Slide 6

Lethal damage [33, 34]. This is irreversible, irreparable damage, resulting in cell

death.

This usually results from the direct effect of radiation.

Double strand breakage in DNA (+).

Particularly observed in high-LET radiation.

Slide 8

Potentially lethal damage [34].

This is repairable, depending on the changes in the cell environment after exposure to
radiation.
Under normal conditions, this type of damage is lethal to cells undergoing mitosis
that are exposed to radiation.
Prevention from dividing (Mitosis) increases the chance of cell
survival.
However, such damage can be repaired in suboptimal environmental conditions after
exposure to radiation because the cell gets the signal of that suboptimal conditions
that are not suitable for mitosis are present.

The cell then prefers to repair this potential damage rather than initiate mitosis.
Done by changing the post- irradiation conditions the cells are in.
Varying environmental conditions after exposure to x rays can alter cell survival
rates.
PL because if under normal cell conditions it can cause cell death. Under different
environmental conditions postirradiation, cell can survive PLD
survival is increased as a result of the manipulation of the postirradiation
environment, PLD is considered to have been repaired.
Balanced salt solution but does not mimic physiological environment and is less
likely to occur
In a density inhibited state Delayed Mitosis when in suboptimal conditions for
growth greater chances for survival
Slide 9
This Graph is an X-ray survival curves for density inhibited stationary phase cells,
Blue immedite explant , Red line 6hour delay , box 12 hours
The y axis is the Surviving faction while the x-axis is the GY the blie
So In this Graph you can see as the dose increases the lower of chance of survival .The cell survival rate
increases if post irradiated cells are allowed to remain in a density inhibited stationary phase cell culture
for 6 to 12 hours before explants ( To assay or subculture) for colony forming abilities
6 hour and 12 hour survival curves have a smaller slope showing that their survival rates are better than
those explanted right away.

Slide 10
 PLD is repaired, and the fraction of cells surviving a given dose of x-rays is enhanced if postirradiation
conditions are suboptimal for growth.
Cells do not have to attempt the complex process of mitosis while their chroomosomes are damaged.
Some damage that is lethal during normal growth can be repaired under suboptimal conditions
Mitomycin C, which selectively affects hypoxic tumor cells, acts through this gene and inhibits PLDR.

Slide 12

As noticed in this graph, if the dose is given at once the cell survival fraction is at
0.005 (15.58 Gy)
If splitted by thirty minutes the cell survival increases. This increase is noticeable
until 2 hours wherein a plateau is observed in the cell surviving fraction.
A further increase in the time interval between the dose fractions is not
accompanied by any significant additional increment in survival.
The increase is a result of the repair of sublethal radiation damage.
Data was gathered between does fractions to avoid further complications as the
cell moves within the cycle.

Observed increase in cell survival when radiation dose is split into 2 separated with
time.

SLD is usually repaired 26 h after the delivery of radiation

SLD is not fatal, but the second dose increases radiosensitivity.

It can be lethal if there is an insufficient repair period between two fractions.

Repair abilities differ among normal tissues and tumors.

Inhibition of SLDR is the rationale for the additive effect of chemoradiotherapy.

SLDR depends on dose rate, and it is evident between dose rates of 0.011 Gy/min

Slide 13

First Dose S phase of the cell 6 hours allowed between dose already in M/G2 phase
(Sensitive) The increase in radiosensitivity exceeds the effect of the repair of SLD the
surviving fraction falls
Therefore, the graph shown above is a three way process occurring simultaneously
1.) A Prompt repair of SLD
3.) An increase of the surviving fraction resultin
2.) Progression of the cells through the cell cycle during time interval between doses
(Reassortment)
g from cell division (Repopulation) if the time interval is from 10 to 12 hours because this
exceeds the length of the cycle
Only in rapidly growing cells because of the time!
4 Rs
Repair
Reassortment
Repopulation
Reoxygenation
If the increase in radiosensitivity in moving from late S to the G2/M period exceeds the
effect of repair of SLD, the surviving fraction falls.

