Normal Tissue Responses to Radiation - RadCCORE · Normal Tissue Responses to Radiation Normal tissue response to radiation classified on the time taken to exhibit clinical injury

Normal Tissue Responses to Normal Tissue Responses to RadiationRadiation

Normal Tissue Responses to RadiationNormal Tissue Responses to Radiation

In clinical RT the total dose of radiation that In clinical RT the total dose of radiation that safely can be administered is limited not by the safely can be administered is limited not by the sensitivity of the tumor itself, but by the risk of sensitivity of the tumor itself, but by the risk of morbidity arising in those normal tissues morbidity arising in those normal tissues unavoidably included within the treatment unavoidably included within the treatment volumevolume


In cellular radiobiology, radiation effects measured in In cellular radiobiology, radiation effects measured in terms of the capacity of individual cells to exhibit terms of the capacity of individual cells to exhibit infinite proliferation, defined as clonogenicityinfinite proliferation, defined as clonogenicity

Normal tissue responses can be viewed in the same Normal tissue responses can be viewed in the same manner; normal tissue injury will reflect the loss of a manner; normal tissue injury will reflect the loss of a particular target cell population as these cells divideparticular target cell population as these cells divide


Normal tissue response to radiation classified on the Normal tissue response to radiation classified on the time taken to exhibit clinical injurytime taken to exhibit clinical injury

Acute responding tissues: express injury during or Acute responding tissues: express injury during or within 2within 2--3 weeks of the completion of radiotherapy 3 weeks of the completion of radiotherapy e.g., skin, oral mucosae.g., skin, oral mucosa

Late responding tissues: express injury several Late responding tissues: express injury several months to years after irradiation e.g., kidney, lung, months to years after irradiation e.g., kidney, lung, CNSCNS

Pathogenesis of RadiationPathogenesis of Radiation--induced induced Normal Tissue InjuryNormal Tissue Injury

Vascular hypothesis: Vascular hypothesis: Rubin and Casarett (1968) Rubin and Casarett (1968) States that late radiation effects are caused by damage to bloodStates that late radiation effects are caused by damage to blood

vessels. This vascular injury, with a long latency reflecting thvessels. This vascular injury, with a long latency reflecting the e slow turnover time of the vasculature, leads to vessel slow turnover time of the vasculature, leads to vessel occlusion, ischemia, and secondary loss of parenchymal cellsocclusion, ischemia, and secondary loss of parenchymal cells

Parenchymal hypothesis:Parenchymal hypothesis: Withers (1979) Withers (1979) Both acute and late effects result directly from cell depletion;Both acute and late effects result directly from cell depletion; the the

rate of development of injury depends upon the rate at which rate of development of injury depends upon the rate at which cells in the tissue normally divide.cells in the tissue normally divide.

Measuring Normal Tissue Responses Measuring Normal Tissue Responses to Radiationto Radiation

Clonogenic assaysClonogenic assaysEndpoint depends directly on the reproductive Endpoint depends directly on the reproductive integrity of individual cells, based on integrity of individual cells, based on techniques developed by Withers and techniques developed by Withers and colleagues. These systems are directly colleagues. These systems are directly analogous to cell survival analogous to cell survival in vitroin vitro


Functional endpointsFunctional endpointsThese are reproducible, quantitative endpoints; These are reproducible, quantitative endpoints; tend to reflect the tend to reflect the minimum number of minimum number of functionalfunctional cells remaining in a tissue or organ, cells remaining in a tissue or organ, rather than the number of clonogenic cellsrather than the number of clonogenic cells


Models of doseModels of dose--response curvesresponse curvesInfer doseInfer dose--response curves by assuming the response curves by assuming the shape of the doseshape of the dose--response curve and response curve and performing a series of multifraction performing a series of multifraction experiments. Allows generation of values for experiments. Allows generation of values for αα//ββ for normal tissues in which these for normal tissues in which these parameters cannot be directly measuredparameters cannot be directly measured

Clonogenic EndpointsClonogenic EndpointsClones regrowing in situ.Clones regrowing in situ.

