Cancer therapy usually involves exposing the body to

agents that kill cancer cells more efficiently than normal

tissue cells. Such therapies must therefore exploit specific
molecular and cellular features of the cancer they are aim-
ing to eliminate. Most cancer cells proliferate more rapidly
than their normal counterparts so most cancer drugs
target the cell cycle. Cell division can be targeted directly
by inhibitors of the mitotic spindle, thus preventing equal
division of DNA to the two daughter cells. The growth sig-
nals that result in entry into the cell cycle can be targeted
by hormonal manipulation, therapeutic antibodies and
drugs that inhibit growth signalling pathways. However,
the most common means of targeting the cell cycle is to
exploit the effect of DNA-damaging drugs. DNA damage
causes cell-cycle arrest and cell death either directly or
following DNA replication during the S phase of the cell
cycle. Cellular attempts to replicate damaged DNA can
cause increased cell killing, thus making DNA-damaging
treatments more toxic to replicating cells than to non-
replicating cells. However, the toxicity of DNA-damaging
drugs can be reduced by the activities of several DNA
repair pathways that remove lesions before they become
toxic. The efficacy of DNA damage-based cancer therapy
can thus be modulated by DNA repair pathways. In addi-
tion, some of these pathways are inactivated in some cancer
types. These two features make DNA repair mechanisms a
promising target for novel cancer treatments.
DNA-damaging agents in cancer treatment
Many cancer drugs employed in the clinic have been
used for several decades and are highly efficient in kill-
ing proliferating cells (FIG. 1). High levels of DNA damage
cause cell-cycle arrest and cell death. Furthermore, DNA
lesions that persist into the S phase of the cell cycle can
obstruct replication fork progression, resulting in the
formation of replication-associated DNA double-strand
breaks (DSBs). DSBs are generally considered to be the
most toxic of all DNA lesions
1,2
.
Common types of DNA damage that interfere with
replication fork progression are chemical modifications
(adducts) of DNA bases, which are created by reactive
drugs that covalently bind DNA either directly or after
being metabolized in the body. These alkylating agents are
grouped in two categories: monofunctional alkylating
agents with one active moiety that modifies single bases
and bifunctional alkylating agents that have two reactive
sites and crosslink DNA with proteins or, alternatively,
crosslink two DNA bases within the same DNA strand
(intra-strand crosslinks) or on opposite DNA strands
(inter-strand crosslinks). Inter-strand crosslinks pose a
severe block to replication forks.
DNA synthesis is sometimes targeted by inhibitors
of DNA replication, such as aphidicolin, which directly
inhibits DNA polymerases
3
, whereas the radical scav-
enger hydroxyurea inhibits ribonucleotide reductase,
which is required for production of the dNTPs that are
used for DNA synthesis
4
. These two replication inhibi-
tors can be regarded as DNA-damaging agents because
they impair replication fork progression and cause DNA
lesions, including DSBs
5,6
.
Antimetabolites, such as 5-fluorouracil (5FU) and thio-
purines, resemble nucleotides, nucleotide precursors or
cofactors required for nucleotide biosynthesis and act
by inhibiting nucleotide metabolism pathways, thus
*Radiation Oncology &
Biology, University of Oxford,
Old Road Campus Research
Building, off Roosevelt Drive,
Headington, Oxford,
OX3 7DQ, UK.

Department of Genetics
Microbiology and Toxicology,
Stockholm University, Svante
Arrhenius vg 16, S-106 91
Stockholm, Sweden.
Correspondence to T.H.
e-mail: thomas.helleday@rob.
ox.ac.uk
doi:10.1038/nrc2342
Published online
7 February 2008
Alkylating agents
Electrophilic compounds that
are reactive either directly or
following metabolism and bind
covalently to electron-rich
atoms in DNA bases (that is,
oxygen and nitrogen).
Antimetabolites
Compounds with similar
chemical structures to
nucleotide metabolites that
interfere with nucleotide
biosynthesis or are
incorporated into DNA.
DNA repair pathways as targets
for cancer therapy
Thomas Helleday*

