第七章射线的生物学效应等演示文稿

第七章射线的生物学效应等演示文稿本文档共313页；当前第1页；编辑于星期三\9点33分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、灭菌本文档共313页；当前第2页；编辑于星期三\9点33分CellsFourconcepts(collectivelyknownascelltheory):thecellisthebasicstructuralandfunctionalunitoflivingorganisms-definingcellpropertiesdefineslifetheactivityofanorganismisdependentonboththeindividualandcollectiveactivitiesofitscellsaccordingtotheprincipleofcomplementarity,thebiochemicalactivitiesofcellsaredeterminedandmadepossiblebyspecificsubcellularstructurescontinuityoflifehasacellularbasisThehumanbodyhas~50-60trillioncells本文档共313页；当前第3页；编辑于星期三\9点33分ChemicalConstituencyofCellsWaterProteins蛋白质

-aminoacidchains氨基酸链Carbohydrates碳水化合物

-sugars,starches,etc.;Cx(H2O)Nucleicacids-DNA,RNALipids-fatsSalts-NaClandKCl本文档共313页；当前第4页；编辑于星期三\9点33分IdealizedSchematicofaCellTwomajorsections:cytoplasmandnucleus本文档共313页；当前第5页；编辑于星期三\9点33分图2—4动物细胞亚显微结构示意图图2—3植物细胞亚显微结

构示意图本文档共313页；当前第6页；编辑于星期三\9点33分Cytoplasm细胞质Cytoplasmcellularmaterialinsidetheplasmamembraneandoutsidethenucleusthesiteofmostmetabolicfunctionsofthecell:anabolism(buildingup)andcatabolism(breakingdown)oforganiccompoundsconsistsofthreemajorelements:Cytosol细胞液-viscoussemitransparentfluidthatsuspendstheorganelleswithinthecytoplasmOrganelles细胞器

-membraneboundstructuresthatcompartmentalizethecytoplasmandallowthecelltooperateinahighlyorganizedmannerInclusions-chemicalsubstancessuchaslipiddropletsormelaningrains(notpresentinallcells;notfunctioningunits)本文档共313页；当前第7页；编辑于星期三\9点33分TheCellNucleusLargestorganelle(~5mmdia.)thickermembraneandmoreviscousfluidContainsthenucleolus核仁andchromatin染色质