Skin: Withers (1967) determined the survival curves for mouse Skin: Withers (1967) determined the survival curves for mouse skin cells skin cells in vivoin vivo

Hair plucked from an area on the back of a mouse, and a superficHair plucked from an area on the back of a mouse, and a superficial (30 ial (30 kV) x ray machine used to irradiate an annulus of skin to ~30 GykV) x ray machine used to irradiate an annulus of skin to ~30 Gy

This produced a This produced a ““moatmoat”” of dead cells, in the center of which was an island of dead cells, in the center of which was an island of intact skin protected during irradiation by a metal sphere (bof intact skin protected during irradiation by a metal sphere (ballall--bearing) bearing)

Moat of dead cells used to prevent migration of viable skin cellMoat of dead cells used to prevent migration of viable skin cells into the s into the irradiated area during the time course of the study irradiated area during the time course of the study

Clonogenic EndpointsClonogenic EndpointsThe small area irradiated with a test dose (D Gy) and subsequentThe small area irradiated with a test dose (D Gy) and subsequently ly observed for skin regrowthobserved for skin regrowth

If If ≥≥1 stem cells survived, a nodule of recovering cells could be see1 stem cells survived, a nodule of recovering cells could be seen later.n later.

Clonogenic EndpointsClonogenic EndpointsObtained a straight cell survival Obtained a straight cell survival

curve, Dcurve, D00 = 1.35 Gy= 1.35 Gy

Some limitations to the techniqueSome limitations to the technique

Cannot irradiate too large an area Cannot irradiate too large an area on the back of the mouse to on the back of the mouse to produce the moatproduce the moat

Even 30 kV x rays scatter, Even 30 kV x rays scatter, therefore field cannot be too therefore field cannot be too smallsmall

Clonogenic EndpointsClonogenic EndpointsCannot directly obtain values of Cannot directly obtain values of nn (extrapolation number), because don(extrapolation number), because don’’t know t know

how many skin stem cells are present/unit area, and thus cannot how many skin stem cells are present/unit area, and thus cannot convert convert data to SFdata to SF

However, can calculate However, can calculate n n indirectly by obtaining a survival curve for doses indirectly by obtaining a survival curve for doses given in 2 fractions separated by 24 hours; measures repair of Sgiven in 2 fractions separated by 24 hours; measures repair of SLDLD

This allows calculation of DThis allows calculation of Dqq, where, where

DDqq = D= Doo loglogee ((nn))

and logand logee nn = D= Dqq/D/Doo

Clonogenic EndpointsClonogenic EndpointsMouse jejunal crypt cellsMouse jejunal crypt cellsWithers and Elkind (1969): allows determination of survival charWithers and Elkind (1969): allows determination of survival characteristics of acteristics of

crypt cellscrypt cells

Mice receive TBI (11Mice receive TBI (11--16 Gy), sterilize all dividing cells in the crypt, 16 Gy), sterilize all dividing cells in the crypt, has no has no effect on noneffect on non--dividing differentiated cellsdividing differentiated cells

After 3 days, animal sacrificed and sections made of the jejunuAfter 3 days, animal sacrificed and sections made of the jejunum. At this time m. At this time the crypts are just starting to regenerate and it is relatively the crypts are just starting to regenerate and it is relatively simple to see simple to see them them

Radiation damage scored as number of regenerating crypts/circumfRadiation damage scored as number of regenerating crypts/circumference. Plot erence. Plot as a function of dose, and yields the survival curveas a function of dose, and yields the survival curve

Clonogenic EndpointsClonogenic EndpointsLimitations:Limitations:

DonDon’’t plot the SF, but t plot the SF, but number of surviving number of surviving cryptscrypts

Experiments can only Experiments can only be done at doses of be done at doses of ≈≈10 Gy or more, as 10 Gy or more, as need sufficient level need sufficient level of biological injury to of biological injury to be able to quantitate.be able to quantitate.

