radiation biology lecture 1

7/30/2019 Radiation Biology Lecture 1

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Cellular Radiation Effects

Cell membrane - Alteration in permeability

Cellular organelles - Functional Aberrations

Nuclear membrane - Altered permeability &

Function

DNA - Chromosomes - Functional aberrations


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DNA (Chromosomes)

The DNA makes up the chromosomes of the cell and carries all ofthe functional encoding information of the cell or organism

All of the chromosomes together make up the genome

The genome is composed of many genes (60,000 in humans)

The individual genes are composed of sequences of nitrogenousbases attached to the molecular backbone. These sequencesencode for protein functions etc. which control all cell functions

Large areas of a DNA strand may not be expressed in individualcells


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DNA Structure

Double stranded helix (twisted ladder millions ofrungs long) with side rails of ladder composed ofSugar molecules bound together by a phosphate

Rungs are composed of the nitrogenous basesAdenine, Thymine, Guanine and Cytosine.

Adenine and Thymine combine to make up onetype of rung and Guanine and Cytosine combine

to make up another type. A given base may be on either side of the

helix


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DNA Structure

DNA is a very large molecule. There are about

2 x 109 base pairs in the mammalian genome

distributed across 15-100 chromosomes.

The stearic configuration (shape) of the

molecule changes constantly and is important to

function.

DNA is replicated at cell division


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DNA Structure


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DNA Structure


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Mechanism of radiation Injury

Direct ionization of a portion of the DNA

molecule.

Indirect injury by free radicals in the DNA

environment.

H+, 0H-, H2

02

-, etc.


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Mechanism of radiation Injury


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DNA Radiation Injuries

Base pair deletion

Cross-linking injuies

Single Strand Break Double Strand Break

Multiple (complex) lesions


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DNA Replication

DNA is replicated during S Phase prior to

the onset of mitosis

The original DNA is used as a template for

the building of the new DNA.

Quite rapid process, requires less than 15

hours.


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DNA Replication


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Cell Division

Mitosis Multistep process

DNA organizes into identifiable chromosomes

(Prophase )

DNA aligns with centromeres on equatorial plate

(Metaphase)

DNA Separates and moves to opposite ends of cell

(Anaphase)

Cell cytoplasm divides at equatorial plate

(Telophase)


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Cell Division


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Mitosis

Cell resumes normal functional operations

(interphase)

Through this process radiation induced

aberrations in the DNA may result insignificant loss of DNA to one or both of

the daughter cells.

Only requires about one hour


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Radiation Induced Chromosomal

Aberations

Chromatid exchanges.

Sister Unions

Acentric Fragments Rings

Dicentric Unions


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Aberations


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Aberations


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Cell Cycle

Tissues grow and are maintained throughcell replication (regeneration)

Some cells never divide once adulthood is

reached. There are a specific set of steps involved

G1 (G0) Gap Phase 1 Functional cell

S Synthesis DNA synthesis G2 Gap phase 2 Rest

M Mitosis Cell Division


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Cell Cycle


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Repair of Radiation Injury

Cellular mechanisms are in place which

can repair most if not all types of radiation

injury to the DNA.

Repair is a time sensitive process

Repair is a cell cycle dependent process

Repair is a dose rate dependent process Repair is dose dependent

Repair is radiation type dependent


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Cellular Mechanisms of Repair

Nucleotide Excision Repair (NER)

Repairs DNA damage due to pyrimidine dimeradducts added to the DNA by injury.

- Enzymatic removal of lesion and associatedbackbone.

- Lesion is then sealed by DNA polyemeraseand ligase.

- Defective mechanism increases sensitivity toUV light


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Double Strand Break Repair

Nonhomologous End Joining

Occurs primarily in S phase when no sister

chromatid is present. In some instances the base pair sequence is filled

in by repair processes without a template.

Complex process with multiple pathways

Because it is an error prone process it tends topromote development of mutations.


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Double Strand Break repair

Homologus Recombination repair

Uses sister chromatid as a template to faithfully

recreate the damage section and join the endstogether properly

Occurs in G1 phase when sister chromatids

present

Error free process Loss of ability increase radiation sensitivity and

mutation rate.


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Single strand break repair

Occurs via similar pathway to Base

Excision Repair.

Efficiently done and vast majority of

lesions are repaired.


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Because of the efficiency of repairmechanisms for all but double strandbreaks the majority of the cell killing

occurring at low doses is due to doublestrand breaks which are not repaired.

At high doses accumulated DNA injurydue to many single strand breaks andbase pair deletions becomes moreimportant.


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Types of DNA Damage

Lethal Damage

Irreversible and irreparable fatal to cell

Potentially Lethal Damage (PLD

Damage which is lethal unless modified by

post irradiation events

Sublethal Damage (SLD)

Repairable injury to the DNA


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Lethal Damage

Non repairable injury associated with

double strand breaks

Increases with LET up to a point

Increases with higher doses


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Potentially Lethal Damage

Not repaired and lethal under normalcircumstances.

Repair increased by conditions which are

suboptimal to the division of the cell Reduced temperature

Hypoxia

Low pH Others

Increased capability = radioresistance


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Sublethal Damage Repair (SLD)

Refers to DNA damage that is repaired

Splitting radiation dose increases survival

Occurs in 1-6 hours after irradiation Affected by phase of cell cycle

Affected by cell cycle time

Long cycle usually increases repair Indicated by shoulder on survival curve


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Repair is a time sensitive process

Repair of DNA injury of all types is

essentially complete by 6 hours post

irradiation.

External factors that affect cellular

metabolic rate may delay or accelerate it

Foundation of modern radiotherapy


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Repair is a cell cycle dependent

process

Different phases have different repair

capabilities

Mitosis has the least repair capability

G2

G1/G0

S phase has the most repair capability

Capability varies in G1 and S


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S-phase Radiation Resistance

Likely due to Homologous Recombination

Can result in cell population synchrony

S G2

blockade and increased survival in S

More important in rapidly dividing cells

May be important in some tumor lines


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Reassortment

Cells in G2 & M are preferentially killed

Cells in S are preferentially spared.

Alters proportion of cells in each phase Cell population tends to reestablish normal

proportions within 2-3 cycles.

Killed cells replaced by cells from G1 Moves cells to more sensitive G2 & S


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Repair - dose rate dependency

Dose rate decreased by two mechanisms

Splitting dose into smaller fractions w/ time

between the fractions

Smaller fractions increase time if spacing constant

Reducing the actually rate at which dose is

delivered

Repair between ongoing during doses

Repopulation may occur


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Repair is dose rate dependent

At very low dose rates repair of SLD can

keep up with radiation damage.

SLD predominate type of injury.

Repopulation can account for LD and SLD

Dependent on cycling cell population

Cell cycle time short relative to dose rate

Affected by radiation quality

Mutation rates may be increased


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Repair is dose dependent

Lethal Damage increase with dose

PLD increases with dose

Accumulation of SLD increase with dose Survival curve is continuously bending

Some repair always present

Various forms of damage interact


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Repair is radiation type dependent

Low LET radiation is repaired

Little repair of High LET radiation injury

Dense ionization track

Double strand breaks more likely

Energy deposition curve dependent

Sublethal damage less important

Single strand breaks, base pair deletion, etc.


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LET vrs. Survival

radiation biology lecture 1

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