Gene-containingcontrolcenterthecellbrainregulatescellularprocessesMostcellscontainonenucleus,however,someareanucleate(nonucleus)-redbloodcellscannotreproduce;dieafterafewmonthsmulti-nucleate(severalnuclei)-skeletalmusclecells本文档共313页；当前第8页；编辑于星期三\9点33分Chromosomes染色体Genes（基因）Chromatin（染色质）DNALife’sBuildingBlocks本文档共313页；当前第9页；编辑于星期三\9点33分DNADNA(deoxyribonucleicacid脱氧核糖核酸)isacoileddouble-helicalpolymer（聚合体）(strandsofproteinsandsugars)ThebaseunitofDNAiscalledthenucleotide（核苷酸）composedofadeoxyribose-sugarmoleculeslinkedtoaphosphategroup(adenine,guanine,cytosine,thymine)本文档共313页；当前第10页；编辑于星期三\9点33分DNAandChromatinSolenoidNucleosomeDNAH1CoreParticlechromatiniscomposedofnearlyequalamountsofDNAandglobular（球状）histone（组蛋白）proteinshistonesprovideaphysicalmeansofpackagingtheDNAmoleculeinaverycompactandorderlyway;playsimportantroleingeneregulation本文档共313页；当前第11页；编辑于星期三\9点33分LevelsofDNAcondensationDNAdouble-strandhelix.Chromatinstrand(DNAwithhistones).Condensedchromatinduringinterphase（间期）withcentromere（着丝点）.Condensedchromatinduringprophase.(TwocopiesoftheDNAmoleculearenowpresent)Chromosomeduringmetaphase.本文档共313页；当前第12页；编辑于星期三\9点33分ChromosomedetailsItisdifficulttoappreciatedetailsofchromosomestructureevenwithanelectronmicroscope.However,onelabelthemwithdyesthatarepreferentiallytakenupbycertainregionsThesemodificationscreateabandingpatternthatcanbeusedtoidentifyandcharacterizeindividualchromosomes.本文档共313页；当前第13页；编辑于星期三\9点33分DNAandChromosomesTounderstandhowtheDNAandhistonesareorganizedinachromosome,wemustappreciatethefactthatthenucleusisonly6micrometersindiameter.ThetotallengthofDNAinthehumangenomeis1.8meters.Thus,inordertopacktheDNAintothenucleusasinthephotographofthemetaphasechromosome,theremustbeseverallevelsofcoilingandsupercoiling.Thereisnearlya10,000-foldreductioninlengthinaninterphasenucleus.Eachchromosomecontains1longmoleculeofDNAplusassociatedhistones(basicproteins)whichhelpinthecondensationandregulationprocesses.本文档共313页；当前第14页；编辑于星期三\9点33分ChromosomeOrganizationDifferentlevelsofuncoilinginthechromosomeareshown.4nmDNAfilamentsarelabeledthe"DNAhelix".DoublestrandedDNAiswrappedaroundsetsof8histonestoforma10nmfilament.Setsof8histoneswrappedbyDNAareseparatedbyspacerregionsof4nmDNAfilament(doublestrandedDNA)andHistoneH1.arecalled"nucleosomes".Nnextlevelofcoilingproduces30nmnucleoproteinfibersFurtherloopingofnucleoproteinfibersaroundaproteinscaffoldformstheindividualmetaphasechromosomes本文档共313页；当前第15页；编辑于星期三\9点33分GenesTheunitofgeneticmaterialresponsiblefordirectingcytoplasmicactivityandtransmittinghereditaryinformationEachgenecontainsafinitesectionofDNAwithspecificbasesequencecodingEachgenesoccupiesaspecificchromosomallocus本文档共313页；当前第16页；编辑于星期三\9点33分ChromosomesEachchromosomecontainsmanygenesarrangedinaspecificlinearsequenceConstrictedatcertainpointsbyacentromere,aclearregionnecessaryformovementofthechromosomeduringcelldivisionChromosomesareconstantinnumberforeachspecies本文档共313页；当前第17页；编辑于星期三\9点33分RelativeSizesofGeneticMaterials本文档共313页；当前第18页；编辑于星期三\9点33分TheCellLifeCycleTheseriesofchangesacellgoesthroughfromthetimeitisformeduntilitreproducesisitslifecycleThelifecycleiscomprisedoftwomajorperiods:Interphase间期cellgrowsandcarriesonitsusualactivitiesMitosis有丝分裂(mitoticphase)cellularreproduction本文档共313页；当前第19页；编辑于星期三\9点33分TheCellCycle本文档共313页；当前第20页；编辑于星期三\9点33分InterphaseThe“growthphase”;preparingfornextdivisionTotalperiodfromcellformationtocelldivisionDuringInterphasethechromosomalmaterialisseenintheformofdiffusechromatinInterphaseisdividedintoG1,S,andG2sub-phases:G1-(1stgrowthperiod)cellssynthesizeproteinsandgrowvigorouslyS-(synthesis)replicationofDNAG2-(2ndgrowthperiod)enzymes酶/proteinsneededfordivisionaresynthesizedandmovedtotheirpropersites本文档共313页；当前第21页；编辑于星期三\9点33分DNAReplicationSphaseMustoccurbeforedivision,sothatidenticalcopiesofthecell’sgenescanbepassedonProcessincludes:anenzymeuncoils,untwistsandseparatestheDNAmoleculeintotwocomplementarynucleotide核苷酸chainstwoidenticalstrandsofDNAresulteachstrandhashalfoftheoldDNAmoleculeandhalfisnewlysynthesized本文档共313页；当前第22页；编辑于星期三\9点33分MitosisCelldivisionDividedintofourdistinctphases:prophase(earlyandlate)metaphaseanaphase

