Radiobiology Lecture 3

Front 1

Cell Survival Curve

Back 1

Front 2

Cellular Damage from radiation can be divided into three categories:

Back 2

-lethal damage
-sub-lethal damage
- potentially lethal damage

Front 3

Lethal Damage

Back 3

Kills the cell, irreversible and is not repairable.

Front 4

Sublethal Damage

- repairable damage has the potential to repair

Back 4

Repairable damage, does not kill the cell unless further damage occurs.
Evident from split does experiments, Applies to X and gamma radiation only. No evidence from for repair from densely ionizing radiations.

Front 5

Potentially Lethal Damage

Back 5

Component of radiation damage that can be altered by the post irradiation environmental conditions.

Front 6

For mitotic cell deaths caused by radiation the chromosomes lethal aberrations can be placed into two groups:

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those caused by when a single photon creates two defects in a chromosome, and those caused by when two photons create two defects in a chromosome.

Front 7

According to theory, it takes

Back 7

2 strands to kill a cell.

Front 8

The defects caused by the single photon when graphed on a survival curve make up the linear portion.

Back 8

The defects caused by two photons make up the quadratic portion of the survival curve. ** See P.P

Front 9

Damage which can be repaired (causes survival curve to bend), causes the quadratic portion of the survival curve.

Back 9

In theory, when the first dose is given, a single strand breaks occurs. When dose is broken up over time, you increase the odds of a cell surviving.

Front 10

During the time period doses, some of these single strand breaks can be repaired before

Back 10

a second lethal strand break from another photon can occur.
- Can't give caner patient radiation all at once, radiation therapy over a 5 week span time.

Front 11

The more we _____________ the does, the more chance for repair

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fractionate

Front 12

Repair of sublethal damage is only significant for cellular damage caused by

Back 12

photons.
- Neutrons and other high LET radiations ( alpha particles & neutrons) show little repair of damage ( as indicated by the survival rate) when the dose is fractionated.

Front 13

Potentially Lethal Damage (3rd Type)
- Cells need time to repair radiation damage.
- Cells that replicate often are more prone to damage vs. cells that don't replicate often.

Back 13

That damage which is repairable to by the cell only if the cell is removed to an environment which puts it in stasis. For a cell, this type of environment is one which is absent of nutrients, causing a hault in division.

Front 14

Potentially Lethal Damage (PLD)
-This is most likely be it delays the next mitosis.

Back 14

During mitosis, damage to the chromosomes is actually expressed. Deprived of nutrients, the cell cannot grow or progress through the cell cycle. The delay in mitosis increases the surviving fraction of cells exposed to X or gamma rays.

Front 15

Potentially Lethal Damage (PLD)
cont.

Back 15

Damage done by densely ionizing/high LET radiation shows no PLD repair. This includes damage done by neutrons.

Front 16

Potentially lethal damage (PLD)
cont. b

Back 16

Repair of PLD has been proved to occur in vitro. If cells are irradiated in vivo and then excised to an environment which stops their growth, repair also occurs.

Front 17

Repair of sublethal damage is only significant for cellular damage caused by

Back 17

photons.
- Neutrons and other high LET radiations ( alpha particles & neutrons) show little repair of damage ( as indicated by the survival rate) when the dose is fractionated.

Front 18

Potentially Lethal Damage (3rd Type)
- Cells need time to repair radiation damage.
- Cells that replicate often are more prone to damage vs. cells that don't replicate often.

Back 18

That damage which is repairable to by the cell only if the cell is removed to an environment which puts it in stasis. For a cell, this type of environment is one which is absent of nutrients, causing a hault in division.

Front 19

Potentially Lethal Damage (PLD)
-This is most likely be it delays the next mitosis.

Back 19

During mitosis, damage to the chromosomes is actually expressed. Deprived of nutrients, the cell cannot grow or progress through the cell cycle. The delay in mitosis increases the surviving fraction of cells exposed to X or gamma rays.

Front 20

Potentially Lethal Damage (PLD)
cont.

Back 20

Damage done by densely ionizing/high LET radiation shows no PLD repair. This includes damage done by neutrons.

Front 21

Potentially lethal damage (PLD)
cont. b

Back 21

Repair of PLD has been proved to occur in vitro. If cells are irradiated in vivo and then excised to an environment which stops their growth, repair also occurs.

Front 22

Potentially lethal damage (PLD)
cont. b

Back 22

Whether this has any bearing on repair of radiation damage to humans is a matter of debate.

Front 23

Different asynchronous cell populations exhibit different amounts of repairable damage:

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Example: Intenstinal jejunum cells exhibit a large shoulder on a survival curve, indicating a large amount of repair.
- Bone marrow stem cells have a narrow shoulder and exhibit a little repair.

Front 24

However, different cell types are almost equally

Back 24

radiosensitive when they are in mitosis.

Front 25

If all cells are radiosensitive during mitosis, it implies

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that differences in cell type radiosensitivity occur mostly during interphase.

Front 26

Death by apoptosis also varies with cell type. Radioresistant cells show little death by apoptosis, whereas,

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radiosensitive cells, like WBC's show a large amount of apopptic death.

Front 27

Fractionating dosage

Back 27

Breaking up the doses over time.

Front 28

Sublethal Damage and Split Dose experiments

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If we fractionate the dose given to a population of cells, that is divide one large dose into two or more smaller doses, the % of cells surviving increases.
- This is due to the repair by the cell of sub-lethal damage

Front 29

Repair of sublethal damage chart....

