a model of radiationinduced cell death biophysical mechanisms and possible applications for hadron therapy BI ophysical AN alysis of C ell death and chromosome A berrations ID: 385365
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BIANCA*, a model of radiation-induced cell death: biophysical mechanisms and possible applications for hadron therapy*BIophysical ANalysis of Cell death and chromosome Aberrations
Francesca Ballarini1,2, Mario P. Carante1,21University of Pavia, Physics Department2INFN, Sezione di Paviafrancesca.ballarini@unipv.it
14
th
International Conference on Nuclear Reaction Mechanisms, Varenna (Italy), June 15 - 19, 2015Slide2
cell death: loss of the cell ability of duplicating and forming a colonychromosome aberrations: incorrect rearrangements
of chromosome fragments
typical dose-response: S =
exp (-D - D2)
typical
dose-response
: Y =
D +D
2
aberration involving chromosomes 11 and 12 in blood cells of an astronaut (www.nasa.gov)Slide3
Outline Rationale Methods assumptions simulation of target & projectile Results
comparison with experimental data implications for the mechanisms example of applications for
hadron therapy
Conclusions & future developments Slide4
Rationale/Background (1)further investigation needed on the action of ionizing radiation in biological targets, including cell killing by protons and carbon ions ( hadrontherapy)we (also) need models (mechanistic…but not too much)
what are the features of the critical DNA damage(s) leading to cell death and other biological effects? (sub-m scale), and what is the role of their spatial distribution in the cell nucleus? (m scale)how can this
information be used to
improve hadrontherapy?
general
specific Slide5
Rationale/Background (2)
2 mondi
Mechanistic
modelsmany parameters
cellular
/
subcellular
level
used
to
interpret
biophysical
mechanisms
Phenomenological
models
few
parameters
cell
/
tissue
/
organ
level
used
in
radiotherapy
BIANCA ?Slide6
Outline Rationale Methods assumptions simulation of target & projectile Results
comparison with experimental data implications for the mechanisms example of applications for
hadron therapy
application to
the BioQuaRT chromosome aberration data
Conclusions
& future
developments
Slide7
Assumption I radiation DNA damageradiation induces DNA “Cluster Lesions” (CLs
); each CL produces two independent chromosome fragments
mean
number of
CLs Gy
-1
cell
-1
is
the 1
st
adjustable
parameter
,
mainly
dependent
on
particle
type
&
energy
double
helix
chromosome
clusters
of
DNA
double-strand
breaks
(
DSBs
)
are
critical
because
they
disrupt
the
continuity
of
the chromatin fibre (Schipler and Iliakis 2013)
chromatin
fibreSlide8
Assumption IIDNA damage chromosome damage
only chromosome fragments with initial distance <d undergo
rejoining, producing
“chromosome
aberrations” in case of rejoining
with
the
incorrect
partner
d
is
the 2
nd
, and last,
adjustable
parameter
,
dependent
on the target
cell
features
evidence
for
“
repair
centres
”,
where
multiple
DSBs
migrate
for
repair
after travelling
a few microns (Neumaier et al. 2012) Slide9
Assumption
IIIchromosome damage
cell
death
some
chromosome-aberration
types
(
dicentrics
,
rings
and
deletions
,
called
“
Lethal
Aberrations
”)
lead
to
cell
death
cell
survival
probability
S = P
0
lethal
events
= e
–LA/
cell
one-to-one
relationship
between
LA/
cell
and
–lnS
in AG
human
cells
exposed
to
X-rays
(
Cornforth
&
Bedford
1987)
dicentric
ring
deletionSlide10
Simulation of cell nucleus nucleus modelled as cylinder or sphere chromosome territories modelled by the union of cubic voxels (0.2 m side) currently available genomes: human, hamster, rat
front view top viewexperimental visualization
of the 46 “chromosome territories
” (regions of the cell nucleus occupied by the various chromosomes) in a human cell
(Bolzer et al. 2005)
Reality…
..