telophase(andcytokinesis)本文档共313页；当前第23页；编辑于星期三\9点33分TheCommonTheoryofBiologicalDamageResultingfromRadiationExposure本文档共313页；当前第24页；编辑于星期三\9点33分Review-EnergyLossbychargedparticlesHeavychargedparticleslosekineticenergyviaasequenceofsmallenergytransferstoatomicelectronsinthemedium.Mostenergydepositionoccursintheinfratrack,anarrowregionaroundtheparticletrackextendingabout10atomicdistances.Ionizationoutsidetheinfratrackiscausedbyveryenergeticparticlesthatescapefromtheinfratrackandsecondaryelectrons.Themoreenergeticinteractionsejectelectronsfromtheirparentatomsandgenerateprimaryion-pairs.AnapproximateexpressionforthemaximumenergytransfertoanelectronfromaheavychargedparticleofmassnumberAandenergyE(MeV)isgivenby:Wmax=215E/AwhereWmaxisineV.Thussecondaryelectronsgeneratedbya5MeValphaparticlerangeuptoabout300eVofkineticenergy.本文档共313页；当前第25页；编辑于星期三\9点33分EnergyLossbychargedparticlesEnergeticsecondarye’scaninitiateadditionalionizations,whilelessenergeticonesinduceelectronicexcitations.Lowestenergysecondarye’sarereferredtoas"sub-excitation",whoseroleinbiologicalradiationdamageremainsunclear.Onlyasmallfractionofinitialenergyistransferredateachevent,atrackconsistingofclustersofionsorspursisgeneratedalongthepathofthemovingparticle.Mostspursinwatercomprise1-5ion-pairs.Thesetracksmaybevisualizedinacloudchamberbytheirvaportrail.High-energysecondaryelectronsareoccasionallygenerated.Energylossbytheseenergeticelectronsleadstoshortbranchingtracksor"deltarays"Deltaraysmayterminateinlargerpear-shapedregionsofionisationor"blobs".Similarconsiderationsapplyforenergytransfertoafluidmediuminindirectaction.本文档共313页；当前第26页；编辑于星期三\9点33分EnergyLossbychargedparticlesSpursandexcitationsinthetrackofanalpha-particleinwater.Eachcircledepictsanionizationorexcitationevent.Thebranchingtracksare"deltarays".100Angstrom本文档共313页；当前第27页；编辑于星期三\9点33分DistributionofIon-pairsinwaterfrompassageoffastelectronsandbetaparticlesFastelectrons&betasloseenergybyinelasticcollisionswithelectronsofthemedium.Electronstracksarelessdensethanthetracksofheavychargedparticles,owingtothelowerLET,andthespursaremorewidelyspacedwithmorefrequentdeltaraysterminatingwithblobs.Onlyabout20%ofbetaparticlespenetratetothemaximumrangeowingtotheirbroadenergydistribution.Inadditiontoenergydeposition,electronsundergoelasticelectron-electroncollisionsleadingtomultiplescatteringandcurvatureofthetrackswhichcomplicatethedosimetryinextendedsources本文档共313页；当前第28页；编辑于星期三\9点33分Shorttracks>5000eV<5000eVPrimarypathSpurs100to500eVblobs<100eVDeltaRaysBranchtracksIonpaircreationinwaterfromSecondaryElectrons本文档共313页；当前第29页；编辑于星期三\9点33分DirectandIndirectActionBiologicaleffectsofradiationresultprincipallyfromdamagetotheDNADNAisthe“criticaltarget”Targetcanreceivedirectdamagedbyphysicalinteractionwithradiation,orindirectdamagedbyfreeradicalsformedwhenradiationinteractswithwatermoleculesinthecell本文档共313页；当前第30页；编辑于星期三\9点33分DirectActionPhysicalinteractionthatdirectlyionizestheDNAmoleculeDNAdamageresultsfromthephysicalbreakageofchemicalbondswithintheDNAbackboneNucleotidebonds,phosphatebondsorstrandbreaksmayresultfromradiationdamageThisdamagemayormaynotberepairable本文档共313页；当前第31页；编辑于星期三\9点33分IndirectActionH2O+hn-->H2O++e--->H•+•OHChemicalinteractionsH2O+isanion(charged)electronejectedfromthewatermolecule•OHisthehydroxyradicalafreeradicalhasanunpairedelectronfromabrokencovalentbondandisveryreactivemustbeincloseproximitytoDNAtodoitsdamagebychemicalreaction本文档共313页；当前第32页；编辑于星期三\9点33分DirectandIndirectAction:

