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Cell Cycle and Radiosensitivity

Cell Cycle and Radiosensitivity. Wenqing Sun Sept. 27, 2000. Agenda. Definition of cell cycle Radiosensitivity at different cell phase Cell cycle checkpoint Other aspects of radiation biology and cell cycle. Definition of Cell Cycle.

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Cell Cycle and Radiosensitivity

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  1. Cell Cycle and Radiosensitivity Wenqing Sun Sept. 27, 2000

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

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

  4. Phases of Cell Cycle • Mitosis - M phase • One cell divides into two identical cells. • Typically lasts for 30 minutes.

  5. 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.

  6. Cell populations and cell cycle phases

  7. Cell growth and DNA content during the cell cycle

  8. Comparison of Cell Cycle - Hamster and Hela

  9. Radiosensitivity at different cell phase

  10. Time-survival fraction for Hamster cell

  11. Time-survival fraction for HeLa cell

  12. 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 G1has an appreciable length, a resistant period is evident early in G1 phase, followed by a sensitive period toward the end of G1 phase • G2phase is usually sensitive, perhaps as sensitive as M phase

  13. Cell Cycle Checkpoint • Definition of cell cycle checkpoint • Events that can initiate the arrest of cell cycle at checkpoints • Arrests of each phase

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

  15. Events can initiate arrest • Nutrient deprivation • Temperature changes • Nucleotide depletion • Damage to the DNA

  16. DNA-damage-responded checkpoint

  17. 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

  18. G1 phase arrest • Avoid DNA replication • Dependent on the function status of p53

  19. G1 arrest and p53 pathway • Irradiation--->DNA damage---> increasing level of p53 protein---> activation of p21WAF1/CIP1 gene---> inhibition the activity of cyclin/CDK---> G1 arrest

  20. 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

  21. G2 phase arrest • Very important checkpoint • Prevent the cells with damaged DNA to progress into mitosis

  22. Mechanism of G2 arrest • The control gene in yeast • cyclin B1 and p34cdc2 • ras oncogene

  23. Methods to control checkpoint • Gene therapy: success and difficulty • drugs

  24. Other aspects of cell cycle • LET • Hyperthermia • Cell cycle redistribution

  25. LET and cell cycle

  26. LET-Respond Cell Cycle Sensitivity

  27. Hyperthermia and cell cycle

  28. Cell Age-respond Sensitivity to Hyperthermia

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

  30. Cell Cycle Redistribution

  31. 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

  32. Artificial synchronization • Redistribution(re-assortment)

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