…..and
modelSlide11
Simulation of DNA damage inductionX- or -rayslow-energy light ions (like p and He)
heavier ions (like C)
S
’
> S
CLs
also
outside
the “
core
”
of
the
primary
track
CLs
randomly
distributed
in the
nucleus
volume
number
of
CLs
in a
given
cell
nucleus
is
extracted
from
a
Poisson
distribution
(
mean
value
is
an
adjustable
parameter
)
S
CLs
along
(
parallel
)
segments
representing
the
various
primary
ions
number
of
primary
ions
traversing
a
given
cell
nucleus
extracted
from
a
Poisson
distribution
with
mean
value
n = D
S/(0.16
LET
*
)
number
of
CLs
induced
by
a
given
primary
ion
extracted
from
a
Poisson
distribution
with
mean
value
(
CL
Gy
-1
cell-1) x0.16xLET/S along each primary ion, CLs are located randomly
h
*Linear
Energy Transfer =
Stopping
PowerSlide12
Outline Rationale Methods assumptions simulation of target & projectile Results
comparison with experimental data implications for the mechanisms example of applications for
hadron therapy
Conclusions
& future developments Slide13
Comparisons with chromosome aberration data (1)broad beam exp. the model/code can predict chromosome aberrations by different radiations in different cellshuman lymphocytes
human fibroblasts(
Ballarini et al 2002, Radiat
Prot Dosim)
dicentrics
rings
-rays
alphas LET 116
X-rays
(
Ballarini
et al 2014,
Radiat
Environ
Biophys
)Slide14
Comparison with chromosome aberration data (2) microbeam exp. (EU project “BioQuaRT”) simulations: number of ions and ion
positions like in experiments (5 positions with variable number of ions)
x x
x x x
bottom view
of
cell
nucleus
PRELIMINARY
irradiations
performed
at
PTB-Braunschweig
,
Germany
,
with
a
microbeam
exact
number
of
ions
in
selected
cell
nuclei
E (
MeV
) LET (keV/m) ions/cell aberrations/cell
(
exp.) CLs/particle
10 90 10 0.61
(0.600.06)
0.69
20 37 25 0.35
(0.360.04)
0.20
p 10 5 200 0.35
(0.360.06)
0.024
good
agreement
between calculated and observed
chromosome aberrations
observed chromosome aberrations
were
interpreted
in
terms
of
CLs
/
particleSlide15
Comparison with cell survival data (Carante et al. 2015)
V79
AG
X
X
X or
AG
V79
10.1
(3.7
MeV
)
17.8
(1.8
MeV
)
27.6
(1.1
MeV
)
1.1
11.9
22.6
H
V79
AG
C 13
(290
MeV
/u
)
C 75
C 49
Fe 300
(400
MeV
/u)
C 148
C or Fe
parameters
:
d=5 m,
independent
of
radiation
quality
;
CL
2-16
CLs
Gy
-1
cell
-1
,
depending
on
radiation
quality
lethal
chromosome
aberrations
lead
to
cell
death
not
only
for
AG1522
cells
exposed
to
X-rays
,
but
also
for
other
cells
and
radiationsSlide16
Outline Rationale Methods assumptions simulation of target & projectile Results
comparison with experimental data implications for the mechanisms example of applications for hadron
therapy
Conclusions & future
developments Slide17
Cluster Lesions – dependence on radiation quality mean number of CLs per Gy per cell
CLs increased with LET, consistent with the hypothesis that CLs are a DNA cluster damage (for a given LET, light ions were more effective than heavier ions,
reflecting their nm-level
track structure)
more CLs for AG cells than for V79 cells,
reflecting
differences
in
radiosensitivity
H
He
C
Fe
(
Carante
et
al 2015,
Radiat
Environ
Biophys
)
AG
human
cells
V79
hamster
cellsSlide18
Cluster Lesions – (attempt of) characterizationtrend shown by CLs was more similar to the trend of kbp-fragments with respect to
bp- or Mbp-fragments (also) kbp fragments may be good candidates as a critical DNA damage (Carante et
