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BIOLOGICAL EFFECTS OF IONIZING

RADIATION AT MOLECULAR AND


CELLULAR LEVELS

Module VIII-a

Historical background

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Discovery of X rays
(1895)

Wilhelm Conrad Roentgen

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Discovery of uraniums natural


radioactivity

Antoine Henri Becquerel

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Marie Curie

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First reports on harmful


effects of radiation
First radiation-induced skin cancer reported
in 1902
First radiation-induced leukemia described
in 1911
1920s: bone cancer among
radium dial painters
1930s: liver cancer and leukemia
due to Throtrast administration
1940s: excess leukemia among
first radiologists

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Studies of Japanese
A-bomb survivors

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Effects of radiation on cells at


atomic level

Excitation
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Ionization
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Mechananisms of damage
at molecular level

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Direct action
Ionizing radiation + RH

R - + H+

Bond breaks

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OH
O
I
II
R C = NH2
R C = NH
imidol (enol)
amide (ketol)
Tautomeric Shifts

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Indirect action

X ray
ray
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eP+

OHH+
Ho

OHo

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Radiolysis of H2O
molecule

Shared electron

Shared electron

H-O-H H+ + OH- (ionization)


H-O-H H0+OH0
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(free radicals)
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Reactions with free radicals


H0 + OH0 HOH (recombination)
H0 + H0 H2 (dimer)
OH0 + OH0 H2O2 (hydrogen peroxide)
OH0+RH R0+HOH (radical transfer)

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Effects of oxygen on free


radical formation
Oxygen can modify the reaction by
enabling creation of other free radical
species with greater stability and longer
lifetimes
H0+O2 HO20 (hydroperoxy free radical)
R0+O2 RO20 (organic peroxy free radical)
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Lifetimes of free radicals


RO2o

HO2

Ho

OHo

OHo

3nm
Ho

Because short life of simple free radicals (1010


sec), only those formed in water column of 2-3
nm around DNA are able to participate in
indirect effect

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Relation between LET and


action type
Direct action is predominant with
high LET radiation, e.g. alpha
particles and neutrons
Indirect action is predominant with
low LET radiation, e.g. X and
gamma rays

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Biochemical reactions
with ionizing radiation

DNA is primary target for cell damage from ionizing radiation


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Types of radiation induced


lesions in DNA
Base damage

Single-strand breaks
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Double strand breaks


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Mechanisms of DNA
repair

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DNA restoration failure

Unrejoined DNA
double strand breaks

Cytotoxic effect

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Incorrect repair of
DNA damage

Mutations

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Chromosomes

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DNA lesions and


chromosome aberrations

DNA SNGLE
STRAND BREAK
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DNA DOUBLE
STRAND BREAK
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Radiation induced
chromosomal aberrations

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Effect of radiation on cell


Cell kinetics

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Radiosensitivity of cell
in cell cycle
Relative
Survivability

G1

G2

G1

Relative survivability of cells irradiated in different phases of the


cell cycle. Synchronised cells in late G2 and in mitosis (M) showed
greatest sensitivity to cell killing.
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Mitotic death

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NORMAL

IRRADIATED

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Bergoni and Tribondeaus


law (1906)
The most radiosensitive cells are
actively proliferating/dividing at the
time of exposure
undifferentiated (non-specialized in
structure and function)

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Interphase death
Why are peripheral blood lymphocytes highly
sensitive to radiation, although well differentiated?

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Radiation induced
membrane damage

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Modification of radiation
injury
Dose rate and fractionation
Radiation quality
Temperature
Chemical modification
Oxygen
Radiosensitizing agents
Radioprotective agents

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Dose rate and


fractionation
3

2.5

2.5

1.5

1.5

0.5

0.5
0

Acute
exposure
with high
dose rate

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Time
Prolonged exposure
with lower dose rate

Acute
dose Fractionated
dose
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Time

Radiation quality

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Survival curve for mammalian cells


exposed to
high- (A) and low-LET (B) radiation
n

Dq

,037

1-1/e

1-1/e
D0

D0

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Temperature
For cell kiling effects, tissues are
more radiosensitive at higher
temperatures
Chromosome aberrations increase
at lower temperatures (suppression
of repair process)

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Chemical modification:
oxygen
Dissolved oxygen in tissues increases
stability and toxicity of free radicals
Oxygen enhancement ratio (OER) is
determined by:
OER =

Dose required to cause effect without oxygen


Dose required to cause effect with oxygen

The OER has a maximum value of 3.0


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Radiosensitizing agents
Halogenated
and
substituted
analoges of DNA bases: 5-bromouracil and 6-thio-guanine
Electroaffinic compounds:
Nitroimidazoles
(misonidazole,
nitroimidazole, and nitrofuran)
sensitization
enhancement
ratio
(SER) of 1.2 to 1.4
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Radioprotective
agents
Thiols (cysteine, 2-mercaptoethylamine,
cystamine and thiourea). Thiols have dose
reduction factor (DRF) ratio of 1.4 to 2.0
They are thought to protect cells by
scavenging free radicals
producing hypoxia
temporarily inhibiting DNA synthesis, allowing
time for the repair enzymes to complete repair
of sublethal damage
forming disulphide bonds in proteins, thereby
strengthening them
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