Clonogenic EndpointsClonogenic Endpoints

Can give high doses by Can give high doses by using a large number of using a large number of small fractions, as long as small fractions, as long as the total dose gives the the total dose gives the biological responsebiological response

AssumeAssume

Each dose/fraction gives Each dose/fraction gives same level of cell killsame level of cell killCertain number of Certain number of clonogens/cryptclonogens/crypt



Cells transplanted to Different Site/Transplantation Cells transplanted to Different Site/Transplantation AssaysAssays

SingleSingle--cell suspensions made from irradiated tissue and cell suspensions made from irradiated tissue and transplanted to suitable sites in immunologically transplanted to suitable sites in immunologically identical animal.identical animal.

Clonogenic EndpointsClonogenic EndpointsTill and McCulloch (1961) Till and McCulloch (1961) Developed technique to determine the Developed technique to determine the

survival curve for colonysurvival curve for colony--forming bone forming bone marrow cells. Requires a marrow cells. Requires a donor donor and a and a recipientrecipient mouse.mouse.

Donor: used to withdraw suspension of Donor: used to withdraw suspension of nucleated isologous bone marrow cells. nucleated isologous bone marrow cells. A known number of these are injected A known number of these are injected into the recipient mouse.into the recipient mouse.

Recipient: receives TBI (9 Gy), sterilizes Recipient: receives TBI (9 Gy), sterilizes the spleen. Then injected with donor the spleen. Then injected with donor cells, some of which lodge in the spleen cells, some of which lodge in the spleen and form colonies. and form colonies.

Spleen removed 9Spleen removed 9--10 days later, and 10 days later, and colonies counted.colonies counted.


Majority of donor cells are fully differentiated cells and will Majority of donor cells are fully differentiated cells and will not form colonies, thus not form colonies, thus require require ≈≈ 101044 cells per colony cells per colony

SF for a dose D = SF for a dose D = Colonies countedColonies countedCells innoculated x PECells innoculated x PE

PE = plating efficiency, # cells required to produce a colony inPE = plating efficiency, # cells required to produce a colony in an unirradiated animal.an unirradiated animal.

Clonogenic EndpointsClonogenic EndpointsRepeat the process for a Repeat the process for a range of doses, and obtain a range of doses, and obtain a survival curvesurvival curve

These bone marrow cells These bone marrow cells are the most sensitive are the most sensitive mammalian cells to die a mammalian cells to die a mitotic deathmitotic death

DD00 is ~ 0.95 Gy, with little is ~ 0.95 Gy, with little or no shoulderor no shoulder

Dose Response Relationships for Dose Response Relationships for Functional EndFunctional End--PointsPoints

Can use essentially any functional endCan use essentially any functional end--point to point to determine tissuedetermine tissue’’s response to radiation, providing s response to radiation, providing the endpoint can be reproducibly quantified/assessedthe endpoint can be reproducibly quantified/assessed

One of the most widely used systems in experimental One of the most widely used systems in experimental radiobiology has been the skinradiobiology has been the skin

Advantages: relatively simple system, easy to assess Advantages: relatively simple system, easy to assess injuryinjury

Dose Response Relationships: Pig SkinDose Response Relationships: Pig Skin

The use of pig skin was pioneered by Fowler The use of pig skin was pioneered by Fowler and colleagues (1963)and colleagues (1963)

Fields were tattooed onto the flank of pigs and Fields were tattooed onto the flank of pigs and irradiated with graded doses of X raysirradiated with graded doses of X rays

Reactions were scored daily using an arbitrary Reactions were scored daily using an arbitrary scalescale


Moist desquamation of > Moist desquamation of > 50% of irradiated area50% of irradiated area

55

Moist desquamation of < Moist desquamation of < 50% of irradiated area50% of irradiated area

44Marked erythemaMarked erythema33

ErythemaErythema22Faint erythemaFaint erythema11

No visible reactionNo visible reaction00REACTIONREACTIONARBITRARY SCOREARBITRARY SCORE


Due to statistical difficulties Due to statistical difficulties in analyzing such nonin analyzing such non--parametric ordinal data, a parametric ordinal data, a scoring system based purely scoring system based purely on the incidence of a on the incidence of a particular reaction has been particular reaction has been developed in Oxford by developed in Oxford by Hopewell Hopewell et alet al

Response of pig skin is Response of pig skin is biphasic. biphasic.


