This document summarizes a review article by Dr. Stephen Kron on the relevance and irrelevance of the DNA damage response to radiotherapy. It discusses how scientists have discovered the cellular mechanisms of DNA damage and repair in response to radiation, but there remains a gap in applying this knowledge to improve patient outcomes in radiotherapy. The document also reviews several studies examining factors like tumor hypoxia, oxidative damage, and DNA repair inhibition that influence radiotherapy effectiveness, noting that further research is still needed to better inform clinical practice.

1. Brian
Covello
Cell
Biology
Review:
“Relevance
and
irrelevance
of
DNA
damage
response
to
radiotherapy”
This
summer
I
will
be
working
under
Dr.
Stephen
Kron
at
the
University
of
Chicago.
As
an
MD/PhD
graduate,
Dr.
Kron
directs
his
research
towards
translation
of
scientific
discoveries
at
the
bench
to
improve
patient
outcomes,
and
his
review
article,
“Review:
Relevance
and
irrelevance
of
DNA
damage
response
to
radiotherapy,”
serves
to
highlight
the
translational
gap
that
currently
exists
between
doctors
and
scientists.
As
a
molecular
geneticist
and
biomolecular
engineer
he
seeks
to
understand
and
improve
targeted
ionizing
radiation
for
treating
human
malignancies.
As
a
doctor,
he
seeks
to
cure
his
patients
of
cancer.
Dr.
Kron
provides
a
brief
historical
background
of
ionizing
radiation,
followed
by
an
in
depth
review
of
the
specific
cellular
mechanisms
that
are
currently
molecular
targets
for
drug
therapies.
Since
the
time
of
this
review
in
2004,
Dr.
Kron
has
analyzed
histones,
chaperone
proteins,
cyclin,
various
tyrosine
kinase
receptors,
and
a
breadth
of
cell
cycle
checkpoints
in
various
model
organisms
in
an
attempt
to
comprehend
the
mechanisms
of
DNA
damage
and
repair.
For
the
past
century,
two
conventional
routes
have
existed
for
treating
cancer
–
radiotherapy
and
chemotherapy,
or
surgery.
With
the
discovery
of
ionizing
radiation
at
the
end
of
the
19th
century,
physicians
sought
to
selectively
target
tumors,
while
leaving
normal
tissue
unscathed.
Within
50
years,
scientists
had
discovered
that
the
target
of
radiation
damage
was
DNA,
yet,
this
scientific
discovery
had
little
effect
on
the
practice
of
physicians,
as
methods
for
assessing
success
of
radiotherapy
never
depended
upon
measurement
of
DNA
damage.
Within
the
realm
of
medicine,
efficient
radiotherapy
relies
heavily
on
the
damage
to
tumor
tissue
as
compared
to
that
of
normal
tissue.
This
ratio
is
called
the
tumor
control

2. Brian
Covello
Cell
Biology
probability,
and
different
histological
environments
provide
tumors
with
different
probabilities
of
susceptibility
to
radiotherapy.
In
essence,
therapeutic
indices
are
different
for
different
types
of
cancer.
As
such,
doctors
aim
to
determine
potential
risks
and
benefits
of
radiotherapy
for
each
individual.
Doctors
may
prescribe
radiotherapy
as
a
palliative
or
curative
treatment.
To
this
extent,
doctors
may
adjust
the
radiation
intensity
or
temporal
treatment
schedule.
Without
scientific
input,
doctors
may
do
little
more
than
guesswork
based
off
of
past
and
present
experiences.
To
propel
the
field
of
medicine
and
science,
a
coalition
between
these
disparate
fields
is
a
necessity.
EJ
Hall
et
al.
found
that
the
average
radiotherapy
treatments
that
doctors
prescribe
cause
roughly
40
double
stranded
DNA
breaks
per
diploid
genome,
and
thousands
of
single
strand
breaks
and
base
lesions.
Several
experiments
on
animal
models
have
found
that
normal
tissues
are
better
equipped
to
tolerate
small
repeated
doses
of
radiation,
yet
controversy
surrounding
treatment
schemes
and
radiation
dosage
are
pervasive.
Further
research
in
animal
models
is
required
to
scientifically
assess
the
therapeutic
index
for
cancer.
Several
cellular
mechanisms
are
known
to
synergize
with
radiation,
including
oxidative
damage
and
DNA
interacting
drugs.
TG
Graeber
et
al.
found
that
tumor
hypoxia
led
to
aggressive
forms
of
tumors
that
consisted
of
p53
mutations.
Physicians
attempted
to
utilize
this
research
for
patient
treatments
by
utilizing
various
methods
to
increase
blood
oxygen
levels
including
red
blood
cell
transfusions,
erythropoietin
treatments,
and
hyperbaric
oxygen
inhalation.
Clinical
treatments
with
the
various
methods
yielded
mixed
results,
ultimately
suggesting
complex
mechanisms
of
actions
for
various
tumors.
Medicine
is
in
need
of
more
in
vitro
and
in
vivo
studies
regarding
oxygen
free
radical
damage.
JM

