Transcript Biological effects of ionizing radiation at molecular and cellular levels

BIOLOGICAL EFFECTS OF IONIZING
RADIATION AT MOLECULAR AND
CELLULAR LEVELS
Module VIII-a
Historical background
Module Medical VIII.
-2
Discovery of X rays
(1895)
Wilhelm Conrad Roentgen
Module Medical VIII.
-3
Discovery of uranium’s natural
radioactivity
Antoine Henri Becquerel
Module Medical VIII.
Marie Curie
-4
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
radium dial painters
among
• 1930s: liver cancer and leukemia
due to Throtrast administration
• 1940s: excess leukemia among
first radiologists
Module Medical VIII.
-5
Studies of Japanese
A-bomb survivors
Module Medical VIII.
-6
Effects of radiation on cells at
atomic level
Excitation
Module Medical VIII.
Ionization
-7
Mechananisms of damage
at molecular level
Module Medical VIII.
-8
Direct action
Ionizing radiation + RH

R- + H+

Bond breaks
Module Medical VIII.
OH
O
I
II
R – C = NH
R – C = NH2
imidol (enol)
amide (ketol)
Tautomeric Shifts
-9
Indirect action
H
X ray
 ray
Module Medical VIII.
eP+
O
H
OHH+
Ho
OHo
- 10
Radiolysis of H2O
molecule
Shared electron
Shared electron
H-O-H  H+ + OH- (ionization)
H-O-H  H0+OH0
Module Medical VIII.
(free radicals)
- 11
Reactions with free radicals
H0 + OH0 HOH (recombination)
H0 + H0  H2 (dimer)
OH0 + OH0  H2O2 (hydrogen peroxide)
OH0+RH R0+HOH (radical transfer)
Module Medical VIII.
- 12
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)
Module Medical VIII.
- 13
Lifetimes of free radicals
RO2o
HO2o
H
o
OHo
OHo
3nm
Ho
Because short life of simple free radicals (1010sec), only those formed in water column of 2-3
nm around DNA are able to participate in
indirect effect
Module Medical VIII.
- 14
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
Module Medical VIII.
- 15
Biochemical reactions
with ionizing radiation
DNA is primary target for cell damage
from ionizing radiation
Module Medical VIII.
- 16
Types of radiation induced
lesions in DNA
Base damage
Single-strand breaks
Module Medical VIII.
Double strand breaks
- 17
Mechanisms of DNA
repair
Module Medical VIII.
- 18
DNA restoration failure
Unrejoined DNA
double strand breaks
Cytotoxic effect
Module Medical VIII.
Incorrect repair of
DNA damage
Mutations
- 19
Chromosomes
Module Medical VIII.
- 20
DNA lesions and
chromosome aberrations
DNA SİNGLE
STRAND BREAK
Module Medical VIII.
DNA DOUBLE
STRAND BREAK
- 21
Radiation induced
chromosomal aberrations
Module Medical VIII.
- 22
Effect of radiation on cell
Cell kinetics
Module Medical VIII.
- 23
Radiosensitivity of cell
in cell cycle
Relative
Survivability
G1
S
G2
M
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.
Module Medical VIII.
- 24
Mitotic death
Module Medical VIII.
NORMAL
IRRADIATED
- 25
Bergonié and Tribondeaus’
‘law’ (1906)
The most ‘radiosensitive’ cells are
 actively proliferating/dividing at the
time of exposure
 undifferentiated (non-specialized in
structure and function)
Module Medical VIII.
- 26
Interphase death
Why are peripheral blood lymphocytes highly
sensitive to radiation, although well differentiated?
Module Medical VIII.
- 27
Radiation induced
membrane damage
Module Medical VIII.
- 28
Modification of radiation
injury
Dose rate and fractionation
Radiation quality
Temperature
Chemical modification
Oxygen
Radiosensitizing agents
Radioprotective agents
Module Medical VIII.
- 29
Dose rate and
fractionation
3
3
2.5
2.5
2
2
1.5
1.5
1
1
0.5
0.5
0
0
Acute
exposure
with high
dose rate
Module Medical VIII.
Time
Prolonged exposure
with lower dose rate
Acute
dose Fractionated
dose
Time
- 30
Radiation quality
Module Medical VIII.
- 31
Survival curve for mammalian cells
exposed to
high- (A) and low-LET (B) radiation
n
Dq
1-1/e
1-1/e
,037
D0
D0
B
A
Module Medical VIII.
- 32
Temperature
For cell kiling effects, tissues are
more
radiosensitive
at
higher
temperatures
 Chromosome aberrations increase
at lower temperatures (suppression
of repair process)
Module Medical VIII.
- 33
Chemical modification:
oxygen
Dissolved oxygen in tissues increases
stability and toxicity of free radicals
Oxygen enhancement ratio (OER) is
determined by:
Dose required to cause effect without oxygen
OER =
Dose required to cause effect with oxygen
The OER has a maximum value of 3.0
Module Medical VIII.
- 34
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
Module Medical VIII.
- 35
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
Module Medical VIII.
- 36