Neutrons本文档共313页；当前第33页；编辑于星期三\9点33分DirectandIndirectAction:

PhotonsIndirectActionDominantforLowLETRadiation本文档共313页；当前第34页；编辑于星期三\9点33分EnergyAbsorptioninRadiobiologyEnergyisabsorbed,butdamageisdonebybreakingchemicalbondsEnergydepositedincellsandtissuesunevenlyindiscretepacketsaverageabsorptionperionizingevent~34eVtypicalC=Cbindingenergy4.9eVremaindergoesintootherionization,excitation,andbiologicaldamage本文档共313页；当前第35页；编辑于星期三\9点33分TimeScaleofEventsInitialionization:~10-15secFree-ionlifetime:~10-10secFree-radicallifetime:~10-5secBreakageofbondsandexpressionofbiologicaleffectscelldeath:hourstodaysoncogenesis:yearsgermcellmutation:generations本文档共313页；当前第36页；编辑于星期三\9点33分ClassicParadigmofRadiationInjury←1s→←min-hrs→←days→←weeks→←months→←years→←generations→IonizingRadiationDNADamageCellDeathDNAMutationHeritableEffectsCancerDevelopmentaleffects(fetal)LateeffectsChemicalRepair(ionsrecombine)Ionizations(freeradicalformation,etc)ExcitationsHeatEnzymaticDNARepairEarly(Acute)Effects(Radiationsickness)本文档共313页；当前第37页；编辑于星期三\9点33分DNAStrandBreaksDNAcansuffersingleanddoublestrandbreaksStrongcircumstantialevidencethatDNAisprincipaltargetforcellkillingAsingle-strandbreakoccurswhenonlyoneofthehelicessuffersabreakAdouble-strandbreakoccurswhenbothhelicessufferabreakeitherdirectlyoppositeoneanotherorwhenseparatedbyonlyafewbasepairs本文档共313页；当前第38页；编辑于星期三\9点33分DiagramofsingleanddoublestrandDNAbreaksGGGGCCCCAAATTT2nmBlob7nmdiameter,12ionpairsSpur4nmdiameter,3ionpairs本文档共313页；当前第39页；编辑于星期三\9点33分DiagramofsingleanddoublestrandDNAbreaksGGGGCCCCAAATTTSinglestrandbreak本文档共313页；当前第40页；编辑于星期三\9点33分DiagramofsingleanddoublestrandDNAbreaksGGGGCCCCAAATTTWellseparateddoublestrandbreak本文档共313页；当前第41页；编辑于星期三\9点33分DiagramofsingleanddoublestrandDNAbreaksGGGCCCCAAATTTAdjacentdoublestrandbreakGGGGCCCAAATTT本文档共313页；当前第42页；编辑于星期三\9点33分Single-StrandBreaksReadilyrepairedusuallydoesnotleadtomutationsorcelldeathImproperrepairispossiblenormallyleadstomutationsordeath本文档共313页；当前第43页；编辑于星期三\9点33分Double-StrandBreaksDifficultorimpossibletorepairmayleadtoprogrammedcelldeath(apoptosis),mutationorcarcinogenesisIfnotrepaired,orrepairisinerror,mutationsmaybereplicatedmayleadtocellsthatfunctionimproperlyandhaveunregulatedcellgrowth(e.g.,cancer)本文档共313页；当前第44页；编辑于星期三\9点33分FragmentBehavior(post-break)RepairbreaksmayrejoinintheiroriginalconfigurationAberrationbreaksmayfailtorejoinbrokenendsmayrejoinotherbrokenends,etcoccursatnextmitosis本文档共313页；当前第45页；编辑于星期三\9点33分ChromosomalAberrationsOftencausedbybreakageandincorrectrejoiningbrokensegmentsmayremainseparatedfromminutestohours;endsaresaidtobe“sticky”theyarecapableofreattachingtoanyotherbrokensegments(mostoftenrejoiningintheiroriginalconfiguration)breaksduringspecificphasesofmitosisresultindifferentendpoints(aswewillsee)本文档共313页；当前第46页；编辑于星期三\9点33分Radiation-InducedAberrationsOccurwhencellisirradiatedbeforethechromosomematerialhasbeenduplicatedFrequencyofsingle-strandbreaksincreaseslinearlywithradiationdoseFrequencyofdouble-strandbreaksincreaseswithdoseasapowerfunction(powerof~1.5to2)本文档共313页；当前第47页；编辑于星期三\9点33分Radiation-InducedAberrationsDose-rateeffectforsingle-strandbreakslowerdoseratesallowforgreaterprobabilityofrepairprovidedthereissufficienttimeforthesingle-strandbreaktoberepairedpriortotheformationofadouble-strandbreakinthevicinitythus,twoneighboringsingle-strandbreaks(identicaltoadouble-strandbreak)lesslikelypossibilityofa“threshold”doserate本文档共313页；当前第48页；编辑于星期三\9点33分Radiation-InducedAberrations3majorlethalaberrationsdicentricringanaphasebridge2majornon-lethalaberrationstranslocationdeletion本文档共313页；当前第49页；编辑于星期三\9点33分Example:Dicentric双着丝(lethal)Stepsintheformationofadicentricandanacentricfragment本文档共313页；当前第50页；编辑于星期三\9点33分Example:Ring(Lethal)Stepsintheformationofachromosomalring本文档共313页；当前第51页；编辑于星期三\9点33分Example:Bridge(Lethal)Stepsintheformationofananaphasebridgeandanacentricfragment本文档共313页；当前第52页；编辑于星期三\9点33分RearrangementsNotlethal;involvedincarcinogenesistranslocationbreaksintwochromosomesthestickyendsareexchangeddeletiontwobreaksinonechromosomeinformationbetweenthetwobreaksislost本文档共313页；当前第53页；编辑于星期三\9点33分SymmetricTranslocation(nonlethal)Pre-replicationchromosomesRadiationinducesbreaksinadjacentchromosomesBrokenpiecesexchangedNotnecessarilylethaltocellMayleadtocancerbecauseoflossofsuppressorgene(infragment)本文档共313页；当前第54页；编辑于星期三\9点33分SmallInterstitialDeletion(nonlethal)Pre-replicationchromosomesRadiationinducesadjacentbreaksinchromosomeFragmentlostatnextmitosisNotnecessarilylethaltocellMayleadtocancerbecauseoflossofsuppressorgene(infragment)Acentricring本文档共313页；当前第55页；编辑于星期三\9点33分ImplicationsPotentialforsomeaberrationstoleadtodisease,i.e.cancerSpecifictranslocationshavebeenassociatedwithseveralhumanmalignanciesNon-lethalaberrationscanbedetectedinirradiatedpersonsforupto40yearsafterexposurebiologicaldosimeters本文档共313页；当前第56页；编辑于星期三\9点33分ImplicationsTheformationofadicentric,ring,orbridgeusuallyleadstocelldeath“Cellsurvivalcurves”areusedtoquantifytheeffect本文档共313页；当前第57页；编辑于星期三\9点33分FrequencyofChromosomalAberrationsLinear-quadraticfunctionofdoseAberrationsresultfrom2separatebreaks本文档共313页；当前第58页；编辑于星期三\9点33分CellSurvivalCurveThecurveischaracterizedbytworegions:linearregion(aD)double-strandbreakfromasingleentitytheprobabilityofthissingleeventisproportionaltodose(D)quadraticregion(bD2)two,single-strandbreaksfromtwodifferententitiestheprobabilityofthesetwoeventsisproportionaltodose*dose(D2)本文档共313页；当前第59页；编辑于星期三\9点33分ReproductiveDeathCelldeathcanhavedifferentmeanings:lossofaspecificfunction-differentiatedcells(nerve,muscle,secretorycells)lossoftheabilitytodivideindefinitely–proliferatingcellssuchasstemcells干细胞inhematopoietic造血systemorintestinalepitheliumlossofreproductiveintegrity-“reproductivedeath”60本文档共313页；当前第60页；编辑于星期三\9点33分ReproductiveDeathConverse-“Survival”-retentionofreproductiveintegritythecapacityforsustainedproliferationincellsthatnormallyproliferate61本文档共313页；当前第61页；编辑于星期三\9点33分ReproductiveDeathMitoticDeathorApoptosisEndresultthesame–celllosesabilitytoproliferateindefinitely62本文档共313页；当前第62页；编辑于星期三\9点33分RelevantDose100Gydestroyscellfunctioninnon-proliferatingsystems(forexample:nerve,musclecells)2Gymeanlethaldoseforlossofproliferativecapacity63本文档共313页；当前第63页；编辑于星期三\9点33分SurvivalCurvesDescribesrelationshipbetweenradiationdoseandthefractionofcellsthat“survive”thatdoseUsedtoassessbiologicaleffectivenessfordifferentradiationtypesTheshapeofsurvivalcurvesaretell-tale64本文档共313页；当前第64页；编辑于星期三\9点33分SurvivalCurveShapeThesearethegeneralshapesofsurvivalcurvesformammaliancellsexposedtoradiationSemi-logplotsaretypicalMoredetaillater65本文档共313页；当前第65页；编辑于星期三\9点33分LinearEnergyTransfer(LET)传能线密度LETistheaverageenergylocallyimparted(deposited)perunittracklength(keV/mm)Differentthan“stoppingpower”(energyloss)TrackaveragedvsenergyaveragedSometypicalvalues66本文档共313页；当前第66页；编辑于星期三\9点33分EnergyDepositionLow-LET(sparselyionizingradiation)x-raysgammabetas(higherenergy)High-LET(denselyionizingradiation)alphasbetas(lowerenergy)protonsneutrons67本文档共313页；当前第67页；编辑于星期三\9点33分LETofChargedParticlesEnergyLET68本文档共313页；当前第68页；编辑于星期三\9点33分PhotonEnergy-DepositionPathsClosestinshapeandstructuretothoseofbetasDistancebetweeninteractionsinoftenordersofmagnitudegreaterPhotonsaremuchmorepenetratingthanchargedparticles69本文档共313页；当前第69页；编辑于星期三\9点33分LETofPhotonsLETofphotonstendstoincreasewithenergyveryhighenergiesareanexception70本文档共313页；当前第70页；编辑于星期三\9点33分EnergyDepositionPathsforAlphasandBetasAlphapathsaregenerallystraightwithveryconcentratedenergydepositionBetapathsareveryrandom,energydepositioninteractionsaremoredispersed71本文档共313页；当前第71页；编辑于星期三\9点33分TypicalEnergyDepositionPathsforVariousRadiations72本文档共313页；当前第72页；编辑于星期三\9点33分73本文档共313页；当前第73页；编辑于星期三\9点33分SurvivalCurvesandLETIncreasingLET:increasestheslopeofthesurvivalcurveresultsinamorelinearcurveshoulderdisappearsduetoincreaseofkillingbysingle-events74本文档共313页；当前第74页；编辑于星期三\9点33分CharacteristicsofSurvivalCurvesLow-LETradiations:lowdoseregionsurvivalcurvebeginsaslinearonsemi-logplotsurvivingfractionisanexponentialfunctionofdosemiddoseregionshoulderregionappearshighdoseregionsurvivalcurvebecomeslinearagainandsurvivingfractionreturnstoanexponentialfunctionofdosesurvivingfractionisadualexponentialS=e-(aD+bD2)75本文档共313页；当前第75页；编辑于星期三\9点33分CharacteristicsofSurvivalCurvesHigh-LETradiations:survivalcurveislinearsurvivingfractionisapureexponentialfunctionofdoseS=e-(aD)76本文档共313页；当前第76页；编辑于星期三\9点33分SurvivalCurveExplanationSimpletoqualitativelydescribecurvesDifficultyliesinexplainingunderlyingbiophysicaleventsManymodelshavebeenproposedBiologicdatanotsufficientlyprecisetochooseamongthemodels77本文档共313页；当前第77页；编辑于星期三\9点33分TwoGeneralSurvivalModelsLinear-quadratic线性二次型model“dualradiationaction”firstcomponent-cellkillingisproportionaltodosesecondcomponent-cellkillingisproportionaltodosesquaredMulti-targetmodelbasedonprobabilityofhittingthe“target”widelyusedformanyyears;stillhasmerit78本文档共313页；当前第78页；编辑于星期三\9点33分LinearQuadraticModelS=e-(aD+bD2)where:SrepresentsthefractionofcellssurvivingDrepresentsdose