3. Brian
Covello
Cell
Biology
Yuhas
et
al.
found
that
free
radical
scavengers
that
reduce
oxidative
damage
increase
radioresistance
in
myriad
tumors.
Due
to
this
discovery,
physicians
are
concerned
with
the
effects
of
thiol
drugs
in
patients
undergoing
radiotherapy.
Again,
no
further
research
has
been
conducted
to
assess
the
validity
of
this
concern.
From
a
scientific
perspective,
nucleoside
analogs
may
serve
as
another
method
to
radio-­‐sensitize
tumor
cells
to
IR,
yet
selective
targeting
to
tumor
cells
is
difficult.
Without
a
scientific
backing,
physicians
found
that
5-­‐flurouracil,
a
nucleoside
analog,
is
effective
in
reducing
rectal,
head,
neck,
esophageal,
and
anal
cancers.
The
efficiency
of
this
drug
has
never
been
tested
experimentally.
With
respect
to
ionizing
radiation,
science
is
primarily
concerned
with
cell
cycle
arrest,
induction
of
stress
responses,
DNA
repair,
and
apoptosis.
Within
these
various
aspects
of
cellular
biology
lies
numerous
potential
for
therapy.
One
approach
to
therapy
is
induction
of
sensitization
to
cancer
cells
through
inhibition
of
repair
mechanisms.
SJ
Collis
et
al.
found
that
siRNA
silencing
of
signaling
proteins
ATM
and
ATR
have
effectively
inhibited
IR-­‐induced
DNA
repair
mechanisms.
AJ
Belenkov
et
al.
sought
to
change
expression
of
Ku70,
Ku86,
and
DNA-­‐PKcs,
proteins
that
participate
in
non-­‐homologous
end
joining
(NHEJ),
a
repair
mechanisms
for
double
stranded
breaks.
Various
experiments
utilized
the
chemotherapeutical
agent
Wortmannin
to
inhibit
the
activation
of
those
proteins
studied
by
AJ
Belenkov.
Scientists
have
also
sensitized
cancer
cells
by
inhibited
RAD51
expression
and
targeting
histone
H2AX.
In
order
for
these
discoveries
to
translate
into
beneficial
molecular
therapies,
scientists
and
physicians
must
develop
methods
for
selective
delivery
to
tumors,
leaving
normal
cells
uninhibited
and
able
to
repair
DNA