al 2015)
comparison with
yields of DNA fragments with
size
at 3
different
scales
:
base-pair
(
double-helix
),
kilobp
(nucleosomes
)
and
Mbp
(
chromatin
fibre
loops
)
double-helix
nucleosomes
chromatin
fibre
loops
0.1-9
kilo-basepairs
p
He
C
FeSlide19
Outline Rationale Methods assumptions simulation of target & projectile Results
comparison with experimental data implications for the mechanisms example of application for hadron
therapy
Conclusions & future
developments Slide20
Example of application for hadron therapy (1)
62-MeV modulated proton beam @INFN-LNS in Catania, Italy (eye tumor therapy)
(
Chaudhary et al. 2014)
experiment
:
survival
of
AG01522
human
cells
irradiated
in 6
different positions
( 6 LET values)
of a therapeutic proton beam
simulations
:
survival
of
the
same
cells
exposed
to
6
proton
beams
having
the
same LET valuesX-rays
11.9
1.1
22.6
4.0
18.0
7.0Slide21
Example of application for hadron therapy (2) increase of biological effectiveness in the distal region of the SOBP
for 1 mm beyond the SOBP, both effects are higher with respect to the beam entrance damage to normal tissue
may be
higher than
expected applying a constant RBE (Relative Biological Effectiveness
)
of
1.1 (
like
in
clinics
)
important
in case
of
critical
organs just beyond the tumour
(e.g. retina)
calculation
/
prediction
of
cell
death
and
lethal
aberrations
for
AG
cells
@Catania
beam
Depth (mm)
Dose, Lethal Aberrations and cell death (a. u.)
LA/Cell
Dose
Cell deathSlide22
Example of application for hadron therapy (3) confirmed the increase of biological effectiveness in the distal region and the
shift of the “biological peak” for V79 cells (radioresistant), peak in biological effectiveness was sharper with respect to AG cells (radiosensitive)
V79
hamster cells (“virtual
experiment”)prediction of
cell
death
and
lethal
aberrations
for
V79
cells
@Catania
beam
lethal
aberrations
/
cell
fraction
of
inactivated
cells
doseSlide23
Outline (Rationale) Methods assumptions simulation of target & projectile Results
comparison with experimental data implications for the mechanisms example of applications for hadron
therapy
Conclusions & future
developments Slide24
Concluding remarksfundamental role of: - DNA cluster damage @sub-m scale (kbp?) - “proximity effects” @m scale
- lethal chromosome aberrationsGeneralSpecific
model
of cell death and DNA/
chromosome
damage
,
which
is
mechanism-based
but
uses
only
two
adjustable
parametersSlide25
Weak points… ...& strong pointsparameter CL depends not only on projectile, but also on target current version not suitable for cells showing high levels of
apoptosis (“cellular suicide”)not fully mechanistic… … …only two adjustable parameters
no use
of experimental RBE values,
which can be affected by uncertaintiesSlide26
extend to other cell types, including tumor cells model explicitly the cell-line radiosensitivity (now “included” in CL)
include other mechanisms, e.g.: apoptosis (“cellular suicide”) non-lethal chromosome aberrations second cancers integrate with
radiation transport
codes hadrontherapy
… …
…
…
…
future
developmentsSlide27
Acknowledgementsinfo/data sharing: M. Durante, K. Prise & G. Schettino, A. Tabocchini, A. Testa, C. Patrono & Uni Giesen (EU project BioQuaRT, coordinated by H. Rabus, PTB-Braunshweig, Germany)funding: INFN (National Institute of Nuclear Physics), projects “MiMo-Bragg” (2012-13) and “ETHICS” (ongoing
)…and the audience