第七章 射线的生物学效应等ppt课件

.,第七章射线的生物学效应及辐射剂量,.,辐射生物学效应辐射剂量应用放射治疗辐射育种辐射保鲜辐射杀虫、灭菌,.,Cells,Fourconcepts(collectivelyknownascelltheory):thecellisthebasicstructuralandfunctionalunitoflivingorganisms-definingcellpropertiesdefineslifetheactivityofanorganismisdependentonboththeindividualandcollectiveactivitiesofitscellsaccordingtotheprincipleofcomplementarity,thebiochemicalactivitiesofcellsaredeterminedandmadepossiblebyspecificsubcellularstructurescontinuityoflifehasacellularbasisThehumanbodyhas50-60trillioncells,.,ChemicalConstituencyofCells,WaterProteins蛋白质-aminoacidchains氨基酸链Carbohydrates碳水化合物-sugars,starches,etc.;Cx(H2O)Nucleicacids-DNA,RNALipids-fatsSalts-NaClandKCl,.,IdealizedSchematicofaCell,Twomajorsections:cytoplasmandnucleus,.,图24动物细胞亚显微结构示意图,图23植物细胞亚显微结构示意图,.,Cytoplasm细胞质,Cytoplasmcellularmaterialinsidetheplasmamembraneandoutsidethenucleusthesiteofmostmetabolicfunctionsofthecell:anabolism(buildingup)andcatabolism(breakingdown)oforganiccompoundsconsistsofthreemajorelements:Cytosol细胞液-viscoussemitransparentfluidthatsuspendstheorganelleswithinthecytoplasmOrganelles细胞器-membraneboundstructuresthatcompartmentalizethecytoplasmandallowthecelltooperateinahighlyorganizedmannerInclusions-chemicalsubstancessuchaslipiddropletsormelaningrains(notpresentinallcells;notfunctioningunits),.,TheCellNucleus,Largestorganelle(5mmdia.)thickermembraneandmoreviscousfluidContainsthenucleolus核仁andchromatin染色质Gene-containingcontrolcenterthecellbrainregulatescellularprocessesMostcellscontainonenucleus,however,someareanucleate(nonucleus)-redbloodcellscannotreproduce;dieafterafewmonthsmulti-nucleate(severalnuclei)-skeletalmusclecells,.,Chromosomes染色体,Genes（基因）,Chromatin（染色质）,DNA,LifesBuildingBlocks,.,DNA,DNA(deoxyribonucleicacid脱氧核糖核酸)isacoileddouble-helicalpolymer（聚合体）(strandsofproteinsandsugars)ThebaseunitofDNAiscalledthenucleotide（核苷酸）composedofadeoxyribose-sugarmoleculeslinkedtoaphosphategroup(adenine,guanine,cytosine,thymine),.,DNAandChromatin,Solenoid,Nucleosome,DNA,H1,CoreParticle,chromatiniscomposedofnearlyequalamountsofDNAandglobular（球状）histone（组蛋白）proteinshistonesprovideaphysicalmeansofpackagingtheDNAmoleculeinaverycompactandorderlyway;playsimportantroleingeneregulation,.,LevelsofDNAcondensation,DNAdouble-strandhelix.Chromatinstrand(DNAwithhistones).Condensedchromatinduringinterphase（间期）withcentromere（着丝点）.Condensedchromatinduringprophase.(TwocopiesoftheDNAmoleculearenowpresent)Chromosomeduringmetaphase.,.,Chromosomedetails,Itisdifficulttoappreciatedetailsofchromosomestructureevenwithanelectronmicroscope.However,onelabelthemwithdyesthatarepreferentiallytakenupbycertainregionsThesemodificationscreateabandingpatternthatcanbeusedtoidentifyandcharacterizeindividualchromosomes.,.,DNAandChromosomes,TounderstandhowtheDNAandhistonesareorganizedinachromosome,wemustappreciatethefactthatthenucleusisonly6micrometersindiameter.ThetotallengthofDNAinthehumangenomeis1.8meters.Thus,inordertopacktheDNAintothenucleusasinthephotographofthemetaphasechromosome,theremustbeseverallevelsofcoilingandsupercoiling.Thereisnearlya10,000-foldreductioninlengthinaninterphasenucleus.Eachchromosomecontains1longmoleculeofDNAplusassociatedhistones(basicproteins)whichhelpinthecondensationandregulationprocesses.,.,ChromosomeOrganization,Differentlevelsofuncoilinginthechromosomeareshown.4nmDNAfilamentsarelabeledtheDNAhelix.DoublestrandedDNAiswrappedaroundsetsof8histonestoforma10nmfilament.Setsof8histoneswrappedbyDNAareseparatedbyspacerregionsof4nmDNAfilament(doublestrandedDNA)andHistoneH1.arecallednucleosomes.Nnextlevelofcoilingproduces30nmnucleoproteinfibersFurtherloopingofnucleoproteinfibersaroundaproteinscaffoldformstheindividualmetaphasechromosomes,.,Genes,TheunitofgeneticmaterialresponsiblefordirectingcytoplasmicactivityandtransmittinghereditaryinformationEachgenecontainsafinitesectionofDNAwithspecificbasesequencecodingEachgenesoccupiesaspecificchromosomallocus,.,Chromosomes,EachchromosomecontainsmanygenesarrangedinaspecificlinearsequenceConstrictedatcertainpointsbyacentromere,aclearregionnecessaryformovementofthechromosomeduringcelldivisionChromosomesareconstantinnumberforeachspecies,.,RelativeSizesofGeneticMaterials,.,TheCellLifeCycle,TheseriesofchangesacellgoesthroughfromthetimeitisformeduntilitreproducesisitslifecycleThelifecycleiscomprisedoftwomajorperiods:Interphase间期cellgrowsandcarriesonitsusualactivitiesMitosis有丝分裂(mitoticphase)cellularreproduction,.,TheCellCycle,.,Interphase,The“growthphase”;preparingfornextdivisionTotalperiodfromcellformationtocelldivisionDuringInterphasethechromosomalmaterialisseenintheformofdiffusechromatinInterphaseisdividedintoG1,S,andG2sub-phases:G1-(1stgrowthperiod)cellssynthesizeproteinsandgrowvigorouslyS-(synthesis)replicationofDNAG2-(2ndgrowthperiod)enzymes酶/proteinsneededfordivisionaresynthesizedandmovedtotheirpropersites,.,DNAReplication,SphaseMustoccurbeforedivision,sothatidenticalcopiesofthecellsgenescanbepassedonProcessincludes:anenzymeuncoils,untwistsandseparatestheDNAmoleculeintotwocomplementarynucleotide核苷酸chainstwoidenticalstrandsofDNAresulteachstrandhashalfoftheoldDNAmoleculeandhalfisnewlysynthesized,.,Mitosis,CelldivisionDividedintofourdistinctphases:prophase(earlyandlate)metaphaseanaphasetelophase(andcytokinesis),.,TheCommonTheoryofBiologicalDamageResultingfromRadiationExposure,.,Review-EnergyLossbychargedparticles,Heavychargedparticleslosekineticenergyviaasequenceofsmallenergytransferstoatomicelectronsinthemedium.Mostenergydepositionoccursintheinfratrack,anarrowregionaroundtheparticletrackextendingabout10atomicdistances.Ionizationoutsidetheinfratrackiscausedbyveryenergeticparticlesthatescapefromtheinfratrackandsecondaryelectrons.Themoreenergeticinteractionsejectelectronsfromtheirparentatomsandgenerateprimaryion-pairs.AnapproximateexpressionforthemaximumenergytransfertoanelectronfromaheavychargedparticleofmassnumberAandenergyE(MeV)isgivenby:Wmax=215E/AwhereWmaxisineV.Thussecondaryelectronsgeneratedbya5MeValphaparticlerangeuptoabout300eVofkineticenergy.,.,EnergyLossbychargedparticles,Energeticsecondaryescaninitiateadditionalionizations,whilelessenergeticonesinduceelectronicexcitations.Lowestenergysecondaryesarereferredtoassub-excitation,whoseroleinbiologicalradiationdamageremainsunclear.Onlyasmallfractionofinitialenergyistransferredateachevent,atrackconsistingofclustersofionsorspursisgeneratedalongthepathofthemovingparticle.Mostspursinwatercomprise1-5ion-pairs.Thesetracksmaybevisualizedinacloudchamberbytheirvaportrail.High-energysecondaryelectronsareoccasionallygenerated.EnergylossbytheseenergeticelectronsleadstoshortbranchingtracksordeltaraysDeltaraysmayterminateinlargerpear-shapedregionsofionisationorblobs.Similarconsiderationsapplyforenergytransfertoafluidmediuminindirectaction.,.,EnergyLossbychargedparticles,Spursandexcitationsinthetrackofanalpha-particleinwater.Eachcircledepictsanionizationorexcitationevent.Thebranchingtracksaredeltarays.,100Angstrom,.,DistributionofIon-pairsinwaterfrompassageoffastelectronsandbetaparticles,Fastelectronsendsaresaidtobe“sticky”theyarecapableofreattachingtoanyotherbrokensegments(mostoftenrejoiningintheiroriginalconfiguration)breaksduringspecificphasesofmitosisresultindifferentendpoints(aswewillsee),.,Radiation-InducedAberrations,OccurwhencellisirradiatedbeforethechromosomematerialhasbeenduplicatedFrequencyofsingle-strandbreaksincreaseslinearlywithradiationdoseFrequencyofdouble-strandbreaksincreaseswithdoseasapowerfunction(powerof1.5to2),.,Radiation-InducedAberrations,Dose-rateeffectforsingle-strandbreakslowerdoseratesallowforgreaterprobabilityofrepairprovidedthereissufficienttimeforthesingle-strandbreaktoberepairedpriortotheformationofadouble-strandbreakinthevicinitythus,twoneighboringsingle-strandbreaks(identicaltoadouble-strandbreak)lesslikelypossibilityofa“threshold”doserate,.,Radiation-InducedAberrations,3majorlethalaberrationsdicentricringanaphasebridge2majornon-lethalaberrationstranslocationdeletion,.,Example:Dicentric双着丝(lethal),Stepsintheformationofadicentricandanacentricfragment,.,Example:Ring(Lethal),Stepsintheformationofachromosomalring,.,Example:Bridge(Lethal),Stepsintheformationofananaphasebridgeandanacentricfragment,.,Rearrangements,Notlethal;involvedincarcinogenesistranslocationbreaksintwochromosomesthestickyendsareexchangeddeletiontwobreaksinonechromosomeinformationbetweenthetwobreaksislost,.,SymmetricTranslocation(nonlethal),Pre-replicationchromosomesRadiationinducesbreaksinadjacentchromosomesBrokenpiecesexchangedNotnecessarilylethaltocellMayleadtocancerbecauseoflossofsuppressorgene(infragment),.,SmallInterstitialDeletion(nonlethal),Pre-replicationchromosomesRadiationinducesadjacentbreaksinchromosomeFragmentlostatnextmitosisNotnecessarilylethaltocellMayleadtocancerbecauseoflossofsuppressorgene(infragment),Acentricring,.,Implications,Potentialforsomeaberrationstoleadtodisease,i.e.cancerSpecifictranslocationshavebeenassociatedwithseveralhumanmalignanciesNon-lethalaberrationscanbedetectedinirradiatedpersonsforupto40yearsafterexposurebiologicaldosimeters,.,Implications,Theformationofadicentric,ring,orbridgeusuallyleadstocelldeath“Cellsurvivalcurves”areusedtoquantifytheeffect,.,FrequencyofChromosomalAberrations,Linear-quadraticfunctionofdoseAberrationsresultfrom2separatebreaks,.,CellSurvivalCurve,Thecurveischaracterizedbytworegions:linearregion(aD)double-strandbreakfromasingleentitytheprobabilityofthissingleeventisproportionaltodose(D)quadraticregion(bD2)two,single-strandbreaksfromtwodifferententitiestheprobabilityofthesetwoeventsisproportionaltodose*dose(D2),.,60,ReproductiveDeath,Celldeathcanhavedifferentmeanings:lossofaspecificfunction-differentiatedcells(nerve,muscle,secretorycells)lossoftheabilitytodivideindefinitelyproliferatingcellssuchasstemcells干细胞inhematopoietic造血systemorintestinalepitheliumlossofreproductiveintegrity-“reproductivedeath”,.,61,ReproductiveDeath,Converse-“Survival”-retentionofreproductiveintegritythecapacityforsustainedproliferationincellsthatnormallyproliferate,.,62,ReproductiveDeath,MitoticDeathorApoptosisEndresultthesamecelllosesabilitytoproliferateindefinitely,.,63,RelevantDose,100Gydestroyscellfunctioninnon-proliferatingsystems(forexample:nerve,musclecells)2Gymeanlethaldoseforlossofproliferativecapacity,.,64,SurvivalCurves,Describesrelationshipbetweenradiationdoseandthefractionofcellsthat“survive”thatdoseUsedtoassessbiologicaleffectivenessfordifferentradiationtypesTheshapeofsurvivalcurvesaretell-tale,.,65,SurvivalCurveShape,ThesearethegeneralshapesofsurvivalcurvesformammaliancellsexposedtoradiationSemi-logplotsaretypicalMoredetaillater,.,66,LinearEnergyTransfer(LET)传能线密度,LETistheaverageenergylocallyimparted(deposited)perunittracklength(keV/mm)Differentthan“stoppingpower”(energyloss)Trackaveragedvsenergyaveraged,Sometypicalvalues,.,67,EnergyDeposition,Low-LET(sparselyionizingradiation)x-raysgammabetas(higherenergy)High-LET(denselyionizingradiation)alphasbetas(lowerenergy)protonsneutrons,.,68,LETofChargedParticles,Energy,LET,.,69,PhotonEnergy-DepositionPaths,ClosestinshapeandstructuretothoseofbetasDistancebetweeninteractionsinoftenordersofmagnitudegreaterPhotonsaremuchmorepenetratingthanchargedparticles,.,70,LETofPhotons,LETofphotonstendstoincreasewithenergyveryhighenergiesareanexception,.,71,EnergyDepositionPathsforAlphasandBetas,AlphapathsaregenerallystraightwithveryconcentratedenergydepositionBetapathsareveryrandom,energydepositioninteractionsaremoredispersed,.,72,TypicalEnergyDepositionPathsforVariousRadiations,.,73,.,74,SurvivalCurvesandLET,IncreasingLET:increasestheslopeofthesurvivalcurveresultsinamorelinearcurveshoulderdisappearsduetoincreaseofkillingbysingle-events,.,75,CharacteristicsofSurvivalCurves,Low-LETradiations:lowdoseregionsurvivalcurvebeginsaslinearonsemi-logplotsurvivingfractionisanexponentialfunctionofdosemiddoseregionshoulderregionappearshighdoseregionsurvivalcurvebecomeslinearagainandsurvivingfractionreturnstoanexponentialfunctionofdosesurvivingfractionisadualexponential,S=e-(aD+bD2),.,76,CharacteristicsofSurvivalCurves,High-LETradiations:survivalcurveislinearsurvivingfractionisapureexponentialfunctionofdose,S=e-(aD),.,77,SurvivalCurveExplanation,SimpletoqualitativelydescribecurvesDifficultyliesinexplainingunderlyingbiophysicaleventsManymodelshavebeenproposedBiologicdatanotsufficientlyprecisetochooseamongthemodels,.,78,TwoGeneralSurvivalModels,Linear-quadratic线性二次型model“dualradiationaction”firstcomponent-cellkillingisproportionaltodosesecondcomponent-cellkillingisproportionaltodosesquaredMulti-targetmodelbasedonprobabilityofhittingthe“target”widelyusedformanyyears;stillhasmerit,.,79,LinearQuadraticModel,S=e-(aD+bD2)where:SrepresentsthefractionofcellssurvivingDrepresentsdoseaandbareconstantsthatcharacterizetheslopesofthetwolinearportionsofthesemi-logsurvivalcurvebiologicalendpointiscelldeath,.,80,LinearQuadraticModel,LinearandquadraticcontributionstocellkillingareequalwhenthedoseisequaltotheratioofatobD=a/boraD=bD2acomponentisrepresentativeofdamagecausedbyasingleevent(hit,double-strandbreak,“initiation/promotion”,etc.)bcomponentisrepresentativeofdamagecausedbymultipleevents(hit/hit,2strandbreaks,initiationthenpromotion,etc.),.,81,aandbDetermination,100,10-1,10-2,0,12,3,6,9,a/b,bD2,aD,Dose,Gy,Survival,.,82,Multi-targetModel,Quantifiedintermsof:measureofinitialslopeduetosingle-eventkilling,D1measureoffinalslopeduetomultiple-eventkilling,D0widthoftheshoulder,DqornD1andD0arereciprocalsoftheinitialandfinalslopesthedosesrequiredtoreducethefractionofsurvivingcellsby37%thedoserequiredtodeliver,onaverage,oneinactivatingeventpercell,.,83,Why37%?,S=exp-aD,buthowdowedefinea?ifwedefineaastheslope,wherea=x/D0,thenxisthefractionalreductionofsurvivingcellsifallcellsareassumedtotakeonelethalhit,thenx=1anda=1/D0,sothatS=exp-D/D0=e-1=0.37Inradiationtherapy,itisusefultocalculatethemulti-fractioneddoserequiredtokill90%ofthepopulation(10%survival)0.1=exp-D10/D0D10=2.3D0,.,84,Multi-targetModel,Shoulder-widthmeasures:thequasi-thresholddose(Dq)thedoseatwhichtheextrapolatedlinefromthestraightportionofthesurvivalcurve(finalslope)crossesthedoseaxisat100%survivaltheextrapolationnumber(n)“broadshoulder”resultsinlargervalueofn“narrowshoulder”resultsinsmallvalueofnn=expDq/D0,.,85,Multi-TargetModel,Dose,Gy,100,10-1,10-4,0,12,3,6,9,Survival,10-3,10-2,Initialslopemeasure,D1,duetosingle-eventkilling,Finalslopemeasure,D0,duetomultiple-eventkilling,Dq,n,norDqrepresentsthesizeorwidthoftheshoulder,.,86,ModelParameters,Linear-QuadraticModel,Multi-TargetModel,.,87,RelativeBiologicalEffectiveness相对生物效应,Relatesbiologicaleffecttoa“standard”neededbecauseequalenergydepositionevents(doses)fromdifferentradiationsdonotproduceequaleffectsinbiologicalsystemsDefinition:RBEisdefinedastheratioofthestandarddosetothetestdoserequiredforequalbiologicaleffect2standards:250kVpxrays;60Cograysforexample:LD50for250kVpx-rays=6Gy(thestandard)LD50for2MeVneutrons=3Gy(thetestradiation)thus,theRBEfor2MeVneutronsis2,.,88,RBEandFractionatedDoses,WhathappenstotheRBEforneutronswhenthedoseisfractionated?,.,89,RBEandFractionatedDoses,FractionatingthedoseincreasestheRBEforneutrons,notbecauseitincreasesthedamagedonebyneutrons,butbecauseitdecreasestheeffectofx-rays,endpoint=1%survival,.,90,RBEforDifferentCells/Tissues,RBEalsovariesdependingontissuetypeandbiologicalendpointCellshavingaphotonsurvivalcurvewithalargeshoulder,indicatingthattheycanincurandrepairalargeamountofsublethalradiationdamage,showalargeRBEforneutronsCellshavingasmallshoulderintheirphotonsurvivalcurvehavesmallneutronRBEvaluesPhotonresponseimpactsneutronRBE,.,91,VariabilityinRBE,RBEdependsonmanymorefactors:radiationqualitybiologicalendpointbiologicalsystemchoiceofradiation“standard”radiationdoseanddoseratenumberofdosefractions(producingmostbiologicaleffectperunitdoseseparationbetweenionizingeventsthediameterofDNAdoublehelixhighestprobabilityofdoublestrandbreakperunitdoseMoredenselyionizingradiationisjustaseffectivepertracklength,butlesseffectiveperunitdosesometimesreferredtoas“overkill”,.,94,CellSurvivalatVariousStagesofCellCycle-ChineseHamsterCells,Dose(rad),600,800,1000,1200,1400,0.001,0,200,400,0.01,0.1,1.0,Single-CellSurvival,0.0005,M,ES,G2,LS,Mx2.5(hypoxic),G1,.,95,SurvivingFractionofHeLaCells(3Gy),Time(hoursaftershake-off),10,14,18,22,0.1,0,2,6,0.2,0.3,0.4,0.5,Colony-SurvivingFraction,0,M,S,.,96,Radiosensitivity&MitoticCycle,Radiosensitivity(generally)cellsaremostsensitiveclosetomitosisresistanceisgreatestinlatterpartofS-phaseforlongG1-phases,resistanceearlyfollowedbysensitivitylateG2andMequallysensitiveRepairislikelythekey,.,97,MolecularCheckpointGenes,CellularprogressionthroughcycleiscontrolledbycheckpointgenestoensurecompletionofeventspriortoprogressionatG2,cellsarehaltedtoinventory&repairdamagebeforemitosiscellswherecheckpointgeneisinactivated.movedirectlytomitosis,evenwithdamagedchromosomesaremoresensitivetoUVorionizingradiation(oranyDNAdamagingagent),.,98,LifeCycle&CheckpointGenes,G2,M,S,G1,.,99,EffectsofOxygenation,Oxygenenhancementratio(OER)aeratedcellsaremoreradiosensitive(dueto“fixing”)oxygenreactswithfreeradicalstoproduceperoxide,whichconstitutesnon-repairabledamagetypicalvalues:2.5-3forgandx-raysG1:2.3S:2.8G2:intermediate(1.5)Providesimplicationsforradiationtherapymodes,.,100,UtilizingCycleSensitivityinTumorTherapy,TumorcellsinitiallyasynchronousDosedeliveredMostsensitivecells(Mphase)killedPopulationis(roughly)synchronizedCellsallowedtoprogress“Sensitized”cyclingpopulation.,.,辐射剂量,.,一、辐射场的定义和相关要素,电离辐射场就是电离辐射在其中通过、传播乃至经由相互作用传递辐射能量的整个空间范围。从广义上讲，辐射场涉及的范围是无限的。在狭义上，我们通常关心的某辐射场常常是具体的和有限的。,.,辐射场性质的内涵包括：1、辐射场的类型（辐射场，辐射场，辐射场、中子辐射场和混合辐射场等）；2、粒子的能量（单能辐射场、具有能量分布的辐射场）；3、粒子的运动方向（单向辐射场、多向辐射场）。简单来说就是位置、时间、方向、类型和能量等五个要素。,.,辐射场的描述电离辐射居留的空间称为电离辐射场。常用以下量来描述：,粒子数:发射，转移或接收的粒子数目。粒子数的单位是1。辐射能:发射，转移或接收粒子的能量（不包括静止能）。辐射能的单位是J粒子数密度:单位体积中的粒子数目，是表征辐射场疏密程度的物理量n=dN/dV单位是m-3辐射场中每一个粒子都具有一定的能量，将所有粒子能量（不包括静止能量）求和，即得辐射能,.,粒子注量（率）和能量注量（率）,粒子注量：T时间内，进入以r点为球心的单位截面积小球的粒子数，