Joint Institute for Nuclear Research Flerov Laboratory of Nuclear Reactions
Р Л Б Radiobiology of accelerated heavy...
Transcript of Р Л Б Radiobiology of accelerated heavy...
Л
Р
Б
Radiobiology of
accelerated heavy ions
What fundamental problems
were solved by the “classical
radiobiology”?
β
Interpretation of
“Radiobiological Paradox”
Why the small doses in
thermal equivalent (10
Gy) does kill all kinds
mammalians? This dose
increases the temperature
of human organism
barely up to 0.0010 C
0 100 200 300 400 500 600 700 800
1E-6
1E-5
1E-4
1E-3
0,01
0,1
1
10
100
Surv
ival cells
,%
Dose, Gy
S = e-D
Discovery of mutagenic
effect of irradiation
Ionizing radiation induces the
different types of mutations with high
frequency
Guanine
Ionizing radiation
induces a cancer
Solid cancer
The DNA is a targetin irradiated cells
Ionizing radiation induces the
different DNA damages
Discovery of complicated
hierarchy of DNA repairmechanisms
The DNA repair system is the
main mechanism of the
genome stability
Investigation of biological
effects of accelerated heavy
ions forms the “new
radiobiology”
The sources of heavy ions
of high energies
On Earth - accelerators of
heavy charged particles
In space – cosmic rays from
Galaxy
The JINR accelerators
LabEnergy
(up to)
ParticlesAccelerator
LNP660MeVProtonsPhasotron
LNR10MeV/amuHeavy ionsU-200
LNR50 MeV/amuHeavy ionsU-400M
LHE6 GeV/amuProtons,
Heavy ions
Nuclotron
LHE10 GeV/amuProtons,
Heavy ions
Sinchrophasotron
Accelerator of heavy ion U-400M
Heavy ion
beams with
energy up to 50
MeV/nucleon
Synchrophasotron
Nuclotron
The nuclotron beams
2.10710484Kr
10710656Fe
3.10810824Mg
7.10910912C
10101094He
10131010 - 1011p, d
In 2007Present statusBeam
Intensity (particles per cycle)
The maximal energy of particles up to 6 GeV/amu
50 um
Fe
Сегменты треков тяжелых ионов
в ядерной эмульсии
Tracks of heavy ions in
nuclear emulsion
1 unit of the dose 1 unit of the dose
X-rays Fe ion
The dose distribution of
radiation in matter
Радиус трека, см
Радиус трека, смРадиус трека, смr, cм
D o
s e
, G
yExp. Varma
----- Katz
….. Chatterjee
Radial dose
distribution in track
of heavy ion (12C,
2,57 MeV/u)
What radiobiological
problems can be solved at use
of the accelerated heavy
particles?
A.
Heavy ions is a powerful tool for
the solve of fundamental problems
of radiation genetics
The RBE problem was solved at
the Flerov Lab accelerators
DNA repair capacity of the
living cells determines the
type of RBE on LET
dependence
block of DNA repair
normal repair
super fast repair
Bacterial cells
Повреждение
основания
Повреждение сахара
Single strand break
Base damage
Sugar damage
Single DNA damages
Clustered DNA damages
Fragment of DNA
Clustered DNA damages
Double strand break of DNA
Sugar damage
Base damages
Base damages
Yield of clustered damages on
both DNA strands versus LET
D = 0 Гр D = 5 Гр
D = 40 Гр D = 20 Гр
D =10 Гр
D = 60 Гр0 10 20 30 40 50 60
0
500
1000
1500
2000
2500
3000
Доза, Гр
7Li
ДР
/ге
но
м
“Comet assay” for detection of DNA
lesions
The mechanism of DSB DNA repair in human cells
Ku70-Ku80 + ДНК PK
связывает концы ДНК
Rad50/Mre11/NBS1
заполняет гэп
XRCC4/lig4 зачищает и
связывает концы
Нити восстановлены
(репарация с ошибками)
Rad50/Mre11/NBS1 резицирует 5’
концы. 3’ концы защищены RPA
Rad51соединяет 3’
концы
Rad51/52/54 обеспечивает
поиск гомологии и миграцию
ветвей
Синтез гомологичных ветвей
Завершение репарации
лигированием концов и разрешение
структуры
MRE11
белок
DSB (-H2AX) in human cells after X-ray
(А) and heavy ion irradiation (B)
А B
-rays
Bismuth ions (4.1 MeV/amu)
Radiation induced mutagenesis
Nm
/N
Nm
/N 10
-5
tonB colB tonB