, Eva Petermann*, Cecilia Lundin*, Ben Hodgson*and

Ricky A. Sharma*
Abstract | DNA repair pathways can enable tumour cells to survive DNA damage that is
induced by chemotherapeutic treatments; therefore, inhibitors of specific DNA repair
pathways might prove efficacious when used in combination with DNA-damaging
chemotherapeutic drugs. In addition, alterations in DNA repair pathways that arise during
tumour development can make some cancer cells reliant on a reduced set of DNA repair
pathways for survival. There is evidence that drugs that inhibit one of these pathways in
such tumours could prove useful as single-agent therapies, with the potential advantage
that this approach could be selective for tumour cells and have fewer side effects.
REVI EWS
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Non-homologous end
joining
Connection and resealing of
the two ends of a DNA double-
strand break without the need
for sequence homology
between the ends.
Homologous recombination
A process that can copy a DNA
sequence from an intact DNA
molecule (often the newly
synthesized sister chromatid)
to repair or bypass replication
lesions.
Base-excision repair
A repair pathway that replaces
missing or modified DNA
bases, such as those produced
by alkylating agents or in
spontaneously degraded DNA,
with the correct DNA base.
Nucleotide-excision repair
A process that removes large
DNA adducts or base
modifications that distort the
double helix and uses the
opposite strand as template
for repair.
Alkyltransferases
A class of enzymes that
directly reverse DNA base
modifications that are induced
by alkylating agents by
transferring the alkyl group
from the base onto the
protein.
depleting cells of dNTPs. They can also impair replication
fork progression by becoming incorporated into the DNA
7
.
In general, the molecular mechanisms through which
anti-metabolites induce cell death are poorly understood.
Another means of interfering with replication is to
exploit DNA strand breaks that arise naturally during the
process of DNA synthesis. Topoisomerases are a group
of enzymes that resolve torsional strains imposed on
the double helix during DNA replication. They induce
transient DNA breaks to relax supercoiled DNA or allow
DNA strands to pass through each other
8
. Resealing of
these breaks can be prevented by the use of topoisomer-
ase poisons that trap the enzymes in complex with the
DNA. The nature of the damage that is caused depends
on which type of enzyme is targeted. Topoisomerase II
poisons cause DSBs, and topoisomerase I poisons cause
positive supercoils in advance of replication forks
134

and replication-associated DSBs
1,2
. This is a strategy
commonly used for cancer treatment.
Ionizing radiation and radiomimetic agents such as
bleomycin cause replication-independent DSBs that can
kill non-replicating cells. In addition, such treatments
can also rapidly prevent DNA replication by activation of
cell-cycle checkpoints to avoid formation of toxic DNA
replication lesions
9
.
Cell-cycle checkpoints are regulated by effector kinases,
such as ataxia telangiectasia mutated (ATM) and ATM
and Rad3-related (ATR)
1012
, which regulate the activities
of downstream checkpoint proteins, such as checkpoint
kinases 1 (CHK1) and 2 (CHK2). Defects in DNA dam-
age checkpoint pathways result in sensitivity to a range of
anticancer treatments, for example, loss of ATM results in
sensitivity to ionizing radiation
13
. The triggering of these
checkpoints and subsequent DNA repair activity largely
determines the efficacy of anticancer drugs in causing
tumour regression.
Efficient repair of chemotherapy lesions
Direct DSBs are mainly repaired by non-homologous
end joining
14
, whereas replication-associated DSBs
are repaired by homologous recombination (HR)
15
and
related replication repair pathways. DNA adducts, such
as those created by alkylating agents, may be excised
and repaired before they are confronted by the replica-
tion machinery. This is achieved by base-excision repair,
excising a single damaged DNA base or a short strand
containing the damaged base
16
or nucleotide-excision
repair (NER), which excises a single-stranded DNA
molecule of approximately 2430 base pairs contain-
ing the DNA lesion
17,18
. Damaged DNA can also be
repaired without removal of the damaged base, in a
process that directly reverses the DNA alkylation
19
. The
O-6-methylguanine-DNA methyltransferase (MGMT)
is an alkyltransferase that removes alkylations on the O
6