Initial response erythema, can be followed by moist Initial response erythema, can be followed by moist desquamation. Always seen approx. 5 weeks PIdesquamation. Always seen approx. 5 weeks PI

Second wave: DuskySecond wave: Dusky--mauve erythema, and dermal necrosis, mauve erythema, and dermal necrosis, seen approx. 10seen approx. 10--16 weeks PI16 weeks PI

Major disadvantage: large size of animal, expensive to keepMajor disadvantage: large size of animal, expensive to keep

Alternative is to use rodents, e.g. use mouse leg/footAlternative is to use rodents, e.g. use mouse leg/foot

Usually irradiate one hindUsually irradiate one hind--limb, other serves as control. Score limb, other serves as control. Score daily using arbitrary numerical scale.daily using arbitrary numerical scale.

Dose Response Relationships: Dose Response Relationships: Mouse SkinMouse Skin

Dose Response Relationships: Dose Response Relationships: Mouse LungMouse Lung

Travis Travis et alet al (1980) developed a non(1980) developed a non--invasive invasive assay of breathing frequency to assess early assay of breathing frequency to assess early and late damage to mouse lungand late damage to mouse lung

Observed that breathing rate Observed that breathing rate ↑↑ progressively progressively with dose following a threshold of ~11 Gy with dose following a threshold of ~11 Gy

Dose Response Relationships: Dose Response Relationships: Mouse LungMouse Lung

Between 14Between 14--24 weeks PI increased frequency reflects early pneumonitic 24 weeks PI increased frequency reflects early pneumonitic phasephase

By 52 weeks the increased frequency is associated with the late By 52 weeks the increased frequency is associated with the late fibrotic phasefibrotic phase

Dose Response Relationships: Dose Response Relationships: Rat Spinal CordRat Spinal Cord

DoseDose--response curves can be generated following response curves can be generated following local irradiation of the rat spinal cord (van der Kogel local irradiation of the rat spinal cord (van der Kogel 1980) 1980)

After latent periods of ~ 4After latent periods of ~ 4--12 months animals start to 12 months animals start to exhibit signs of radiation myelopathy e.g. hind limb exhibit signs of radiation myelopathy e.g. hind limb paralysisparalysis

Can construct doseCan construct dose--response curves by plotting the response curves by plotting the incidence or probability against doseincidence or probability against dose

Dose Response Relationships: Dose Response Relationships: Rat Spinal CordRat Spinal Cord

Determining Determining αα//ββ from from Multifraction ExperimentsMultifraction Experiments

Can determine parameters of dose response curve for any Can determine parameters of dose response curve for any normal tissue system in which a functional end point can be normal tissue system in which a functional end point can be observed by performing a multifraction experimentobserved by performing a multifraction experiment

Determine total dose required to give a defined biological Determine total dose required to give a defined biological response following multifraction irradiationresponse following multifraction irradiation

Assume: Assume: DoseDose--response relationship is adequately response relationship is adequately represented by the Lrepresented by the L--Q formulaQ formula


S = e(S = e(--ααD D -- ββD2)D2)

where S = SF cells following Dose D, where S = SF cells following Dose D, αα and and ββ are constantsare constants

Experimental studies have shown that each successive fraction inExperimental studies have shown that each successive fraction in a a fractionated regimen is equally effective, so that the effect (Efractionated regimen is equally effective, so that the effect (E) of ) of n n fractions can be expressed asfractions can be expressed as