Slide 14
In neither case, there is a dramatic dip in the curve at 6 hrs.
Because the cell cycle is long.
More repair in small 1-day tumors than in large hypoxic 6-day tumors.
Repair is an active process requiring oxygen and nutrients

Dramatic dip in the curve at 6 hrs caused by reassortment.

More repair in small 1-day tumors than in large hypoxic 6-day tumors.
Repair is an active process requiring oxygen and nutrients.

Slide 17

asymmetric chromosomal aberrations such as dicentrics and rings. This, in turn, is

consequence of an interaction between two (more) double-strand breaks in the DNA.
Based on this interpretation, the repair of SLD is simply the repair of double-strand
breaks. If a dose is split into two parts separated by a time interval, some of the double-
strand breaks produced by the fi rst dose are rejoined and repaired before the second
dose. The breaks in two chromosomes that must interact to form a lethal lesion such as a
dicentric may be formed by (1) a single track breaking both chromosomes (i.e.,
singletrack damage), or (2) separate tracks breaking the two chromosomes (i.e.,
multiple-track damage).

Slide 19
The shoulder on the acute survival curve and the amount of SLD repair indicated
by a split-dose experiment vary with the type of radiation used.
The effect of dose fractionation with x-rays and neutrons is compared in Fig 5.7
Sub lethal damage repair is almost nonexistent for what type of radiation?
NEUTRONS
The prompt repair of SLD when x-rays are used is seen in the graph.

Slide 20
Curve F is obtained if each dose is given as a series of small fractions the size of
Dose 1 with time interval sufficient for SLD repair to occur.
As the dose rate is reduced, the slope ofthe survival curve becomes shallower, and
the shoulder tends to disappear.
Curve F is obtained if each dose is given as a series of small fractions the size of
Dose 1 with time interval sufficient for SLD repair to occur.
The shoulder of the survival curve is repeated for each dose
Notice that F has no shoulder because it can be considered to be an infinite
number of infinitely small fractions
Cell survival is greater for a delivered radiation dose if the dose rate is decreased (Fig.
2.32).
This is due to the proliferation of undamaged living cells and SLD repair during
radiotherapy.
 This effect is very important in brachytherapy applications. The dose rate in external
therapy is 100 cGy/min. Low dose rates are used in brachytherapy, and high doses can
be given due to normal tissue repair and repopulation.

Slide 23

At LDR, the survival curves fan out. Show greater variation of slope Inherent
radiosensitivity ( evident in HDR)

And variant range of repair times of SLD.

Slide 25

Decreasing the dose rate results in increased cell killing.

Slide 26

At higher dose rates, they are frozen in the phase of the cycle they are in at the start of
the irradiation.

Slide 28

Brachy ; (Gr) short range

Endo ; (Gr) within

Developed early before teletherapy.

Intrachavity irradiation , using radiaoactive sources place in body cavities in proximity to

the tumor

Interstitial brachytherapy using radioactive wire or seeds implanted directly into tumor
volume

Slide 29

LDR - Can be used to several body parts especially uterine cervix

Radium is 1st used but safety concerns using an encapsulated source that can leak
radioactive then Cs-137 but now ir-192 short half life and lower gamma ray enery make
for ease of radiation protection, especially conjunction with a remote after loaded
Slide 30

Temoparary implants used radium but now ir-192 .. LDR 5% usage in radiotherapt

The dose-rate range used in these treatments is in the region of the dose-rate spectrum
in which the biologic effect varies rapidly with dose rate.

The maximum dose that can be delivered without unacceptable damage to the
surrounding Normal tissue:

depends on the volume of tissue irradiated and on the dose rate, which is in turn a
function of the number of radioactive sources used and their geometric distribution.

To achieve a consistent biologic response, the total dose used should be varied according
to the dose rate employed.

Slide 31

Show how the total dose should be adjusted with the dose rate.

Notice the brown curve : the higher the activity plus having a higher Dose rate for
treatment, should tell us to use a lower total dose

For example,

a dose rate of 0.64 Gy/h would produce an equivalent biologic effect with a total dose of
only 46 Gy in a treatment time of 3 days

The variation of total dose with dose rate is much larger for late- than for early-
responding tissues because of the lower a/b characteristic of such tissues.