The frequency of tonB and colB mutation
induction after γ-ray and heavy ion irradiation
Dose, Gy Dose, Gy Dose, Gy
FMNH2+ RCHO + O2 FMN + RCOOH +H2O + h
luciferase
Induction of mutagenic
DNA repair by heavy ions
Mutagenic belt of heavy particle track
Cor
- -rays;
- 4He (20 keV/μm);
- 4He (50 keV/μm);
- 4He (78 keV/μm);
- 12C (200 keV/μm)
Induction of tonB-trp- deletion
mutations by heavy ions
0,8
1,0
1,2
1,4
1,6
1,8
2,0
2,2
2,4
2,6
2,8
3,0
0,1 1 10 100 1000
x
x
x
x
L E T , keV/m
R B
E
x
3,2
1
2
3
RBE on LET dependence
1 – tonB mutations
2 – tonBtrp- deletions
3 – lethal effect
Formation of unstable
chromosomal aberration after heavy
ion irradiation of human cells
Unstable
chromosomal
aberration
Block of cell division
Stable
chromosomal
aberration
Formation of stable
chromosomal aberration after
heavy ion irradiation of human
cells
-rays
Successful of cell division
0,1 1 10 100 1000
0
1
2
3
4
5
6
+
+ +
+
+
+
+ +
+
R
B
E
L E T
+
1
2
3
1 - survival
2 - chromosomal aberrations
3 - mutagenesis
RBE as a function of LET on
induction of mutations, chromosomal
aberrations and cell inactivation
B.
Accelerated heavy ions is a tool
for modeling of biological action
of space radiation
Heavy charged particles from Galaxy
are the most dangerous type of cosmic
radiation
Земля
The GCR flux
The integral flux of GCR
particles of carbon and iron
groups equals to 107 part cm-2
per year
The relative flux
of GCR particles
Отн
оси
тельн
ый
пото
к
Заряд ядра (Z)
The energy spectrum of GCR and
Nuclotron accelerator
Beam
Sample
Multiwire proportional
chamber
Monitor
ionization
chamberActivation
detector
Holder of TLD
matrix
Experimental Layout
Consequences of action of
Galactic heavy ions
Induction of cancer;
Formation of gene and structural
mutations;
Violation of visual functions:
lesions of retina;
cataract induction.
The frequency of cells with unstable
chromosome aberrations
Human lympho-
cytes exposed to
protons 1 GeV,12C, 24Mg ions
with energy 500
MeV/nucleon
D o s e , G y
Cel
ls w
ith
ch
rom
oso
mal
ab
erra
tio
ns,
%
D o s e , G y
Nu
mb
er o
f a
ber
rati
on
s p
er 1
00
cel
ls
b)a)
Chronic myeloid leukemia as a
result of gene translocation ABL gene
BCR gene
ABL BCR
chromosome 9
chromosome 22
chr. 9
chr. 22
c h i m e r a
Chronic myeloid leukemia
Accelerated heavy
ions and CNS
A B
A B
Fe
p
p
p
e
Mixed Field
Multi-hit
Cosmic ray hit frequencies in CNS critical areas
CNS in General
2 or 13% cells will be hit at least one Fe
particle
8 or 46% would be hit by at least one
particle with Z15
Every nucleus will be traversed by a
proton once every 3 days and a alpha
particle once every 30 days.
0 cGy 50 cGy
100 cGy 200
cGy
TRACK DIRECTION
FE ION TRACKS VISUALIZED BY MARKERS OF DNA DSBs (γH2AX)
Accelerated heavy ions
and cancer therapy
Depth dose distribution
Depth dose distribution
0
10
20
30
40
50
60
70
80
90
100
110
20 40 60 80 100 120 140 160 180
Thickness of water, мм
Rel
ati
ve
dose
, %
Depth-Dose Distribution of 12C beam 04.07.04
0
1
2
3
4
5
6
7
8
9
10
11
27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
t, g/cm 2 of Plexiglass
Do
se t
o P
uls
, cG
y
Therapeutic 170 MeV proton beam
modified by means of the edge filter
12C ion beam generated by
nuclotron
The energy deposition of heavy ions in genetic
structures is characterized of high specifity. This
determine the peculiarities of different radiation
induced effects:
• Induction of cluster DNA damages;
• Repression or inactivation of DNA repair capacity;
• High values of RBE;
• Repression or absence of modification effect of different radiomodificators (oxygen effect, radioprotectors, radiosensitizers).