aandbareconstantsthatcharacterizetheslopesofthetwolinearportionsofthesemi-logsurvivalcurvebiologicalendpointiscelldeath79本文档共313页；当前第79页；编辑于星期三\9点33分LinearQuadraticModelLinearandquadraticcontributionstocellkillingareequalwhenthedoseisequaltotheratioofatobD=a/boraD=bD2

acomponentisrepresentativeofdamagecausedbyasingleevent(hit,double-strandbreak,“initiation/promotion”,etc.)

bcomponentisrepresentativeofdamagecausedbymultipleevents(hit/hit,2strandbreaks,initiationthenpromotion,etc.)80本文档共313页；当前第80页；编辑于星期三\9点33分aandbDetermination10010-110-2012369a/bbD2aDDose,GySurvival81本文档共313页；当前第81页；编辑于星期三\9点33分Multi-targetModelQuantifiedintermsof:measureofinitialslopeduetosingle-eventkilling,D1measureoffinalslopeduetomultiple-eventkilling,D0widthoftheshoulder,DqornD1andD0arereciprocalsoftheinitialandfinalslopesthedosesrequiredtoreducethefractionofsurvivingcellsby37%thedoserequiredtodeliver,onaverage,oneinactivatingeventpercell82本文档共313页；当前第82页；编辑于星期三\9点33分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/D0]D10=2.3D083本文档共313页；当前第83页；编辑于星期三\9点33分Multi-targetModelShoulder-widthmeasures:thequasi-thresholddose(Dq)thedoseatwhichtheextrapolatedlinefromthestraightportionofthesurvivalcurve(finalslope)crossesthedoseaxisat100%survivaltheextrapolationnumber(n)“broadshoulder”resultsinlargervalueofn“narrowshoulder”resultsinsmallvalueofnn=exp[Dq

/D0]84本文档共313页；当前第84页；编辑于星期三\9点33分Multi-TargetModelDose,Gy10010-110-4012369Survival10-310-2Initialslopemeasure,D1,duetosingle-eventkillingFinalslopemeasure,D0,duetomultiple-eventkillingDqnnorDqrepresentsthesizeorwidthoftheshoulder85本文档共313页；当前第85页；编辑于星期三\9点33分ModelParametersLinear-QuadraticModelMulti-TargetModel86本文档共313页；当前第86页；编辑于星期三\9点33分RelativeBiologicalEffectiveness