4. Brian
Covello
Cell
Biology
damage.
To
attain
this
goal,
one
must
exploit
the
cellular
differences
between
cancerous
cells
and
normal
cells.
Compared
to
normal
cells,
tumor
cells
contain
abnormal
G1
checkpoints.
As
such,
molecular
targeting
of
these
checkpoint
mechanisms
provides
hope
for
increased
selectivity
of
therapies.
AJ
Tenzer
et
al.
found
that
targeted
inhibition
of
G2
checkpoint
mechanisms
through
the
drug
pentoxifylline
improved
tumor
response
rates.
This
treatment
allows
cancerous
cells
to
progress
towards
mitosis
at
a
faster
rate,
while
normal
cells
are
protected
due
to
normal
G1
checkpoints.
With
induction
of
mitosis,
the
cancer
cells
invariably
become
disrupted
by
DNA
damage
by
IR.
Physicians
are
currently
running
clinical
trials
to
test
efficacy
of
the
Chk1
inhibitor
UCN-­‐01.
The
consequence
of
IR
induced
DNA
damage
is
cellular
death.
Due
to
this
correlation,
apoptosis
has
been
investigated
extensively.
For
many
years,
scientists
and
doctors
alike
accepted
that
a
positive
correlation
existed
between
apoptosis
and
cancer
without
much
scientific
research.
Common
sense
may
indicate
that
expression
of
anti-­‐
apoptotic
genes
such
as
MDR1
would
serve
to
make
cells
more
resistance
to
IR,
serving
as
a
medicinal
means
to
strengthen
normal
cells
surrounding
cancer.
Yet
research
conducted
by
Ruth
and
Roninson
challenged
this
viewpoint,
and
they
found
that
although
expression
of
anti-­‐apoptotic
genes
resulted
in
reduced
apoptosis,
the
concomitant
increase
in
cells
undergoing
mitosis
followed
by
cellular
death
through
DNA
damage
by
IR
invalidated
expression
of
anti-­‐apoptotic
genes
as
a
valid
protection
against
IR.
Similarly,
BG
Wouters
et
al.
sought
to
increase
apoptotic
genes
in
cancer
cells
and
found
that
cells
became
more
resistant
to
IR
than
normal
cells.
More
research
is
needed
to
discover
the
underlying
mechanisms
of
these
experiments.

5. Brian
Covello
Cell
Biology
The
plasma
membrane
plays
a
critical
role
in
cellular
apoptosis.
The
accumulation
of
phosphatidylserine
on
the
outer
surface
of
the
plasma
membrane
marks
the
cell
for
phagocytosis
by
macrophages.
These
corresponding
signaling
pathway
are
also
a
molecular
therapy
target.
SM
Huang
et
al.
inhibited
the
epidermal
growth
factor
receptor
(EGFR),
whose
induction
by
IR
causes
the
cell
to
resist
apoptosis.
These
molecular
therapies
tend
to
be
cell-­‐type
dependent,
as
such,
the
tumor
microenvironment
must
be
considered.
The
microenvironments
greatly
complicate
the
design
of
therapeutics,
and
this
complexity
necessitates
personalized
medicine.
Tumors
are
also
markedly
distinct
from
normal
cells
due
to
enhanced
angiogenesis
and
microvasculature
formation
required
for
support
of
a
bulk
mass
of
cells.
O’Reilly
and
Folkman
sought
to
inhibit
angiogenesis
through
angiostatin
treatment,
and
the
research
group
found
increased
therapeutic
index
for
the
combined
treatment.
Specifically,
Dr.
Kron’s
laboratory
engineered
a
viral
vector
carrying
the
tumor
necrosis
factor
alpha.
This
vector
had
a
promoter
that
is
only
induced
upon
exposure
to
ionizing
radiation.
Thus,
injection
of
this
vector
into
the
tumor
site
allowed
release
of
an
apoptotic
that
controlled
through
exposure
to
radiation.
Clinical
trials
are
currently
taking
place
and
have
thus
far
proven
to
be
a
highly
effective
therapy.
The
gap
between
scientific
discoveries
and
medicinal
therapies
must
be
filled
for
cancer
therapeutics
to
progress.
As
a
researcher,
I
look
forward
to
working
with
Dr.
Kron
to
design
a
project
that
aims
to
control
inducible
and
selective
genetic
therapies
that
enhance
normal
cellular
response
to
ionizing
radiation
and
decrease
tumor
resistance
to
radiation.
It
is
research
such
as
this
that
truly
motivates
and
inspires
me,
for
I
believe
the
summit
of
intellect
is
the
application
of
knowledge
to
improve
the
wellbeing
of
our
society.