Cell Sensitivity, Target Theory, & Radiation Dose Response Curves

T/F: equal doses of different types of radiation = equal response

false
-response determined by amount of energy deposited per unit mass (dose in Gyt)

Physical Factors affecting Radiosensitivity

LET
RBE
Protraction
Fractionation

Biologic Factors (Patient) affecting Radiosensitivity

OER
Age
Recovery
Chemical agents
Hormesis

LET
(Linear Energy Transfer)

rate at which energy is deposited in form of charged particle/ion pair as it travels thru matter
-closely related to amount of damage done by different types of radiation

Unit for LET

keV/um
kiloelectron volts per micrometer

2 groups from LET

1) Low LET: XR, gamma, beta
2) High LET: alpha, fast neutrons, heavy nuclei

Low LET characteristics

-XR/gamma have no mass/charge
-highly penetrating
-don't give up energy quickly
-don't cause high rate of ionizations per cm
-do relatively little biologic damage
-damage primarily thru indirect effects
-usually sublethal damage (repairable)

High LET characteristics

-don't penetrate well
-give up energy quickly
-cause lots of ionizations per cm
-greater amount of biological damage
-more substantial mass & charge compared to Low LET

Radiation weighting factor (Wr)

used to express radiation quality
-represents ability of radiation to produce biologic damage

Wr values

-XR/gamma = 1
-neutrons >10keV = 5
-neutrons >100keV-2Mev = 10
-alpha = 20

Relative Biological Effectiveness (RBE)

quatitative expression of describing relative effect & increase in biologic damage caused by high LET
-ex) identical doses of radiation (2Gy XR & 2Gy alpha) don't have same bio effects bc of different LETs

RBE compares

amount of radiation needed to do same amount of damage as a known dose of 250 keV XRs

LET & RBE are ______________________.
-as LET increases, RBE __________________.

-proportional
-increases

RBE formula

dose of 250 keV XRs to produce effect/dose of test radiation to produce same effect
-ex) 10Gy 250keV XRs produce same rxn as 2Gy alpha. RBE = 10.2 = 5 RBE

Protraction v. Fractionation

1) Protraction: lose dose delivered continuously
2) Fractionation: dose delivered is equal fractions, typically higher doses

Occupational dose is considered __________________ radiation
1) fractionated
2) protracted

fractionated
-not constantly exposed

Oxygen Effect

aerobic cells are more radiosensitive than anoxic cells

Damage from ______________ ________________ produced from free radicals is considered to be irreversible.

hydrogen peroxide

Oxygen Enhancement Ratio (OER)

impact of oxygen on radiation effects

OER formula

amount of damage anoxic/amount of damage aerobic
-(to produce same effect)
-ex) anoxic tumor dose is 106Gy & 40.5Gy for aerobic. OER = 106/40.5 = 2.6 OER

Age affects on radiosensitivity

-humans most sensitive before birth
-sensitivity decreases w/ age after birth but increases again in old age, but not to same level as kids

4 R's of Radiation Therapy

1. Recover (Repair)
-cells recover btwn doses, some cells have greater capacity for repair
2. Regeneration (Repopulation)
-regeneration from surviving cells assist in recovery
3. Reoxygenation
-hypoxic cells reoxygenate
4. Redistribution (Reassortment)
-irradiation during mitosis, cell population returns to more even distribution of younger dividing cells

4 R's & Fractionation

fractionation spares normal tissue thru repair/repopulation while increasing damage to tumor cells thru redistribution/reoxygenation

Sensitizing Agents

enhance effects of radiation
-ex) chemotherapy

Hormesis

theory that a little radiation is good for you
-possibly stimulates hormonal & immune responses to other toxic environmental agents

Cell Sensitivity
Cells are ID by:

1) rate of proliferation
2) stage of development
-ex) differentiated v. undifferentiated

Differentiation v. Undifferentiated

1) Differentiation: cells specialized structurally/functionally; mature cells
2) Undifferentiated: immature cells whose primary function is to divide; unspecialized cells

3 Classifications of Cells

1) Stem
2) Transit
3) Static

Stem Cells

-aka undifferentiated, precursor, immature, unspecialized cells
-sole purpose is to divide
-no special function
-MOST RADIOSENSITIVE

Transit Cells

-cells in movement to another population
-intermediate radiosensitivity
-ex) reticulocyte to erythrocyte

Static Cells

-aka mature, highly differentiated, specialized cells
-little mitotic activity & specilized
-usually more radioresistant

Cells are MOST SENSITIVE during _________________ phase of cell cycle, & MOST RESISTANT during _______________ phase

1) Mitosis (M)
2) Synthesis (S)

Top 5 Radiosensitive cells

1) Mature Lymphocytes
2) Immature Spermatogonia
3) Erythroblasts
4) Intestinal Crypt Cells
5) Basal cells of Epidermis

Intermediate Radiosensitivity (7)

1) endothelial cells (vasculature)
2) gastric gland cells
3) osteoblasts
4) spermatocytes, spermatids
5) chondroblasts
6) fibroblasts
7) erythrocytes