position of guanine produced by anticancer drugs such
as temozolomide
20
, and the DNA dioxygenases ABH2
(also known as ALKBH2) and ABH3 (also known
as ALKBH3) revert 1-methyladenine and 3-methyl-
cytosine back to adenine or cytosine respectively
21
. The
repair of alkylated lesions is thought to be quick, with
the majority of lesions probably being repaired within
one hour. If the lesions are removed before the initia-
tion of replication, the efficiency of alkylating agents in
killing the tumour is significantly reduced. Thus, modu-
lation of DNA repair clearly influences the efficacy of
alkylating agents, and resistance to alkylating agents is
often explained by increased expression and/or activity
of DNA repair proteins.
Whereas most DNA repair pathways mediate
resistance to DNA damage, mismatch repair is actually
required for the toxicity of several anticancer drugs
(FIG. 1). This has been explained by the futile repair
cycle model in which mismatch repair removes the
newly inserted intact base instead of the damaged base,
triggering subsequent rounds of futile repair which can
be deleterious to the cell
22
. It is also possible that mis-
match repair might have an important role in triggering
checkpoint signalling and apoptosis, which might medi-
ate increased cytotoxicity
23
. It has been established that
a defect in mismatch repair is associated with resistance
to many, but not all, DNA-damaging anticancer agents,
such as monofunctional alkylating agents and cispla-
tin, as well as the antimetabolite 6-thioguanine
7,22,24
. It
should be noted that mismatch repair acts directly at
replication forks and can therefore not prevent them
from encountering damage.
Collapse of replication forks during DNA synthesis
can be avoided by bypassing DNA lesions in a process
called translesion synthesis
25,26
. This process is carried out
by switching the regular polymerases, and , which
are responsible for leading and lagging strand synthesis,
respectively
27,28
, to polymerases with different substrate
specificities, thus enabling them to bypass different types
of damaged bases
29
.
Once a replication fork stalls or collapses, other
repair pathways are required to permit resumption of
replication. Collapsed replication forks are recognized
by the checkpoint machinery, which will in turn trigger

At a glance
Several cancer chemotherapy drugs work by producing excessive DNA damage that
causes cell death directly or following DNA replication. Survival is promoted through
repair of these lesions by a number of DNA repair pathways.
The efficacy of anticancer drugs is highly influenced by cellular DNA repair capacity.
Inhibitors of DNA repair increase the efficacy of DNA-damaging anticancer drugs in
preclinical models. Small-molecule inhibitors of DNA repair have been combined
with conventional chemotherapy drugs in several phase III clinical trials.
Tumour development can be associated with perturbed DNA damage response and
repair pathways. This perturbation results in reduced DNA repair capacity and
increased genetic instability in tumour cells. Defects in one DNA repair pathway can
be compensated for by other pathways. Such compensating pathways can be
identified in synthetic lethality screens and then specifically targeted for treatment
of DNA repair-defective tumours.
Evidence indicates that inhibitors of DNA repair pathways can work as single agents
for the targeted treatment of DNA repair-defective cancers. This hypothesis is
currently being tested in phase II trials in which patients with breast or ovarian
cancers that are defective in homologous recombination are being treated with a
poly(ADP-ribose) polymerase inhibitor.
Tumours often exhibit replication stress as a consequence of oncogene-induced
growth signals or hypoxia-induced replication arrest. We propose that DNA repair
inhibitors could be used to prevent the repair of replication lesions present in tumour
cells and convert them into fatal replication lesions that specifically kill cancer cells.
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Nature Reviews | Cancer
OH

Toxic lesions
Single-strand breaks
Double-strand breaks
Base damage
Includes mismatch
repair-mediated
toxicity
No
Major repair pathways

HR
HR
HR
HR
HR
Yes
Alkylsulphonates
Nitrosourea compounds
Temozolomide
b Monofunctional alkylators
c Bifunctional alkylators
Nitrogen mustard
Mitomycin C
Cisplatin
NER
NER
AT
Yes
?
Cancer treatment
Yes
BER
BER
BER
d Antimetabolites
5-Fluorouracil (5FU)
Thiopurines
Folate analogues
NHEJ
NHEJ
NHEJ
SSBR
SSBR
e Topoisomerase inhibitors
Camptothecins
Etoposide (VP16)
f Replication inhibitors
Aphidicolin
Hydroxyurea
a Radiotherapy and radiomimetics
Ionizing radiation
Bleomycin
TLS
TLS
No
No
FA
FA
FA
FA
O
2
G
RecQ
RecQ
RecQ
RecQ
Double-strand breaks
Replication lesions
Double-strand breaks
Single-strand breaks
Replication lesions
Double-strand breaks
DNA crosslinks
Bulky adducts
Replication lesions
Base damage
Bulky adducts
Replication lesions
ENDO
ENDO
ENDO
ENDO
Replication lesions
Uncharacterized
Base damage
Pt
H
3
C
S
O

