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

Clustered DNA damages in

nucleosome

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).