相对生物效应Relatesbiologicaleffecttoa“standard”neededbecauseequalenergydepositionevents(doses)fromdifferentradiationsdonotproduceequaleffectsinbiologicalsystemsDefinition:RBEisdefinedastheratioofthestandarddosetothetestdoserequiredforequalbiologicaleffect2standards:250kVpxrays;60Cograysforexample:LD50for250kVpx-rays=6Gy(thestandard)LD50for2MeVneutrons=3Gy(thetestradiation)thus,theRBEfor2MeVneutronsis

287本文档共313页；当前第87页；编辑于星期三\9点33分RBEandFractionatedDosesWhathappenstotheRBEforneutronswhenthedoseisfractionated?endpoint=1%survival88本文档共313页；当前第88页；编辑于星期三\9点33分RBEandFractionatedDosesFractionatingthedoseincreasestheRBEforneutrons,notbecauseitincreasesthedamagedonebyneutrons,butbecauseitdecreasestheeffectofx-raysendpoint=1%survival89本文档共313页；当前第89页；编辑于星期三\9点33分RBEforDifferentCells/TissuesRBEalsovariesdependingontissuetypeandbiologicalendpointCellshavingaphotonsurvivalcurvewithalargeshoulder,indicatingthattheycanincurandrepairalargeamountofsublethalradiationdamage,showalargeRBEforneutronsCellshavingasmallshoulderintheirphotonsurvivalcurvehavesmallneutronRBEvaluesPhotonresponseimpactsneutronRBE90本文档共313页；当前第90页；编辑于星期三\9点33分VariabilityinRBERBEdependsonmanymorefactors:radiationqualitybiologicalendpointbiologicalsystemchoiceofradiation“standard”radiationdoseanddoseratenumberofdosefractions(&doseperfraction)91本文档共313页；当前第91页；编辑于星期三\9点33分HowisRBErelatedtoLET?AsLETincreases,thesurvivalcurveslopeincreasesandinitialshoulderdecreasesRBEincreaseswithLETuptoabout~100keV/mm92本文档共313页；当前第92页；编辑于星期三\9点33分TheOptimalLETAt~100keV/mm(~5MeVa)greatestRBE;producingmostbiologicaleffectperunitdoseseparationbetweenionizingevents~thediameterofDNAdoublehelixhighestprobabilityofdoublestrandbreakperunitdoseMoredenselyionizingradiationisjustaseffectivepertracklength,butlesseffectiveperunitdosesometimesreferredtoas“overkill”

93本文档共313页；当前第93页；编辑于星期三\9点33分CellSurvivalatVariousStagesofCellCycle-ChineseHamsterCellsDose(rad)6008001000120014000.00102004000.010.11.0Single-CellSurvival0.0005MESG2LSMx2.5(hypoxic)G194本文档共313页；当前第94页；编辑于星期三\9点33分SurvivingFractionofHeLaCells(3Gy)Time(hoursaftershake-off)101418220.10260.20.30.40.5Colony-SurvivingFraction0MS95本文档共313页；当前第95页；编辑于星期三\9点33分Radiosensitivity&MitoticCycleRadiosensitivity(generally)cellsaremostsensitiveclosetomitosisresistanceisgreatestinlatterpartofS-phaseforlongG1-phases,resistanceearlyfollowedbysensitivitylateG2andMequallysensitiveRepairislikelythekey96本文档共313页；当前第96页；编辑于星期三\9点33分MolecularCheckpointGenesCellularprogressionthroughcycleiscontrolledbycheckpointgenestoensurecompletionofeventspriortoprogressionatG2,cellsarehaltedtoinventory&repairdamagebeforemitosiscellswherecheckpointgeneisinactivated...…movedirectlytomitosis,evenwithdama