O O
H
3
C
S
OCH
3
O O
CH
3
N
N
N
H
N
SH
H
2
N
H
3
N
Pt
NH
3
Cl Cl
DNA dioxygenases
A class of enzymes that
directly reverse DNA base
methylations through an
oxidation mechanism. The
human DNA dioxygenase
ABH2 is thought to act at
replication forks.
Mismatch repair
A process that acts during
DNA replication to correct
base-pairing errors made by
the DNA polymerases.
Figure 1 | Overview of DNA repair pathways involved in repairing toxic DNA lesions formed by cancer
treatments. The DNA-damaging agents that are used in cancer treatment induce a diverse spectrum of toxic DNA
lesions. These lesions are recognized by a variety of DNA repair pathways which are lesion-specific but are
complementary in some respects. a | Ionizing radiation and radiomimetic drugs induce double-strand breaks
(DSBs) that are predominantly repaired by non-homologous end joining (NHEJ). b, c | Monofunctional alkylators (b)
and bifunctional alkylators (c) induce DNA base modifications, which interfere with DNA synthesis. Lesions
produced by some alkylators are processed into toxic lesions in a mismatch repair-dependent manner. The base-
excision repair (BER) and nucleotide-excision repair (NER) pathways are, together with alkyltransferases (ATs),
major repair pathways, whereas other repair pathways repair toxic replication lesions, such as those produced by
interstrand crosslinks. d | Antimetabolites interfere with nucleotide metabolism and DNA synthesis, causing
replication lesions which have not yet been characterized. Mismatch repair mediates the toxicity of some
antimetabolites (for example, thiopurines). The repair pathways involved in repair of antimetabolite-induced
lesions are, apart from BER, poorly characterized. e | Topoisomerase poisons trap topoisomerase I or II in transient
cleavage complexes with DNA, thus creating DNA breaks and interfering with replication. f | Replication inhibitors
induce replication fork stalling and collapse, resulting in indirect DSBs. The relative contributions of the major
repair pathways to the respective types of DNA damage outlined are indicated by the sizes of the boxes. This is
based on the extent of sensitivity of repair-deficient cells to anticancer drugs in each category. ENDO, endonuclease-
mediated repair; FA, Fanconi anaemia repair pathway; HR, homologous recombination; O
2
G, DNA dioxygenases;
RecQ, RecQ-mediated repair; SSBR, DNA single-strand break repair; TLS, translesion synthesis.
REVI EWS
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Translesion synthesis
A mechanism during DNA
replication in which the
standard DNA polymerase is
temporarily exchanged for a
specialized polymerase that
can synthesize DNA across
base damage on the template
strand.
Fanconi anaemia repair
pathway
Proteins of this pathway,
including BRCA2, are mutated
in the hereditary disorder
Fanconi anaemia (FA), resulting
in hypersensitivity to inter-
strand crosslinks. Evidence
suggests that the FA pathway
promotes the repair of stalled
replication forks, possibly by
activating HR and facilitating
ATR- and ATM-dependent
checkpoint signalling.
Endonuclease-mediated
repair
A repair pathway that
introduces a DNA single-
strand break in a DNA
structure to facilitate
continuous repair.
RecQ-mediated repair
A repair pathway that unwinds
complex DNA structure to
facilitate repair.
Therapeutic index
The therapeutic index
describes the ability of a
treatment strategy to kill
cancer cells in preference to
cells in normal tissues.
cell-cycle arrest
12
, DNA repair
30
or cell death through
apoptosis or senescence
3133
. Although we know little
of the nature of replication lesions, there is an increas-
ing body of information concerning pathways that
repair them. HR has a central role in the repair of most
replication lesions formed by anticancer drugs
5,6,15,34
.
There are several ways by which HR is used to restart
replication. The sequence identity between two newly
synthesised DNA molecules can be used to restart rep-
lication behind the replication block. Also, recombina-
tion can be used to bypass DNA lesions in a process
called template switching
35
. Other repair pathways
active at replication forks involve the Fanconi anaemia
(FA) repair pathway
36
, endonuclease-mediated repair, such
as that mediated by the MUS81 endonuclease
37
, and
RecQ-mediated repair, which involves DNA helicases
such as Bloom syndrome (BLM)
38
, Werner syndrome
(WRN)
39,40
and other members of the RecQ family of
helicases
41
. Several of the proteins in these pathways
have been found to be directly linked with HR
42
or the
resolution of recombination products such as Holliday
junctions
38,40,43,44
. However, cells that are defective in
these pathways show distinct differences from HR-
defective cells, indicating that they represent different
but overlapping repair pathways
45
.
Cells defective in a specific DNA repair pathway
exhibit sensitivity to drugs producing DNA lesions that
are normally repaired by that pathway. This sensitivity
has been exploited to isolate hamster cell lines showing
hypersensitivity to cancer treatments such as etoposide,
mitomycin C and ionizing radiation, and also to allow
cloning of genes involved in DNA repair
46
. The DNA
repair pathways involved in the repair of damage caused
by various anticancer agents are summarized in FIG. 1.
These DNA repair pathways can have increased activity
in tumour cells, resulting in resistance to chemotherapeu-
tic drugs
47
. Importantly, these DNA repair pathways can
be inhibited pharmacologically to potentially increase the
efficacy or specificity of anticancer agents.
DNA repair inhibitors in combination therapy
The basic understanding of DNA repair, from the
principles of the DNA lesions created to the pathways
that are capable of repairing these lesions, has increased
considerably during recent years. This knowledge
permits rational combination of cytotoxic agents and
inhibitors of DNA repair to enhance tumour-cell killing.
Understanding lesions and repair pathways enables the
use of DNA-repair inhibitors to exploit tumour defects
or cancer-specific replication lesions (BOX 1). Several
inhibitors of DNA repair have been developed as clinical
agents and clinical trials are ongoing (TABLE 1).
Sensitizers to alkylating agents. Despite the adverse side
effects caused by alkylating agents on bone marrow and
other normal tissues, drugs such as cyclophosphamide,
ifosfamide, chlorambucil, melphalan and dacarbazine
remain some of the most commonly prescribed
chemotherapies in adults and children with various
solid and haematological malignancies, particularly in
combination with anthracyclines and steroids in multi-
agent regimens. More recently, a DNA alkylator and
methylator developed in the 1980s, temozolomide (an
oral prodrug that crosses the bloodbrain barrier), has
changed clinical practice in the treatment of high-grade
gliomas in adults and children
48,49
.
A class of agents currently being tested in clinical
trials in combination with temozolomide therapy con-
sists of the pseudosubstrates for MGMT. The lead com-
pounds in this class have been O
6
-benzylguanine
50
and
lomeguatrib (AstraZeneca, London, UK); the latter is
also known as O
6
-(4-bromothenyl)guanine or PaTrin-2.
Resistance to O
6
-alkylating agents can be overcome in
preclinical models by depletion of MGMT
51
and a rela-
tionship exists between MGMT activity and resistance
to chloroethylating nitrosoureas and methylating agents
in tumour cells grown in vitro and in xenograft mod-
els
52
. O
6
-Benzylguanine and lomeguatrib have recently
been tested in phase III clinical trials and biologically
effective doses have been established for both agents
53
.
In the case of O
6
-benzylguanine, a phase I clinical trial
not only defined the maximum tolerated dose (MTD)
of a single dose of temozolomide when combined with
O
6
-benzylguanine, but it also determined the dose
of O
6
-benzylguanine that was effective in producing
complete depletion of tumour MGMT activity for
48 h
54
. However, results obtained so far indicate that,
when used in combination with cytotoxic chemo-
therapy, myelosuppression is significantly enhanced
by O
6
-benzylguanine and lomeguatrib, necessitating
significant reductions in the doses of alkylating agents
prescribed from those used in standard chemotherapy
55
.
On account of this lack of selectivity for malignant tis-
sue versus normal bone marrow, no improvement in the
therapeutic index has so far been demonstrated in clinical
trials of these agents.
The combination of temozolomide with inhibitors
of poly(ADP-ribose) polymerase 1 (PARP1) is currently
under investigation in several clinical trials (TABLE 1).
PARP1 is required for the efficient base-excision repair
of apurinic sites, the intermediate DNA lesions induced
by temozolomide, and inhibition of PARP1 retards the
repair of these lesions. It was originally shown in 1980
by Durkacz and Shall that specific inhibitors of PARP
can prevent the rejoining of DNA strand breaks that are
caused by dimethyl sulphate, resulting in demonstrable
cytotoxicity in vitro
56
. However, in the absence of PARP1
inhibition, apurinic sites are not generally regarded