Slide 33

Their second report analyzes data from a large group of patients with carcinoma of
the breast who received iridium-192 implants as a boost to external beam
radiotherapy. These results allow an assessment of the effect of dose rate on tumor
control, but provide no information on the effect of dose rate on late effects,
because there was only one case that involved necrosis. The interstitial implant
was only part of the radiotherapy and a fixed standard dose was used, so only
limited conclusions can be drawn

from these data. The results (Fig. 5.18), however, show a correlation between the
proportion of recurrent tumors and the dose rate. For a given total dose, there
were markedly fewer recurrences if the radiation was delivered at a higher dose
rate rather than a lower dose rate.
 Correlation between the proportion of recurrent tumors and the dose rate.

Slide 34

The relatively short half-life of iridium-192 (70 days) means that a range of dose
rates is inevitable, because the activity of the sources decays during the months
that they are in use.
It is important, therefore, to correct the total dose for the dose rate because of the
experience of Mazeron and his colleagues described previously.
Iridium-192 has two advantages: (1) The source size can be small, and (2) its lower
photon energy makes radiation protection easier than with radium or cesium-
137.
Catheters can be implanted into the patient while inactive and then the sources
transferred from the safe by remote control afterthe patient has returned to his
own room. The sources can be returned to the safe if the patient needs nursing
care.

Slide 37

A major advantage of a radionuclide such as iodine-125 is the low energy of the

photons emitted (about 30 keV).

This makes little difference to the dose distribution in an implanted tumor but
greatly simplifies radiation protection problems, because medical and nursing

staff are easily shielded. In addition, the dose falls off rapidly outside the treatment
volume, so that doses to parts of the patients body remote from the implant are
greatly reduced.

Slide 38

Ferritin is an iron-storage protein that is synthesized and secreted by a broad range

of malignancies, including hepatoma, lung cancer, neuroblastoma, acute
myelogenous leukemia, cancer of the breast and pancreas, and Hodgkin disease. It
is not known why ferritin is produced preferentially in tumors.

It has been suggested that messenger RNA for ferritin may resemble that for many
viruses. This suggestion is highly speculative but consistent with the observation

that ferritin is present in tumors that are suspected of having a viral cause. This
connection is strongly suspected for hepatomas, which have been associated with
the hepatitis B virus and probably exists for Hodgkin disease, too.

Slide 39
 that it requires large amounts of radioactivity (about 1,000 MBq); as a
consequence of this, patients must be hospitalized,

self-care is needed, and pediatric patients are excluded. In addition, the dose and
dose rate to the tumor are limited by the relatively weak - emission (0.3 MeV) and
by the total body dose resulting from the -emission, which causes systemic
hematopoietic toxicity.

Slide 40

When iodine-131 was used, the -ray emission allowed tumor localization as well as
providing the bulk of the therapeutic dose.

When pure -emitters such as yttrium-90 were first introduced, it was necessary to
add a -emitter such as indium-111 to allow visualization.

Today, it is no longer acceptable to scan with a conventional -camera because

single photon emission computed tomography (SPECT) provides a clearer

picture. The bremsstrahlung from -emitters can be scanned by this means, so that
radionuclides such as yttrium-90 can be used without the need to add a -emitter
for visualization.

Slide 41

The presence of ferritin perse is not enough to ensure targeting.

In general, tumors with a high degree of vascularity are better targeted with
antiferritin than less vascularized

Uptake also can be affected by radiation or hyperthermia. A dose of external

radiation can act as an initiator.

This first was observed empirically but now is used routinely to enhance the
targeting of the radiolabeled antiferritin. This is probably a consequence of damage
to tumor vasculature, which allows antiferritin to leak out of vessels and into tumor
cells.

Slide

It is remarkable that such a small dose at such an LDR can produce remissions in
patients with tumors of 1 kg or more.

1,000 MBq is administered on day 1, followed by about 700 MBq on day 5.

 Escalation of dose beyond these levels is not helpful because the deposition of labeled
antiferritin becomes saturated.

This response is difficult to explain based on conventional radiobiologic data, but the
clinical results are exciting.