E = E = ααD + D + ββD2D2

if D is delivered in if D is delivered in nn fractions of dose fractions of dose dd then this becomesthen this becomes

E = E = nn((ααdd + + ββdd2)2)


Can be rewritten as the following termsCan be rewritten as the following terms

Equation 1: 1/D = (Equation 1: 1/D = (αα/E) + (/E) + (ββE) E) dd

Equation 2: 1/Equation 2: 1/nn = (= (αα/E)/E)dd + (+ (ββE)E)dd22

FeFe--Plot (Douglas & Fowler 1976)Plot (Douglas & Fowler 1976)Analyze doseAnalyze dose--response curves byresponse curves by

1.1. Plotting effect vs. total dosePlotting effect vs. total dose

2.2. Determine isoDetermine iso--effect doses for effect doses for each fractionation regimeneach fractionation regimen

3.3. Plot 1/D against corresponding Plot 1/D against corresponding dd/F/F

4.4. Should give a straight line with Should give a straight line with slope of slope of ββ/E and intercept on the /E and intercept on the yy axis of axis of αα/E/E

5.5. Where line cuts the Where line cuts the xx axis = axis = --αα//ββ

Alternatively:Alternatively:

1.1. Plot 1/Plot 1/nn vs. vs. dd/F/F

2.2. Gives shape of Gives shape of continuously bending cell continuously bending cell survival curvesurvival curve

3.3. Preferred statistically since Preferred statistically since 1/1/nn and and dd/F axes are /F axes are independentindependent

Volume EffectVolume EffectIn clinical RT, volume of tissue irradiated is an important In clinical RT, volume of tissue irradiated is an important factor determining the clinical tolerance of an organfactor determining the clinical tolerance of an organ

This can be very different from the tissue radiosensitivity This can be very different from the tissue radiosensitivity

Kidney and lung are among the most radiosensitive organs Kidney and lung are among the most radiosensitive organs when the total volume irradiated; TDwhen the total volume irradiated; TD55 ≈≈ 20 Gy in 2 Gy 20 Gy in 2 Gy fractionsfractions

However, if treat small volumes can use much higher doses, However, if treat small volumes can use much higher doses, reflects the marked reserve capacity of these organsreflects the marked reserve capacity of these organs

Volume EffectVolume EffectOrgan radiosensitivity depends largely on its arrangement of Organ radiosensitivity depends largely on its arrangement of FSUs, and ability of these FSUs to migrateFSUs, and ability of these FSUs to migrate

Tissues with a high migratory capacity include skin, mucosa, Tissues with a high migratory capacity include skin, mucosa, and GI tract. Small volumes can be treated to relatively high and GI tract. Small volumes can be treated to relatively high doses, as repopulation will readily occur from outside the doses, as repopulation will readily occur from outside the irradiated volumeirradiated volume

However, once critical distance reached (migration no longer However, once critical distance reached (migration no longer possible) will see cell loss without adequate replacementpossible) will see cell loss without adequate replacement

Above a certain dose will see damage to stroma and Above a certain dose will see damage to stroma and vasculature, which may prevent regenerationvasculature, which may prevent regeneration

Volume EffectVolume EffectSerial arrangement:Serial arrangement:

Integrity of each FSU critical to organ function, elimination oIntegrity of each FSU critical to organ function, elimination of only one f only one resulting in a measurable probability of a complication resulting in a measurable probability of a complication

A good example is the spinal cord. Specific functions are contA good example is the spinal cord. Specific functions are controlled by rolled by specific segments arranged linearly. Since impulses need to passpecific segments arranged linearly. Since impulses need to pass along s along cord, loss of critical cells in any one segment will result in ccord, loss of critical cells in any one segment will result in complete failure omplete failure of the cordof the cord

Thus, as field sizeThus, as field size increases, the probability of complicationsincreases, the probability of complications increases increases steeply; the probability of complications is only related to thesteeply; the probability of complications is only related to the total total irradiated volumeirradiated volume