Box 1 | Strategies using DNA repair inhibitors in cancer treatment
DNA repair inhibitors can be used in combination with a DNA-damaging anticancer
agent. This will increase the efficiency of the cancer treatment by inhibiting DNA
repair-mediated removal of toxic DNA lesions.
DNA repair inhibitors can be used as monotherapy to selectively kill cancer cells
with a defect in the DNA damage response or DNA repair. Synthetic lethal
interactions between a tumour defect and DNA repair pathway can be used to
identify novel treatment strategies.
In the future, DNA repair inhibitors could potentially be used to amplify tumour-
specific replication lesions to selectively kill cancer cells. This strategy would take
advantage of cancer-specific replication stress caused by oncogenes or the tumour
microenvironment.
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as major contributors to the cytotoxicity induced by
temozolomide. The success of the treatment rationale
adopted by current clinical trials of GPI-21016 (Guilford
Pharmaceuticals, Baltimore, Maryland, USA), INO-1001
(Inotek Pharmaceuticals, Beverly, Massachusetts, USA)
and AG-014699 (Pfizer GRD, La Jolla, California, USA)
depends on the overall biological role of and necessity
for PARP in cancer cells that are trying to repair the
DNA damage induced by temozolomide. The role of
PARP in DNA repair has not been fully elucidated and
additional roles for PARP in DNA damage signalling or
repair might explain the increased toxicity of combina-
tion treatments
57,58
.
Platinum chemotherapies. Cisplatin, carboplatin and
oxaliplatin have become three of the most commonly
prescribed chemotherapeutic drugs used to treat solid
cancers in patients
59
. Platinum resistance, either intrin-
sic or acquired during cyclical treatment, is a major
clinical problem as additional agents that can be added
to therapy in order to circumvent tumour resistance do
not currently exist.
Platinum chemotherapy is now being tested with PARP
inhibition in two clinical trials (TABLE 1). The rationale for
combining PARP inhibition with platinum chemotherapy
is based on preclinical observations that PARP inhibitors
preferentially kill neoplastic cells and

