IntroductionIntroduction toto RadiationRadiation ChemistryChemistry

MikeMike Robbins,Robbins, PhDPhD RadiationRadiation BiologyBiology SectionSection DepartmentDepartment ofof RadiationRadiation OncologyOncology WakeWake ForestForest UniversityUniversity SchoolSchool ofof MedicineMedicine IonizingIonizing RadiationRadiation CanCan DissipateDissipate ItsIts EnergyEnergy ByBy TwoTwo MethodsMethods

ÄEXCITATIONEXCITATION

ÄIONIZATIONIONIZATION ExcitationExcitation

AmountAmount ofof energyenergy absorbedabsorbed raisesraises anan electronelectron inin anan atom/moleculeatom/molecule toto aa higherhigher energyenergy levellevel withoutwithout ejectionejection ofof thethe electron.electron.

’ OccursOccurs followingfollowing exposureexposure toto nonnon--ionizingionizing radiationradiation e.g.,e.g., UVUV IonizationIonization

“ OccursOccurs whenwhen thethe absorbedabsorbed radiationradiation hashas enoughenough energyenergy toto ejecteject oneone oror moremore orbitalorbital electronselectrons fromfrom thethe atom/molecule.atom/molecule.

“ RadiationRadiation withwith suchsuch energyenergy calledcalled ionizingionizing radiation,radiation, e.g.,e.g., XX rays,rays, γγ raysrays ElectromagneticElectromagnetic SpectrumSpectrum

Examples:Examples: XX raysrays ((extranuclearextranuclear)) andand γγ raysrays ((intranuclearintranuclear))

CanCan viewview asas eithereither aa wavewave ofof electricalelectrical andand mechanicalmechanical energyenergy oror asas photonsphotons (packets(packets ofof energy)energy) ElectromagneticElectromagnetic RadiationRadiation

“ IrradiatingIrradiating biologicalbiological materialmaterial leadsleads toto unequalunequal distributiondistribution ofof energyenergy inin tissuestissues andand cellscells

“ WithWith ionizingionizing radiationradiation photonsphotons containcontain sufficientsufficient energyenergy toto breakbreak chemicalchemical bondsbonds leadingleading toto biologicalbiological effectseffects IonizationIonization andand RadicalRadical FormationFormation

IonizationIonization ofof waterwater leadsleads toto generationgeneration ofof anan ionion pairpair

+• - HH2OO ++ radiationradiation →→ HH2OO ++ ee

+• H2O is an ion radical: ion is an atom/molecule that is electrically charged since has lost an electron.

Free radical is atom/molecule that possesses one or more unpaired electrons; highly reactive IonizationIonization andand RadicalRadical FormationFormation

+• + • HH2OO →→ HH ++ HOHO

- - ee ++ HH2OO →→ ee aq

A hydrogen free radical can also be produced, together with some hydrogen peroxide: - + • ee aq ++ HH →→ HH

• • HOHO ++ HOHO →→ HH2OO2 IonizationIonization andand RadicalRadical FormationFormation

RadiolysisRadiolysis ofof water:water:

- • • HH2OO ++ radiationradiation →→ ee aq ++ HOHO +H+H ++ HH2OO2

GG valuesvalues 2.632.63 2.722.72 0.550.55 0.680.68

G value: measured yield of molecules produced by absorption of 100 eV X rays. For low LET, highest yields are e-aq and HO•. DirectDirect andand IndirectIndirect EffectsEffects ofof RadiationRadiation

DirectDirect effect:effect: targettarget moleculemolecule itselfitself reactsreacts directlydirectly withwith radiationradiation

RHRH →→ RHRH+

RHRH+ →→ RR• ++ HH+ DirectDirect andand IndirectIndirect EffectsEffects ofof RadiationRadiation

IndirectIndirect effect:effect: ionizingionizing radiationradiation generatesgenerates freefree radicalsradicals fromfrom thethe radiolysisradiolysis ofof waterwater

TheseThese cancan indirectlyindirectly formform radicalsradicals withwith thethe targettarget moleculemolecule

• • RHRH ++ HOHO →→ RR ++ HH2OO

+ • RHRH ++ HH →→ RR ++ HH2 ““FixationFixation”” ofof BiologicalBiological InjuryInjury

“ InIn thethe presencepresence ofof oxygen,oxygen, anan organicorganic peroxylperoxyl radicalradical isis formed.formed. ThisThis cannotcannot easilyeasily bebe repaired,repaired, andand soso actsacts toto ““fixfix”” thethe biologicalbiological injuryinjury • • RR ++ OO2 →→ ROOROO TARGETTARGET THEORYTHEORY