Top 4 Radioresistant Cells

1) Neurons/Nerve Cells
2) Myocytes (muscle)
3) fibrocytes
4) chondrocytes

Bone Marrow Cells

1) erythroblasts-RBC precursors
-most radiosensitive
2) myelocytes- WBC precursors
3) Megakaryocytes- platelet precursors
-most radioresistant

epithelium

covering tissue; lines exposed surfaces of body
-considered radiosensitive

Nervous tissue

neurons; cells have long extension from cell to distant part of body to transmit electrical impulses
-considered more radioresistant

tissues/organs made up of 2 compartments:

1) Parenchymal
-specific cells
2) Stromal
-supporting cells

Organ radiosensitivity exhibits a range & is determined by:

1) Organ function
2) Rate at which cells mature in organ
3) inherent radiosensitivity of cell type

Chemocytotoxic Agent

kills cells

Dose Response Curves

graphic representation of relationship btwn amount of radiation absorbed dose & amount/magnitude of damage response seen

Every dose curve has 2 characteristics:

1) Linear v. Nonlinear
2) Threshold v. Nonthreshold

Linear

-forms straight line
-response is directly proportional to dose
-RN: natural response level & indicates that w/o radiation, rxn still occurs
-Dr: threshold dose

Nonlinear ("Sigmoid")

"S"-shaped curve

Threshold

-response to radiation must reach a certain level to have effect; anything below it will have no efffect
-point at which response to increased stimulai first occurs
-intercept dose axis >0

Nonthreshold

-even smallest dose could cause response
-intercepts dose axis @ 0 or below

4 Possible Graphs

1) Linear Nonthreshold
2) Linear Threshold
3) Nonlinear Threshold
4) Nonlinear Nonthreshold

-Linear Nonthreshold & Nonlinear Threshold most common

Linear Nonthreshold

-any dose can produce response (directly proportional)
-Stochastic/Probablitistic Effects
-Late effects
-increase possibility if rxn w/ increased dose, but no change in severity
-"All or None" response
-random
-sets standards for dose limits & radiation protection

Stochastic/Probablistic

random in nature, statistical

Late Effects (4)

-leukemia
-cancers (solid)
-genetic mutations
-radiation protection

Nonlinear (Sigmoid) Threshold

-implies miminum dose threshold for rxn to occur
-Nonstochastic/Deterministic Effects
-increase in severity as dose increases & threshold is assumed
-usually not occurring in dx XR
-early effects

Deterministic/Nonstochastic

effects considered certain to occur in exposed radiation if threshold is exceeded
-not random

Early Effects (6)

-erythema
-epilation
-cataracts
-fibrosis
-hematopoetic damage
-ARS

Stochastic effects are usually result of _____ doses delivered over ___________ period of time

1) low
2) long
-nonthreshold
-late effects

Deterministic effects are usually result of _________ doses over __________ period of time

1) high
2) short
-threshold
-early effects

What is the Target Molecule?

DNA

Hit

when radiation interacts w/ target molecule
-ionizing event that inactivates target molecule

Hits are considered unrepaired functional damage to chromosomes leading to _______________________ of a portion of genetic code

deactivation

Cells divide & form _____________. As cells are irradiated, __________ ________________ form.

1) colonies
2) less colonies

Interphase Death

cells die before replicating

2 Theories of Target Theory due to cell survival

1) Single Target Single Hit
-simple cells bacteria, enzymes
2) Multi Target Single Hit
-complicated cells, humans

Single Target Single Hit

-single target must be hit to deactivate cell (death)
-in 100 cells, 63% will be hit & 37% will survive
-D37

D37

-radiation dose reaches level that kills 63% & 37% survive
-measures radiosensitivity of cell
-ex) cell A D37 = 2Gy, cell B D37 = 4Gy- takes more dose to kill cell B

Multi Target Single Hit

-cell has 2 halves & both must be hit to damage cell
-represents threshold
-shoulder on curve represents ability of cells to withstand some radiation (until threshold is reached, there is 100% chance survival)
-D0 & DQ

D0

-mean lethal dose
-constant related to radiosensitivity

DQ

-threshold dose
-measure of width of shoulder & related to capacity of cell to recover from sublethal damage

In multi target single hit, @ low radiation levels, survival is ____%, & _________ as dose increases since more cells sustain hits on both targets

100%
decreases

Large DQ

more radioresistant/able to easily recover from sublethal damage

Large D0

radioresistant

small D0

radiosensitive

In multi target single hit, D0 reduces survival to _____% in straight portion

37%

low D37

radiosensitive

high D37

radioresistant

Inflection Point
(Nonlinear Threshold graphs)

where curve stops & begins bending down

linear nonthreshold graphs represent what kind of response?

All or None

In linear graphs, response is _______________ to dose

proportional

Genetic effects occurring prior to conception are ____________ in nature

stochastic (random)

In utero effects are typically ______________

deterministic

Dose response curves have 2 applications in radiology

1) design therapeutic tx routines
2) provide info on effects of low-dose irradiation

Some radiosensitizers such as _____________ _______________ become incorporated into DNA & amplify effects

halogenated pyrimides

What unit expresses radiation quality?

radiation weight factor (Wr)

What substance is necessary for free radical formation? (indirect effect)

oxygen