induce complete
or partial regression of a wide variety of

human tumour
xenografts in nude mice treated with platinum chemo-
therapy
6062
. For example, ABT-888 (Abbott Laboratories,
Chicago, Illinois, USA), a potent inhibitor of PARP1 and
PARP2,

has been shown to potentiate the regression

of
established tumours induced by temozolomide, cisplatin,
carboplatin or cyclophosphamide therapy in rodent ortho-
topic and xenograft models
63
. However, as stated above,
the full function of PARP in DNA repair is not clear
57,58
,
and as a result the biological mechanisms of chemosensiti-
zation of cancer cells to platinum chemotherapy by PARP
inhibition remain to be resolved. Interestingly, as a mono-
therapy in these preclinical models,

ABT-888 exhibits no
significant anticancer activity.
DNA demethylating agents such as 2-deoxy-5-
azacytidine (decitabine; MGI Pharma, Bloomington,
Minnesota, USA) have been combined with cisplatin
or carboplatin to reverse drug resistance caused by the
silencing of mismatch repair genes by hypermethylation.
The toxicity of agents such as cisplatin depends at least
partly on functional mismatch repair (FIG. 1). Preclinical
data from xenograft models and translational studies
from drug-resistant cells and tissues that are mismatch
repair-deficient owing to MLH1 hypermethylation have
demonstrated increased chemotherapeutic efficacy
when a demethylating agent is combined with platinum
chemotherapy
64,65
. Decitabine is currently being tested
in combination with carboplatin in a phase II clinical
trial in patients with ovarian cancer (see Decitabine
and Carboplatin in Relapsed Ovarian Cancer in Further
information).
Table 1 | Ongoing clinical trials of small-molecule inhibitors of the DNA damage response and related signalling pathways
Agent
(company)
Target molecule
or pathway
Monotherapy
or combination
therapy agent(s)
Phase of clinical trial
planned, ongoing or
recently completed
Reference
AZD-2281
(Astra Zeneca)
PARP Gemcitabine
Carboplatin
Topotecan
Monotherapy
Phase I
Phase I
Phase I
Phase II
http://www.astrazenecaclinicaltrials.com/article/525925.
aspx
AG014699
(Pfizer)
PARP Temozolomide
antibody
Temozolomide
Phase I

Phase II
http://www.eddn.org/clinicalTr_caResUK.html
INO-1001 (Inotek) PARP Temozolomide Phase I http://www.inotekcorp.com/content/ino-1001.asp
BSI-201
(Bipar Sciences)
PARP Monotherapy
Gemcitabine
carboplatin
Phase I
Phase II
http://www.biparsciences.com/BSI201.html
ABT-888 (Abbott
Laboratories)
PARP Temozolomide Phase I NCT00526617
TRC-102
(Tracon Pharma)
BER Temozolomide
Pemetrexed
Phase I
Phase I planned
http://www.traconpharma.com/content/pipeline_
overview.html
Lomeguatrib
(Astra Zeneca)
MGMT Irinotecan
Temozolomide
Phase I
Phase II
http://www.astrazenecaclinicaltrials.com/article/525925.
aspx
O
6
-Benzylguanine MGMT Temozolomide Phase II http://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2006-
C-0089.html
Decitabine
(MGI Pharma
121
)
Hypermethylation
of mismatch
repair genes
Epirubicin,
cisplatin,
5-fluorouracil
Carboplatin
Phase I


