Radio Biology of Low Dose Radiation

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



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)



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



Survival curve of cellsSurvival curve of cells

Linear Scale Logarithmic scale



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



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 )



Low dose cell survivalLow dose cell survival

S = e-D-D2

S = e-r(1+( s/ r -1)e-D/Dc)D-D2



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



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



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



Cell cycle and checkCell cycle and check

pointspoints



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



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



DSB Single stranded regions of DNA Resected DSB

G1 S G2 M

Check points

ATM



G1

DSB

ATMMRN

MDCI 53BP1 MRNBRCA 1

p53 CHK2

P21 CDC25A

P21 CDK2

CyclinE

CyclinE CDK2

back



S

Single stranded regions of DNA

ATR


CHK2

CDC25A

Cyclin E / A CDK2

back

Proteolysis



G2 M

RESECTED DSB

ATR


CHK2

CDC25

Cyclin B CDK 1

back

ATM

MRN

CHK 1

14-3-3

Nuclear export



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



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



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

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Radio Biology of Low Dose Radiation