Cellular Radiation Effects by onx77558

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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
            DNA (Chromosomes)
• The DNA makes up the chromosomes of the cell and carries all of
  the 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 nitrogenous
  bases attached to the molecular backbone. These sequences
  encode for protein functions etc. which control all cell functions

• Large areas of a DNA strand may not be expressed in individual
  cells
              DNA Structure
• Double stranded helix (twisted ladder millions of
  rungs long) with side rails of ladder composed of
  Sugar molecules bound together by a phosphate
• Rungs are composed of the nitrogenous bases
  Adenine, Thymine, Guanine and Cytosine.
• Adenine and Thymine combine to make up one
  type of rung and Guanine and Cytosine combine
  to make up another type.
•     A given base may be on either side of the
  helix
              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
DNA Structure
DNA Structure
  Mechanism of radiation Injury
• Direct ionization of a portion of the DNA
  molecule.

• Indirect injury by free radicals in the DNA
  environment.
  – H+, 0H-, H202-, etc.
Mechanism of radiation Injury
        DNA Radiation Injuries
•   Base pair deletion
•   Cross-linking injuies
•   Single Strand Break
•   Double Strand Break
•   Multiple (complex) lesions
DNA Radiation Injuries
DNA Radiation Injuries
         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.
DNA Replication
                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)
Cell Division
                  Mitosis
  – Cell resumes normal functional operations
    (interphase)
• Through this process radiation induced
  aberrations in the DNA may result in
  significant loss of DNA to one or both of
  the daughter cells.

  – Only requires about one hour
    Radiation Induced Chromosomal
               Aberations
•   Chromatid exchanges.
•   Sister Unions
•   Acentric Fragments
•   Rings
•   Dicentric Unions
Radiation Induced Chromosomal
           Aberations
Radiation Induced Chromosomal
           Aberations
               Cell Cycle
• Tissues grow and are maintained through
  cell 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
Cell Cycle
     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
 Cellular Mechanisms of Repair
• Base Excision Repair
  – Damaged bases must be repaired
  – The complementary base on the opposite
    strand serves as a template.
  – This type of repair is quite efficient
  – Loss of this repair mechanism increases the
    incidence of mutations.
 Cellular Mechanisms of Repair
• Nucleotide Excision Repair (NER)
  Repairs DNA damage due to pyrimidine dimer
  adducts added to the DNA by injury.
  - Enzymatic removal of lesion and associated
     backbone.
  - Lesion is then sealed by DNA polyemerase
     and ligase.
  - Defective mechanism increases sensitivity to
     UV light
 Cellular Mechanisms of Repair
• 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 to
      promote development of mutations.
 Cellular Mechanisms of Repair
• Double Strand Break repair
  – Homologus Recombination repair
    • Uses sister chromatid as a template to faithfully
      recreate the damage section and join the ends
      together properly
    • Occurs in G1 phase when sister chromatids
      present
    • Error free process
    • Loss of ability increase radiation sensitivity and
      mutation rate.
 Cellular Mechanisms of Repair
• Single strand break repair
• Occurs via similar pathway to Base
  Excision Repair.
• Efficiently done and vast majority of
  lesions are repaired.
 Cellular Mechanisms of Repair
• Because of the efficiency of repair
  mechanisms for all but double strand
  breaks the majority of the cell killing
  occurring at low doses is due to double
  strand breaks which are not repaired.
• At high doses accumulated DNA injury
  due to many single strand breaks and
  base pair deletions becomes more
  important.
      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
           Lethal Damage
• Non repairable injury associated with
  double strand breaks
• Increases with LET up to a point
• Increases with higher doses
    Potentially Lethal Damage
• Not repaired and lethal under normal
  circumstances.
• Repair increased by conditions which are
  suboptimal to the division of the cell
  – Reduced temperature
  – Hypoxia
  – Low pH
  – Others
• Increased capability = radioresistance
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
 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
  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
 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
            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
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
 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
Repair - dose rate dependency
Repair - dose rate dependency
      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
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.
LET vrs. Survival

								
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