Phase II
http://pfsearch.ukcrn.org.uk/StudyDetail.aspx?TopicID=
&StudyID=2192
XL844 (Exilixis
122
) CHK1, CHK2 Gemcitabine Phase I planned http://www.exelixis.com/pipeline_xl844.shtml
The recent or current stage of development of clinical trials is indicated for individual compounds, which are grouped by molecular target. BER, base excision
repair; CHK, checkpoint kinase; MGMT, O-6-methylguanine methyltransferase; PARP, poly(ADP-ribose) polymerase.
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Synthetic lethality
A genetic phenomenon in
which the combination of two
otherwise non-lethal
mutations results in an
inviable cell. Synthetic lethal
phenotypes are indicative of
an interaction between the
products of the two mutant
genes within the cell.
It has been shown in preclinical models that the major
cisplatin intra-strand crosslinks formed in DNA are rec-
ognized and repaired by the mammalian NER pathway
66
.
One biological predictor of clinical outcome for patients
with completely resected non-small-cell lung cancer
receiving adjuvant cisplatin-based chemotherapy is
expression of the excision repair cross-complementation
group 1 (ERCC1) protein
67
. An immunohistochemical
study of 761 operative specimens of non-small-cell lung
cancer tissue taken before a proportion of the patients in
the study received adjuvant chemotherapy showed that a
significant benefit from cisplatin-based adjuvant chemo-
therapy was associated with the absence of ERCC1 in
56% of the samples studied. The results suggested that
patients with completely resected non-small-cell lung
cancer and ERCC1-negative tumours appeared to
benefit from adjuvant cisplatin-based chemotherapy,
whereas patients with ERCC1-positive tumours did not.
However, it should be noted that, among the patients
who did not receive adjuvant chemotherapy, those with
ERCC1-positive tumours survived significantly longer
than those with ERCC1-negative tumours. It is therefore
conceivable from the results of this study that ERCC1
might not represent a biomarker specific to cisplatin-
based chemotherapy, but it might represent a marker of
prognosis and response to combination chemotherapy
(not necessarily specific to cisplatin) in a poor-prognosis
subset of patients, as has recently been demonstrated for
p53 overexpression in a similar patient subgroup
68
.
Although it has been suggested that ERCC1 is a
potential anticancer drug target, the protein has no
known enzymatic activity, making the means of regu-
lating its activity harder to decipher. Pharmacological
modulation of ERCC1 might therefore be less desirable
than a greater understanding of the clinical relevance of
proteinprotein interactions within the NER machin-
ery or between ERCC1 and other repair pathways, as
potential targets for improving the efficacy of platinum
chemotherapies. For example, UCN-01 (7-hydroxy-
staurosporine) is an anticancer agent that potentiates
cisplatin and carboplatin toxicity (shown in preclinical
models and a phase I clinical trial, respectively), which
has been shown to interfere with the interaction of
ERCC1 and another component of the NER pathway,
xeroderma pigmentosum A (XPA), in vitro
69
.
Attenuators of checkpoint signalling. An alternative
approach to modulating DNA repair activity and poten-
tially improving the therapeutic index is to interfere with
cell cycle checkpoint signalling. XL844 (EXEL-9844) is
a small-molecule inhibitor of CHK1 and CHK2. This
drug causes inhibition of cell-cycle arrest, progressive
DNA damage, inhibition of DNA repair and, ultimately,
tumour cell apoptosis in cancer cells grown in vitro
70
,
although the outcome of inhibiting CHK1 and CHK2
in general can vary in a cell type-dependent manner.
Although concerns have been raised about the potential
toxicity to normal cells of an approach which inhibits
both CHK1 and CHK2 kinases
71
, preclinical data have
suggested that intermittent dosing with XL844 in
combination with the deoxycytidine analogue gemcitabine
is well tolerated by female athymic nude mice used as
a xenograft model
70
. XL844 is currently being tested
in a clinical trial (NCT00475917) in combination with
gemcitabine, which normally causes cell-cycle arrest and
apoptosis by its incorporation into DNA.
Two kinases from the phosphatidylinositol 3-kinase
(PI3K)-related protein kinase (PIKKs) family, ATM and
ATR, are central to cellular responses

to DSBs. When
activated, ATM and ATR phosphorylate a multitude of
proteins, which initiate a cascade that induces cell-cycle
arrest and facilitates