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4 Gy + give more time, you will see more and more repair.

Front 30

The % of cells surviving for a growing population is effected by

Back 30

the time between doses of radiation.

Front 31

However, there is a limit to this effect.

Back 31

After a few hours delay, there is no appreciable increase in surviving fraction.
-All repair that occurs will happen during first few hours

Front 32

Normally, a population is asynchronous. A dose of radiation to a cell population will partially synchronize the cells as more cells are killed which are in sensitive phases of the cell cycle.

Back 32

The surviving fraction change is affected by synchrony in the cell population.

Front 33

Radio sensitivity and the Cell Cycle
G1+G2 = resting phase

Back 33

In a synchronous cell population it is found that there is greater amount of cell killing if radiation is given during (Mitosis and in G2) = very sensitive to radiation.

Front 34

Radio sensitivity and the Cell Cycle cont.

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For most cell types, S phase is the most radio-resistant phase of the cell cycle.

Front 35

The Four R's of radiobiology

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1. Repair
2. Reassortment
3. Repopulation
4. Re-oxygenation

Front 36

Reassortment

Back 36

Redistribution of a cell population as to their place in the cell cycle.

Front 37

Repopulation

Back 37

When the dose is split, or given at a low dose rate, cellular survival increases due to cellular division. (Simply giving cells more time to grow, good for normal tissues not good for cancer cells.)

Front 38

Mammalian Cells on average experience

Back 38

100,000 plus DNA lesions per day.
However, mammalian mutation is very low due to repair mechanisms.

Front 39

Stop Breathing so Much

Back 39

It is calculated that endogenously generated oxygen free radicals makes about 10,000 oxidative interactions with DNA per human cell per day.

Front 40

Antioxidants

Back 40

Antioxidants are chemicals which neutralize free radicals by donating one of their own electrons.

Front 41

Antioxidants (2)

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Vitamin's C and E are good at doing this and may protect against cellular damage.

Front 42

Antioxidants (3)

Back 42

Phytochemical found in fruits and vegetables also do this; free radicals scavengers.

Front 43

Dose Rate Effect

Back 43

In general, the lower dose rate the greater the surviving fraction. Dose rate shows the greatest effects between the rates of 0.001 Gy/min and 1 Gy/min, beyond or below this rate, there is little change in repair of damage or cell survival.

Front 44

Dose Rate Effect cont.

Back 44

Human cells show a great variation in the sensitivity to dose rate. This would indicate that some human cell types are good at repairing damage and others are poor.

Front 45

Survival vs. Dose Rate

Back 45

See. P.P Chart

Front 46

The Oxygen Effect & Re-oxygenation

Oxygen is a _____________

Back 46

radiosensitizer. It must be present during irradiation or immediately after to effect cell sensitivity.

Front 47

Oxygen Enhancement Ratio
OER =

Back 47

The ratio of doses of hypoxic ( low oxygen) vs. aerated cells required to give the same biological effect.

Front 48

OER =

Back 48

Do for hypoxic cells/ Do for oxygenated cells

Front 49

For photon exposure ( X + gamma) most cells have an OER of

Back 49

2.5 to 3.0

Front 50

OER is unity for ___________________ ie alpha's neutrons

Back 50

Ionizing Radiations

Front 51

Oxygen is believed to make

Back 51

permanent the damage from indirectly ionizing radiations.

Front 52

OH- is very damaging

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Smalls amounts of oxygen are sufficient to significantly increase cell killing.

Front 53

Hypooxic

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low oxygen

Front 54

anoxic

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no oxygen

Front 55

necrotic

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dead

Front 56

At 2% oxygen concentration, cell killing is about the same as it would be from normal aeration. Increasing.....

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oxygen concentration beyond that of air even to 100% oxygen, doe not significantly increase the biological effect

Front 57

Tumors larger then 200 microns (small) have necrotic centers.

Back 57

Oxygen can diffuse about 150 microns from a capillary into a tissue.
10-15 % ( not sensitive to radiation, bad for cancer patients) hypoxic cells in tumors is typical.

Front 58

Brachytherapy

Back 58

Is a method of using radioactive isotope to treat tumors and cancerous tissues.
- The sources are either implanted interstitially into the tumor volume or temporally inserted into the body cavities to place then in close proximity to the tumor.

Front 59

Treat by killing cancer cells and sparing good tissues

Back 59

I-125 = half life of 60 days, this is why this is a great therapy.

Front 60

Cs-137,Radium, I-125,Ir-192

Back 60

are some isotopes which have been used for brachytherapy.

Front 61

Cs-125 implants are used in prostate cancer.

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Prostate cancer is slow growing tumor, cells have a long cycle, they do not reproduce quickly.

Front 62

In quickly growing tumor types, tumor cell repopulation will make up

Back 62

for what has been killed by the implant.

Front 63

Dose Rate for interstitial therapy depends upon the amount of isotope implanted.

Back 63

This is obvious, more isotope = greater dose.

Front 64

Total prescribed dose to prostate is about

Back 64

16 Gray

Front 65

External Beam Therapy

- most common cancer treatment

Back 65

The most common method of cancer treatment utilities a linear accelerator. The linac emits high energy X-Rays which are well collimated to the tumor site. A high energy beam is necessary to penetrate deep into the body.

Front 66

Treatment Plans

- All 4 of the R's of radiotheraphy come into play here

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A normal treatment plan is 5 days of therapy with 2 days off. Treatment continues for 5 weeks.