3. OXYGEN EFFECT
• Cells are much more sensitive to radiation in the presence of oxygen
• The formation of RO2·, an organic peroxide, represents a non
restorable form of the target material; that is, the reaction results in a
change in the chemical composition of the material exposed to the
radiation.
• This reaction cannot take place in the absence of oxygen.
• Oxygen fixes ( ie , makes permanent ) the damage produced by free
radicals .
• In the absence of oxygen , damage produced by the indirect action
may be repaired .
4. The oxygen fixation hypothesis.
About two-thirds of the damage produced by x-rays is by indirect action mediated by free radicals. The
damage produced by free radicals in DNA can be repaired under hypoxia but may be “fixed” (made
permanent and irreparable) if molecular oxygen is available .
5. • To produce its effect , molecular oxygen must be present during the
radiation exposure or at least during the lifetime of the free radicals
generated by the radiation .
• Ie , Oxygen effect is time dependent .
1. O2 needs to be present during radiation . or
2. O2 has to be present within milliseconds after radiation .
• Radiation - ion pairs - free radicals
0.01 msec.
OXYGEN IS NATURAL RADIOSENITIZER .
6. • If molecular oxygen is present, DNA reacts with the free radicals (R·).
The DNA radical can be chemically restored to its reduced form
through reaction with a sulfhydryl (SH) group.
• SULFHYDRIL group is a natural radio protector which exert their
effect by scavenging free radicals .
• Oxygen and sulfhydryl only acts on indirect action and they do not
have any effect on direct action of radiation to DNA .
8. • Very little change upto 20 mmHg.
• Sharp fall in sensitivity and reduces to half at around 3
mmHg.
• Maximum radio resistance at 1/100 mm of Hg .
• Oxygen tension in most of tissue is similar at venous
blood O2 tension ,ie 20-40 mmHg .So , MOST OF THE
NORMAL TISSUES HAVE GOOD SENSITIVITY TO
RADIATION.
10. • So , to get the same surviving fraction , dose of RT to be increased
with decreasing oxygen tension .
• The ratio of RT to get the same SF in hypoxic cells to oxic cells is
known as OXYGEN ENHANCEMENT RATIO (OER).
• OER = DH / DO = D hypoxic/D aerobic
• Ratio of doses administered under hypoxic to aerated condition
needed to achieve the same biological effect is called oxygen
enhancement ratio .
11. • For sparsely ionizing radiations, such as x- and γ-rays, the OER at
high doses has a value of between 2.5 and 3.5.
• For a densely ionizing radiation, such as low-energy α-particles, the
survival curve does not have an initial shoulder; which means that all
hits results into cell kill and no sub lethal damage to be fixed by
oxygen .we can say , α-particle radiation is as effective for hypoxic
cells as for oxic cell .
• Intermediate value for fast neutrons , the OER for neutrons is about
1.6. For radiations of intermediate ionizing density, such as neutrons,
the survival curves have a much reduced shoulder
12. Survival curves for mammalian cells exposed to x-rays in the
presence and absence of oxygen are illustrated here;
13. • High dose region ; predominant process of cell kill is by accumulation
of sublethal damage ( cell killing by multiple hit event –MHE ) which
can be repaired ,so oxygen fix it and repair slows down .
• Low dose region ; cell killing is predominantly by single hit event –SHE
,no sublethal damage to be fixed up by oxygen ; so , in low dose
region OER = 2 ( x ray or gamma ray )
14. • 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).
15. • OER varies slightly during cell cycle .
• Cells in G1 phase have a lower OER than those in S, and because G1
cells are more radiosensitive, they dominate the low-dose region of
the survival curve.
• S PHASE > G1 PHASE > G2/M PHASE .
• OER OF S PHASE = 2.8 - 2.9
• OER OF G2/M PHASE = 2.3 -2.4
16. CLINICAL IMPORTANCE
• Various experimental solid tumors in animals have shown to have
hypoxic contents between 10 to 40 %, which limits the radio curability
• However , it should be remembered that even a minute proportion of
hypoxic cells will limit the radiocurability if treated with large single
fraction .
• There are abundant evidences to support the existence of hypoxic
cells in human tumour .
19. LINEAR ENERGY TRANSFER
• Linear energy transfer (LET) is the energy transferred per unit length
of the track.
• The special unit usually used for this quantity is kiloelectron volt per
micrometer (keV/μm) of unit density material.
• The LET (L) of charged particles in medium is the quotient of dE/dl.
• dE is the average energy locally imparted to the medium by a
charged particle of specified energy in traversing a distance of dl.
