It is observed toIt is observed to XrayXray,,pi meson and protonpi meson and proton
irradiationirradiation
Has been shown in skinHas been shown in skinin terms of Basal cellin terms of Basal celldensitydensity
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Cell cycle and checkCell cycle and check
pointspoints
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DNA Damage ResponseDNA Damage Response
1 Gy radiation causes approximately1 Gy radiation causes approximately
10 10 55 ionizationionization
1000 SSB and 20 DSB1000 SSB and 20 DSB
This leads to less than 30 % cell killThis leads to less than 30 % cell kill
DNA has a efficient repair mechanismDNA has a efficient repair mechanism
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MRN
ATM
ATRIP
ATRKu70
KU80 DNAPKcs
Damage signaling
H2AX MDC1, 53BP1, BRCA 1,2; RAD51, p53, p21, BAX, chk1/2, CDC25A /c
EFEECTOR PATHW AY
checkpointsDNA
repair
Cell death
IRIF
5-30 min
MRE, RAD 50,
NBS 1
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DSB Single stranded regions of DNA Resected DSB
G1 S G2 M
Check points
ATM
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G1
DSB
ATMMRN
MDCI 53BP1 MRNBRCA 1
p53 CHK2
P21 CDC25A
P21 CDK2
CyclinE
CyclinE CDK2
back
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S
Single stranded regions of DNA
ATR
MDCI 53BP1 MRNBRCA 1
CHK2
CDC25A
Cyclin E / A CDK2
back
Proteolysis
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G2 M
RESECTED DSB
ATR
MDCI 53BP1 MRNBRCA 1
CHK2
CDC25
Cyclin B CDK 1
back
ATM
MRN
CHK 1
14-3-3
Nuclear export
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00--1 Gy1 GyDose dependent activation
0-0.3 Gy
No G2 cell cycle arrest
Mitotic entry with damage
Apoptosis
HRSHRS
0.3-1.0 Gy
Early G2 arrest
DNA repair
IRR
ATM
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Less than 20 DSB (<0.4Gy) fail to initiate G2M check point
No cell cycle arrest
Cells pass into the cell cycle sustaining the damage
Apoptosis
The early G2 checkpoint is ATM dependent and is dose
independent over the range of 1 to 10 Gy
It has distinct activation threshold in excess of 0.4 Gy
Leading to G2 cell arrest
Molecular mechanismMolecular mechanism
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Questions instead of ConclusionsQuestions instead of Conclusions
Clinical implications of HRSClinical implications of HRS
Effect of HRS on slowly proliferativeEffect of HRS on slowly proliferativenormal tissuenormal tissue
Translation of HRS effect from in vitroTranslation of HRS effect from in vitroto in vivoto in vivo
Transition of HRS to IRR responseTransition of HRS to IRR response
G2 phase synchronizationG2 phase synchronization-- a combineda combinedeffect of cell cycle specificeffect of cell cycle specificchemotherapychemotherapy