Not the case for small volumes; here cell migration plays a domiNot the case for small volumes; here cell migration plays a dominant rolenant role

Volume Effect in Pig SkinVolume Effect in Pig Skin

Volume Effect in Rat Spinal CordVolume Effect in Rat Spinal Cord

Volume EffectVolume Effect

Parallel arrangement:Parallel arrangement:

Organs such as kidney and lung, can lose large Organs such as kidney and lung, can lose large numbers of FSUs before see marked loss of numbers of FSUs before see marked loss of functionfunction

Volume Effect in Mouse LungVolume Effect in Mouse Lung

Proliferative Organization of Proliferative Organization of Normal TissuesNormal Tissues

Cell proliferation in normal tissues is highly organized, with Cell proliferation in normal tissues is highly organized, with cell production under tight homeostatic controlcell production under tight homeostatic control

In adult tissues under nonIn adult tissues under non--pathologic conditions cell pathologic conditions cell production is exactly balanced by loss of differentiated mature production is exactly balanced by loss of differentiated mature cellscells

Number maintained by proliferative activity of precursor cells, Number maintained by proliferative activity of precursor cells, i.e. cells which serve to replace those cells lost due to normali.e. cells which serve to replace those cells lost due to normal““wear and tearwear and tear””

Proliferative Organization of Proliferative Organization of Normal TissuesNormal Tissues

The degree of organization of cells within The degree of organization of cells within proliferative and functional compartments has proliferative and functional compartments has been used to distinguish between two been used to distinguish between two categories of tissues, categories of tissues, hierarchicalhierarchical and and flexibleflexible(Michalowski 1981)(Michalowski 1981)

Hierarchical or HHierarchical or H--type Tissuestype Tissues

Clearly recognizable separation between the stem cell Clearly recognizable separation between the stem cell compartment, an amplification compartment (usually compartment, an amplification compartment (usually proliferating rapidly), and a postproliferating rapidly), and a post--mitotic nonmitotic non--dividing dividing compartment of mature functional cellscompartment of mature functional cells

Mostly rapidly renewing cell systems: include Mostly rapidly renewing cell systems: include hematopoietic tissues, skin epidermis, GI tract hematopoietic tissues, skin epidermis, GI tract mucosa and testicular epitheliummucosa and testicular epithelium



Capacity for clonogenic selfCapacity for clonogenic self--replication restricted to a replication restricted to a small subset of cells called stem cells; not functioning small subset of cells called stem cells; not functioning cellscells

Mature functioning cells develop from stem cells by a Mature functioning cells develop from stem cells by a process of differentiation during which intermediate process of differentiation during which intermediate transit cells progressively lose their capacity for transit cells progressively lose their capacity for proliferation while their functional capacity increases proliferation while their functional capacity increases


Mature cells are lost from the tissue at a characteristic Mature cells are lost from the tissue at a characteristic rate as a result of wear and tearrate as a result of wear and tear

Numbers maintained by a continuous influx of stem Numbers maintained by a continuous influx of stem cells into the differentiation pathway cells into the differentiation pathway

Stem cell number is maintained by selfStem cell number is maintained by self--replication; replication; when not proliferating, the stem cells reside in a when not proliferating, the stem cells reside in a quiescent Gquiescent G00 statestate

Radiation Response of Radiation Response of HH--type Tissuestype Tissues

After irradiation stem cells and cells in transit compartment After irradiation stem cells and cells in transit compartment will die at mitosis; mature functional cells will not be damagedwill die at mitosis; mature functional cells will not be damagedby irradiationby irradiation

Causes reduced flow of cells from the stemCauses reduced flow of cells from the stem--transit transit compartment leading to a reduction in the number of mature compartment leading to a reduction in the number of mature cellscells

Since the lifeSince the life--span of the postspan of the post--mitotic functional cell is mitotic functional cell is limited, depletion becomes evident shortly after irradiation, limited, depletion becomes evident shortly after irradiation, clinically expressed as an early or acute response clinically expressed as an early or acute response


