Cell Cycle and Radiosensitivity

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Cell Cycle and Radiosensitivity

• Wenqing Sun
• Sept. 27, 2000

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Agenda

• Definition of cell cycle
• Radiosensitivity at different cell phase
• Cell cycle checkpoint
• Other aspects of radiation biology and cell cycle

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Definition of Cell Cycle

• Cell Cycle is ordered process by which one cell
  grows and divides into two daughter cells.

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Phases of Cell Cycle

• Mitosis - M phase
• One cell divides into two identical cells.
• Typically lasts for 30 minutes.

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Phases of Cell Cycle - continued

• Interphase
• S phase
• Lasts 6 hours.
• DNA synthesis is restricted to this phase.
• G1 phase
• Duration varies dramatically for different cell
  lines.
• G2 phase
• Lasts 3 hours.

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Cell populations and cell cycle phases
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Cell growth and DNA content during the cell cycle
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Comparison of Cell Cycle - Hamster and Hela
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Radiosensitivity at different cell phase
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Time-survival fraction for Hamster cell
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Time-survival fraction for HeLa cell
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Correlation between variation of radiosensitivity
and age

• Cell are most sensitive at or close to mitosis
• Resistance is usually greatest in the latter part
  of S phase
• If G1 has an appreciable length, a resistant
  period is evident early in G1 phase, followed by
  a sensitive period toward the end of G1 phase
• G2 phase is usually sensitive, perhaps as
  sensitive as M phase

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Cell Cycle Checkpoint

• Definition of cell cycle checkpoint
• Events that can initiate the arrest of cell cycle
  at checkpoints
• Arrests of each phase

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Definition of Checkpoint

• Cell cycle is a highly ordered processthe
  initiation of later event depends on the
  completion of earlier events.
• The control mechanisms that enforce this ordered
  dependency are called cell cycle checkpoint.

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Events can initiate arrest

• Nutrient deprivation
• Temperature changes
• Nucleotide depletion
• Damage to the DNA

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DNA-damage-responded checkpoint
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Some conception

• Oncogenes
• Tumor suppressor genes
• Cyclin is a family of proteins required for the
  activity of some kind of kinases.
• Cyclin-dependent kinases a group of kinases that
  can regulate cell cycle progress

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G1 phase arrest

• Avoid DNA replication
• Dependent on the function status of p53

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G1 arrest and p53 pathway

• Irradiation---gtDNA damage---gt increasing level of
  p53 protein---gt activation of p21WAF1/CIP1
  gene---gt inhibition the activity of
  cyclin/CDK---gt G1 arrest

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S phase arrest

• After relatively high dose irradiation
• Prevent DNA replication errors
• Inhibiting the initiation of replicon or
  inhibiting the elongation of replicon
• The mechanism is not clear

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G2 phase arrest

• Very important checkpoint
• Prevent the cells with damaged DNA to progress
  into mitosis

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Mechanism of G2 arrest

• The control gene in yeast
• cyclin B1 and p34cdc2
• ras oncogene

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Methods to control checkpoint

• Gene therapy success and difficulty
• drugs

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Other aspects of cell cycle

• LET
• Hyperthermia
• Cell cycle redistribution

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LET and cell cycle
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LET-Respond Cell Cycle Sensitivity
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Hyperthermia and cell cycle
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Cell Age-respond Sensitivity to Hyperthermia
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Mechanism of hyperthermia

• Thermersensitivity and cell cycle
• Biological effect of hyperthermia
• hyperthermia and oxygen
• Block the repair of DNA damage

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Cell Cycle Redistribution
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The overall effect of a dose of radiation

• kill cells in a sensitive phase of the cell
  cycle
• Sensitize a cycling population to a later dose of
  radiation.
• Leave majority of cells in a resistant cell cycle
  phase.
• All of the above

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• Artificial synchronization
• Redistribution(re-assortment)