FOUR R’S OF
RADIOBIOLOGY
MODERATOR: DR ARSHAD MANZOOR

CELL CYCLE

Efficacy of fractionation based on radiobiological experiments and clinical evidence is
expressed in terms of FOUR Rs of radiobiology.
Fractionation of dose spares normal tissues because of repair of sublethal damage
between dose fractions and repopulation of cells if the overall time is sufficiently long.
At the same time, it increases damage to the tumour because of reoxygenation and
reassortment of cells into radiosensitive phases of cell cycle between the fractions.

◦REPAIR,
◦REPOPULATION,
◦REDISTRIBUTION,
◦REOXYGENATION.
The “FOUR Rs” are:

REPAIR
Radiation damage to mammalian cells can operationally be divided into three categories:
1. Lethal damage
2. Potentially lethal damage (PLD),
3. Sublethal damage (SLD),
Base damage,
Single-strand breaks (SSBs),
Double-strand breaks (DSBs),

DNA REPAIR PATHWAYS
Base Excision Repair
Nucleotide Excision Repair
DNA Double-Strand Break Repair
◦ Nonhomologous End-Joining
◦ Homologous Recombination Repair
Crosslink Repair
Mismatch Repair

SUBLETHAL DAMAGE REPAIR
By double strand break repair.
Homologous recombination repair
Requires an undamaged DNA strand as a
template.
Error free process
Late S/G2 phase
Non homologous recombination repair
End to end joining.
Error prone, responsibility for
premuagenic lesions
G1 phase.

SIGNIFICANCE OF SUBLETHAL DEMAGE REPAIR.
Tends to improve cell survival.
Repair occurs during intervals of fractions.
Needs 2 hour interval for maximum effect.

Cell survival curves

 The single dose survival curve for most cells has a finite initial slope
apparently due to a (single-hit) non-repairable damage component ,so there
is a limit below which further reduction of the fraction size will no longer
reduce the effective slope of the survival curve.
 At this limit, essentially all the repairable damage is being repaired between
each fraction so that the cell killing is due almost entirely to non-repairable
events.

Redistribution
 If an asynchronous population of cells present in
different phases of cell cycle is exposed to a large dose
of radiation, more cells are killed in the sensitive than
in the resistant phases of the cell cycle. The surviving
population of cells progresses around cell cycle and
said to be partly synchronised.
 In 6 hrs. S (resistant) to G2-M (sensitive) phase.

Repopulation
 It is the Increase in cell division that is seen in normal and malignant cells at some point after
radiation is delivered.
 In normal tissues, repopulation occurs in different speeds depending on the tissue.
 Early responding tissues begin repopulation at about 4 weeks.
 Late responding tissue only begin repopulation after a conventional course of radiation has
been completed and therefore repopulation has minimal effect on these tissues.

ACCELERATED REPOPULATION
Treatment with any cytotoxic agents, including radiation, can trigger surviving
cells (clonogens) in a tumor to divide faster than before. This is known as
accelerated repopulation.

For the oxygen effect to be observed, oxygen must be present during the radiation
exposure or, to be precise, during or within microseconds after the radiation exposure.
The absorption of radiation leads to the production of fast-charged particles.
The charged particles, in passing through the biologic material, produce several ion
pairs. very short life spans (about 10-10
second)
The free radicals are important because although their life spans are only about 10-5
second, that is appreciably longer than that of the ion pairs.

Cells are much more sensitive to x-rays in the presence of molecular oxygen than in its absence (i.e., under
hypoxia). The ratio of doses under hypoxic to aerated conditions necessary to produce the same level of cell killing
is called the oxygen enhancement ratio (OER). It has a value close to 3.5 at high doses (A), but may have a lower
value of about 2.5 at x-ray doses less than about 2 to 3 Gy (B)
Tumor Hypoxia

Chronic hypoxia
Results from the limited diffusion distance of oxygen through tissue that
is respiring.
The distance to which oxygen can diffuse is largely limited by the rapid
rate at which it is metabolized by respiring tumor cells.
Many tumor cells may remain hypoxic for long periods.

Acute hypoxia
Is the result of the temporary closing of a tumor blood vessel owing to
the malformed vasculature of the tumor.
Tumor vasculature lacks smooth muscle and often has an incomplete
endothelial lining and basement membrane.

MECHANISM OF RE-OXYGENATION

SIGNIFICANCE OF REOXYGENATION
If all the human tumors reoxygenate rapidly, use of multifraction
course of radiotherapy, extending over a period of time can deal
effectively with any hypoxic cells of human tumors.

5th R OF RADIOBIOLOGY
Radiosensitivity of the living tissues varies with maturation &
metabolism. Radiosensitive cells are-
Stem cells
Younger tissues
High metabolic activity
High proiferation and growth rate

Response of tissue is determined by amount of energy
deposited per unit mass(dose in Gy).
Physical Factors
linear energy transfer
relative biologic effectiveness
fractionation.
Biological Factors
AGE
oxygen effect
recovery
chemical agents
Two identical doses may not produce identical responses due to other modifying factors

Thankyou.