The 5 R's of radiobiology are repair, reoxygenation, redistribution, repopulation, and radiosensitivity. They explain why radiotherapy is fractionated into multiple smaller doses. Repair allows cells to recover from sublethal damage between fractions. Repopulation and redistribution impact how radiation sensitivity changes over time. Reoxygenation improves oxygenation of hypoxic tumor cells between fractions. Together these concepts maximize cancer cell killing while minimizing damage to normal tissues.

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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