• L=dE/dl
22. • Linear energy transfer (LET) is the average energy deposited per unit
length of track.
• The track average is calculated by dividing the track into equal lengths
and averaging the energy deposited in each length.
• The energy average is calculated by dividing the track into equal
energy intervals and averaging the lengths of the track that contain
this amount of energy.
• The method of averaging makes little difference for x-rays or for
monoenergetic charged particles, but the track average and energy
average are different for neutrons.
• In the case of either x-rays or monoenergetic charged particles, the
two methods of averaging yield similar results.
• In the case of 14-MeV neutrons, by contrast, the track average LET is
about 12 keV/μm and the energy average LET is about 100 keV/μm.
• The biologic properties of neutrons tend to correlate best with the
energy average.
23. RELATIVE BIOLOGIC EFFECTIVENESS (RBE)
• The amount or quantity of radiation is expressed in terms of the
absorbed dose, a physical quantity with the unit of gray (Gy).
• Absorbed dose is a measure of the energy absorbed per unit mass of
tissue.
• Equal doses of different types of radiation do not produce equal
biologic effects.
• For example, 1 Gy of neutrons produces a greater biologic effect than
1 Gy of x-rays.
• The key to the difference lies in the pattern of energy deposition at
the microscopic level.
25. • why radiation with an LET of about 100 keV/μm is optimal in terms
of producing a biologic effect?
• LET of about 100 keV/μm is optimal in terms of producing a biologic
effect .
• At this density of ionization , the average separation in ionizing events
is equal to the diameter of DNA double helix (i.e., about 20 Å or 2 nm)
which causes significant DOUBLE STRAND BREAK .
• DSB are the basis of most biological effects .
• The probability of causing DSBs is low in sparsely ionizing radiation .
• The LET at which the RBE reaches a peak is much the same (about
100 keV/ μm) for a wide range of mammalian cells, from mouse to
human, and is the same for mutation as an end point as for cell
killing.
26.
27. • Variation of relative biologic effectiveness (RBE) with linear energy transfer (LET) for survival of
mammalian cells of human origin.
The RBE rises to a maximum at an LET of about 100 keV/μm and subsequently falls for higher values
of LET.
Curves 1, 2, and 3 refer to cell survival levels of 0.8, 0.1, and 0.01, respectively, illustrating that the
absolute value of the RBE is not unique but depends on the level of biologic damage and,
therefore, on the dose level.
28. • In the case of x-rays, which are more sparsely ionizing, the probability
of a single track causing a DSB is low, and in general, more than one
track is required. As a consequence, x-rays have a low biologic
effectiveness.
• At the other extreme, much more densely ionizing radiations (e.g.,
with an LET of 200 keV/μm) readily produce DSBs.
• But energy is “wasted”
• Because, the ionizing events are too close together. RBE is the ratio
of doses producing equal biologic effect, this more densely ionizing
radiation has a lower RBE than the optimal LET radiation. The more
densely ionizing radiation is just as effective per track but less
effective per unit dose.
29. • The most biologically effective LET is that at which there is a
coincidence between the diameter of the DNA helix and the average
separation of ionizing events.
• Radiations having this optimal LET include neutrons of a few hundred
kiloelectron volts as well as low-energy protons and α-particles.
30. RBE depends on the following:
• Radiation quality (LET) (The type of radiation and its energy, whether
electromagnetic or particulate, and whether charged or uncharged)
• Radiation dose & Number of dose fractions (The shape of the dose–
response relationship varies for radiations that differ substantially in
their LET).
• Dose rate (The slope of the dose–response curve for sparsely ionizing
radiations, such as x- or γ-rays, varies critically with a changing dose
rate. In contrast, the biologic response to densely ionizing radiations
depends little on the rate at which the radiation is delivered)
• Biologic system or end point(RBE values are high for tissues that
accumulate and repair a great deal of sublethal damage and low for
those that do not)
31. x-rays, which are sparsely ionizing, have a low LET,
and consequently exhibit a large OER of about 2.5.
32. Neutrons, which are intermediate in ionizing
density and characteristically show an OER of 1.6.
33. 2.5-MeV α-particles, which are densely ionizing and have a high LET; in
this case, survival estimates, whether in the presence or absence of
oxygen, fall along a common line, and so the OER is unity.
34. Variation of the oxygen enhancement ratio (OER) and the
relative biologic effectiveness (RBE) as a function of the linear
energy transfer (LET) of the radiation involved.
The rapid increase in RBE and the rapid fall of the OER occur at about the
same LET, 100 keV/μm.