“ For bacteria, viruses and some mammalian cell lines, semi-log plot of SF vs. dose gives a straight line

“ Unit increase in dose produces a corresponding fractional decrease in survival

“ Shape of curve explained in terms of Target Theory: certain critical sites in cells must be hit if the cell is to be killed

“ Single hit in a single target would give an exponential survival curve SingleSingle--targettarget SingleSingle HitHit ModelModel

probability of survival p = p (0 hits) = e-D/Do

D = dose applied; D0 = dose that gives an average of 1 hit/target

A dose of D0 will reduce survival from 1 to 0.37 i.e., e-1, or from 0.1 to 0.037, etc.

D/D0 is the average number of hits/target MultiMulti--eventevent ModelsModels

“ MammalianMammalian cellscells tendtend toto showshow aa differentdifferent responseresponse

“ AtAt lowlow dosesdoses seesee aa shoulder,shoulder, onlyonly seesee exponentialexponential responseresponse atat higherhigher dosesdoses

“ VariousVarious multimulti--eventevent modelsmodels havehave beenbeen proposedproposed MultiMulti--targettarget singlesingle--hithit ModelModel

Proposes 2 or more targets in a cell; each must receive a single hit before the cell is killed.

Model is described by the following equation: SF = 1-(1- e-D/D0)n where SF is the surviving fraction after a dose D

D0 is the dose needed to reduce cell SF to 1/e (37%) of its initial value on the exponential portion of the survival curve. Also the reciprocal slope of the survival curve,

n is the extrapolation number. MultiMulti--targettarget singlesingle--hithit ModelModel

“ HasHas provedproved usefuluseful forfor describingdescribing thethe responseresponse ofof mammalianmammalian cellscells atat highhigh dosesdoses

“ However,However, doesdoes notnot describedescribe survivalsurvival responseresponse atat lowerlower moremore clinicallyclinically relevantrelevant dosesdoses

“ ImplyImply zerozero slopeslope atat veryvery lowlow doses;doses; mostmost datadata showshow finitefinite oror nonnon--zerozero initialinitial slopeslope TwoTwo CompartmentCompartment ModelModel

Combines the simple multi-target model with a single-target component.

This model fits the majority of mammalian cell survival curves, implies the possibility of both single and multi-hit events.

f = e-D/D1 [1-(1- e-D/D2)]n

where D1 and D2 refer to the initial and final slopes. TwoTwo CompartmentCompartment ModelModel

Disadvantages:Disadvantages:

“ ChangesChanges inin cellcell survivalsurvival overover thethe rangerange 00--DDq occuroccur almostalmost linearlylinearly

“ ImpliesImplies nono sparingsparing ofof damagedamage atat dosesdoses perper fractionfraction lessless thanthan ~~ 22 GyGy LinearLinear--QuadraticQuadratic ModelModel

Gives a better description of the radiation response of cells in the low dose region (0-3 Gy)

f = e-(αD +βD2)

Gives a continuously bending survival curve with no straight portion at high radiation doses

Shape or bendiness of the curve is determined by the α/β ratio; represents the dose (Gy) at which linear contribution to cell kill equals quadratic contribution. Lethal,Lethal, potentiallypotentially LethalLethal DamageDamage (LPL)(LPL) ModelModel

Ionizing radiation produces 2 kinds of lesions: repairable (potentially lethal) lesions and non-repairable (lethal) lesions. The non-repairable lesions produce single hit lethal events; linear component of cell kill. The effect of the repairable lesions depends on the competing processes of repair and binary misrepair; leads to quadratic component. At higher doses the probability of binary interaction of potentially lethal lesions increases. DNADNA DamageDamage isis thethe CriticalCritical EventEvent inin RadiationRadiation--inducedinduced CellCell deathdeath

“ Microirradiation studies indicate that to kill cells by irradiation the cytoplasm requires much greater doses than the nucleus; >250 Gy compared with ~2 Gy

“ Isotopes such as 3H and 125I that emit short range β particles, when incorporated intercellular DNA, efficiently produce radiation cell kill and DNA damage

“ The incidence of chromosomal aberrations following irradiation is closely linked to cell kill.

“ Thymidine analogues such as IUdr and BrUdr when specifically incorporated into DNA modify radiosensitivity. Substituted deoxyuridines, which are not incorporated into DNA, have no such affect on cellular radiosensitivity.