Since under steadySince under steady--state conditions the rate of state conditions the rate of flow is constant, depopulation of the postflow is constant, depopulation of the post--mitotic pool starts immediately; will proceed mitotic pool starts immediately; will proceed linearly, and be linearly, and be dosedose--independentindependent

Time to reach compete depopulation also Time to reach compete depopulation also dosedose--independentindependent, dependent on the length of , dependent on the length of mature cell longevity mature cell longevity


At low doses, some stem cells will survive and initiate regeneraAt low doses, some stem cells will survive and initiate regeneration; the tion; the time required to reach a certain level of depletion will therefotime required to reach a certain level of depletion will therefore be re be dosedose--dependentdependentWith higher doses, see increased stem cell kill With higher doses, see increased stem cell kill

Regeneration Response of Regeneration Response of HH--type Tissuestype Tissues

Unless all stem cells are lost, regeneration response Unless all stem cells are lost, regeneration response occurs through activation of regulatory homeostasisoccurs through activation of regulatory homeostasis

Subclonogenic proliferation will tend to slow down Subclonogenic proliferation will tend to slow down the rate of cell depletion and delay this homeostatic the rate of cell depletion and delay this homeostatic response with a resultant prolongation of radiation response with a resultant prolongation of radiation damagedamage

Regeneration occurs throughRegeneration occurs through……

Recruitment of proliferating stem cells into the Recruitment of proliferating stem cells into the proliferation pool. If stem cell intact it will proliferation pool. If stem cell intact it will contribute to regenerationcontribute to regeneration

However, if stem cell dies at division will speed up However, if stem cell dies at division will speed up depletion of the stem cell compartment and depletion of the stem cell compartment and stimulate activation of homeostatic control via more stimulate activation of homeostatic control via more intensive proliferation. Therefore, intensive proliferation. Therefore, recruitment of recruitment of cells in Hcells in H--type tissue beneficial type tissue beneficial

Shortening of cell cycle time of proliferating stem Shortening of cell cycle time of proliferating stem cells, usually decrease in Gcells, usually decrease in G11

Radiation Response of Radiation Response of FF--type Tissuestype Tissues

Irradiation will kill actively dividing cells in a Irradiation will kill actively dividing cells in a dosedose--dependent dependent mannermanner

Accompanied by normal and constant normal cell loss. Accompanied by normal and constant normal cell loss. Therefore steepness of initial slope of depopulation will be Therefore steepness of initial slope of depopulation will be dosedose--dependentdependent

These tissues typically have long turnover times, thus an These tissues typically have long turnover times, thus an apparent delay in the expression of damage may be seen, and apparent delay in the expression of damage may be seen, and its duration will be inversely related to doseits duration will be inversely related to dose


Once cell loss detected, proliferation stimulated; Once cell loss detected, proliferation stimulated; could involve either a reduction in cell cycle time could involve either a reduction in cell cycle time and/or an increased growth fractionand/or an increased growth fraction

Can cause an acceleration in the rate of cell loss due Can cause an acceleration in the rate of cell loss due to mitotic death, resulting in a temporary vicious to mitotic death, resulting in a temporary vicious cycle of cell losscycle of cell loss

This second or This second or avalancheavalanche phase will follow the initial phase will follow the initial decline in cell number decline in cell number


Since during this avalanche phase the probability of mitotic faiSince during this avalanche phase the probability of mitotic failure will be doselure will be dose--dependent, the rate of depopulation will also increase with dosedependent, the rate of depopulation will also increase with dose

Therefore, more severe lesions seen earlier than mild injury, inTherefore, more severe lesions seen earlier than mild injury, in contrast to the Hcontrast to the H--type tissue reactions. Takes less time for failure to occur wittype tissue reactions. Takes less time for failure to occur with increasing dose.h increasing dose.

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Normal Tissue Responses to Radiation - RadCCORE · Normal Tissue Responses to Radiation Normal tissue response to radiation classified on the time taken to exhibit clinical injury