5 rs radiotherapy

1. 5 R’s of Radiobiology
Dr Kiran
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2. • The five R’s of radiobiology are the concepts to
explain the rationale behind the fractionation of
radiotherapy.
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3. • Repair (few hrs)
• Reassortment/Redistribution (few hrs)
• Repopulation (5-7 wks)
• Reoxygenation (hrs to few days)
• Radiosensitivity.
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4. Repair
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5. Direct and Indirect Actions of Radiation
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6. • Types of DNA damage:
– Single strand break
– Double strand break
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7. Types of radiation induced damage
• Lethal damage
• Potentially lethal damage
• Sublethal damage
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8. Lethal damage:
• irreversible and irreparable
damage that leads to cell
death.
Eg.
• Dicentric chromosome
• Ring chromosome
• Anaphase bridge
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9. Potentially lethal damage:
• Causes cell death under ordinary circumstances but can be
modified by postirradiation environmental conditions.
• If cells are prevented from dividing by creating suboptimal
growth conditions for 6 hrs after irradiation, the damage can
repair.
• Invitro: by keeping cells in saline or plateau phase
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10. Sublethal damage:
• Repairable in hours under ordinary circumstances unless
additional sublethal damage is added.
• Repair of sublethal damage reflects the repair of DNA
breaks before they can interact to form lethal chromosomal
abberations
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11. Repair
• Base Excision Repair
• Nucleotide Excision Repair
• DNA DSB Repair:
– Homologous Recombination Repair
– Nonhomologous End Joining
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12. Base Excision Repair
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13. Nucleotide excision repair
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14. Homologous Recombination Repair
• Occurs in late S/G2 phase
• Undamaged sister chromatid
acts as template
• slow process
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15. Nonhomologous End Joining
• Occurs in G1 phase of
cell cycle
• Fast but error prone and
thus potentially
mutagenic
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16. • By splitting radiation into small parts, cells are allowed
to repair the sublethal damage
• Damage repair depends upon the ability of cells to
recognise the damage and activate the repair pathways
and cell cycle arrest
• Malignant cells often have suppressed these pathways
• Normal tissues are able to repair by the time next
fraction is given
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17. Reassortment/Redistribution
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18. • Cells may be in different phases of cell cycle during irradiation( S-
phase being radioresistant and M-phase being most
radiosensitive).
• Resistance and sensitivity depends upon the level of sulfhydryl
compounds(radioprotector) in the cell.
• A small dose of radiation given over a short period will kill a lot of
sensitive cells and less of resistant cells.
• Surviving cells continue the cycle and may reach sensitive phase
when second dose of radiation is given
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20. Repopulation
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21. • Repopulation is the process of increase in cell
division seen in normal and malignant cells
after irradiation.
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22. Repopulation in normal tissues
• The time to onset of repopulation after irradiation and the rate at
which it proceeds vary with the tissue.
• Acute-responding tissues(stem cells, progenitor cells, GI epithelium,
oropharyngeal mucosa,skin) begin repopulation early.
• Late-responding tissues(Renal tubular epithelium, oligodendrocytes,
schwann cells, endothelium, fibroblasts) begin repopulation after
completion of conventional course of radiation.
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23. Repopulation of malignant tissues
• The mechanism applies to malignant tissues as well.
• Some tumours exhibit accelerated repopulation, a marked increase
in their growth fraction and doubling time and decrease in cell cycle
time, at 4 wks. Eg. SCC of head and neck, cervix.
• It is a dangerous phenomenon that is countered if treatment time
extends over 5 wks.
• It is mediated through radiation-induced receptor activation and
cellular growth stimulation that occur after a single radiation exposure
of 2 Gy.
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25. • The current standard treatment times confer a benefit by allowing
regeneration of acute-responding tissues, which reduces toxicity.
• Attempts made to deliver the therapy more quickly has caused the
acute responses to become more severe and dose-limiting.
• Growth factors like hematopoietic growth factors( G-CSF, GM-
CSF, erythropoietin, IL-11), keratinocyte growth factor protect the
tissues from radiation injury
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26. Reoxygenation
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27. • Tumours under 1mm size are fully oxic but beyond this size they
develop the region of hypoxia.
• Hypoxia in tumours can result from two different mechanisms.
1. Acute Hypoxia
2. Chronic Hypoxia
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28. Acute Hypoxia
• Develop in tumour as a result of the temporary closing or blockage of
a particular blood vessel owing to the malformed structure which
lacks smooth muscle and often has incomplete endothelial lining and
basement membrane.
• At the moment when a dose of radiation is delivered, a proportion of
the tumor cells may be hypoxic, but if the radiation is delayed until a
later time, a different group of cells may be hypoxic.
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29. Chronic Hypoxia
• It results from the limited diffusion distance of oxygen in respiring
tissue that is actively metabolizing oxygen.
• The distance oxygen can diffuse in respiring tissue is about 70µm.
• Cells that are hypoxic for long periods become necrotic and die.
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31. Reoxygenation
• The phenomenon by which hypoxic cells become
oxygenated after a dose of radiation.
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32. Process of Reoxygenation
•Tumors contain a mixture of aerated and
hypoxic cells.
•A dose of x-rays kills a greater proportion of
aerated than hypoxic cells.
• The pre-irradiation pattern tends to return
because of reoxygenation of hypoxic cells.
• If the radiation is given in a series of
fractions separated in time sufficient for
reoxygenation to occur, the presence of
hypoxic cells does not greatly influence the
response of the tumor.
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33. Time Sequence of Rexygenation
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34. Mechanism of Reoxygenation
• Reoxygenation in tumours have:
– Fast component :
• seen in acute hypoxia
• occurs within hours
• reoxygenation occurs when temporarily closed vessels reopen
– Slow component:
• seen in chronic hypoxia
• occurs within days
• reoxygenation occurs when the tumor shrinks in size and the
surviving cells that were previously beyond the range of
oxygen diffusion, come closer to a blood supply
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35. • The concept of reoxygenation applies mostly to animal tumours
that are experimentally studied.
• The human tumours are assumed to reoxygenate from the
evidence that many tumours respond to the doses on the order of
60Gy in 30#s.
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36. Radiosensitivity, the newer
member of the R’s.
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37. •Apart from previous 4 R’s, there
is an intrinsic radiosensitivity or
radioresistance in different cell
types.
•The radiosensitivity of the tumor
cells is now thought to be the
primary determinant of tumor
response to radiation.
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39. Thank You
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