DNA repair. An inhibitor of ATM
kinase activity, KU55933 (AstraZeneca), is currently
in preclinical development. The rationale behind

the
clinical use of ATM inhibitors depends on the premise
that ATM inhibition should improve the therapeutic
index by hypersensitizing tumour cells to agents

that
cause DSBs. Here again, the feasibility of inhibiting
ATM kinase in patients will depend on the level of
toxicity that such agents cause in normal tissues when
they are used in combination with ionizing radiation or
cytotoxic chemotherapy.
Radiosensitizers. DNA-dependent protein kinase
(DNAPK, also known as PRKDC), a member of the PIKK
family, is important for DSB repair by non-homologous
end joining following ionizing radiation
72
. Cells defective
in DNAPK are highly sensitive to ionizing radiation
73

indicating that inhibition of DNAPK might sensitize
tumours to radiation treatment. Wortmannin, a known
inhibitor of PIKKs at low nanomolar concentrations,
has antiproliferative effects and is a radiosensitizer in
preclinical models
74
, but is unsuitable for clinical appli-
cations owing to its inherent toxicity and instability in
cells
75
. Other small molecules that reversibly inhibit
DNAPK kinase activity at low micromolar concentra-
tions have been synthesized. They are currently in tran-
sition from late preclinical development to early clinical
trials. In particular, NU7441 (REF. 76) has been shown
to sensitize cells to topoisomerase II poisons and can
also function as a radiosensitizer in a manner consistent
with DNAPK inhibition
77
.
DNA repair inhibitors as monotherapy
As discussed above, most of the current small-molecule
inhibitors of DNA repair have so far been tested in early
clinical trials as sensitizers of tumour cells to chemo-
therapy. However, DNA damage also occurs spontane-
ously in cells in the absence of treatments and DNA
repair pathways are therefore essential for the survival
of untreated cells. As several cancers are defective in
DNA damage response and repair pathways (TABLE 2),
the concept of synthetic lethal interactions can be used to
advocate the use of DNA repair inhibitors as monothera-
pies (FIG. 2). DNA repair is an ideal target for inhibition in
cancer cells as the inhibitors should be exclusively toxic
to cancer cells and therefore be associated with minimal
side effects for patients (BOX 2).
Indeed, DNA repair inhibitors have been demon-
strated to work as single agents in patients with DNA
repair-defective tumours. The most notable example so
far is the use of PARP inhibitors to treat patients with
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Table 2 | Synthetic lethal interactions of DNA repair and cell cycle checkpoint genes implicated in cancer by pathway
Protein Syndrome Primary cancers Biomarker SLIs S. cerevisiae
homologue
SLIs in S.
cerevisiae (n)
HR
BRCA1, BRCA2 Breast, ovarian
112, 135
PARP1 (REFS 78,79)
RAD54B NHL, colon cancer
113
PARP1 (REF. 87) rdh54
RAD51B (RAD51L1) Lipoma, uterine
leiomyoma
114
PARP1 (REF. 87) rad51 31
CtIP (RBBP8) Colorectal cancer
115
sae2 5
NHEJ
MRE11 Ataxia
telangiectasia-
like disorder
Colorectal cancer
108
IR sensitivity mre11 40
LIG4 LIG4 Leukaemia
116
IR sensitivity lig4
Artemis (DCLRE1C) Omenn Lymphoma
117
pso2
MMR
MSH2, MLH1, MSH6,
PMS1, PMS2, MLH3
Hereditary nonpolyposis
colorectal cancer
118120
Microsatellite
instability
msh2, mlh1,
msh6, pms1, mlh3
3
RecQ
BLM Bloom Various
121
Increased SCE sgs1 43
WRN Werner Various
122
Increased
telomeric SCE
sgs1 43
RECQL4 Rothmund
Thomson
Skin basal and sqamous
cell, osteosarcoma
122
sgs1 43
Damage signalling
ATM Ataxia-
telangiectasia
Leukaemia
123
IR sensitivity PARP1
(REFS 124,125),
FANC
89
tel1 2
NBS1 Nijmegen
breakage
Various
126
IR sensitivity xrs2 30
p53 LiFraumeni Various
127
-
CHK2 LiFraumeni Various
128
dun1/rad53 37
NER
XPA, XPC, DDB1,
ERCC4, ERCC5, POLH
XP Skin cancers
129
UV sensitivity rad14, rad4,
rad1, rad2, rad30
11
ERCC2, ERCC3 XP, Cockayne,
trichothio-
dystrophy
Skin cancers
129
rad25, rad3 8
ERCC1 Cerebro-oculo-
facio-skeletal
Squamous cell carcinoma,
head and neck
130
rad10 6
FA
FANCA, FANCC,
FANCD2, FANCE,
FANCG
Fanconi
anaemia
Various
131
Impaired FANCD2
ubiqutination
131
ATM
89

FANCB, FANCF, FANCL Fanconi
anaemia
Various
131
Impaired FANCD2
ubiqutination
131

BRIP1 Fanconi
anaemia
Various
131

FANCM Fanconi
anaemia
Various
131
Impaired FANCD2
ubiqutination
131
mph1 1
BER
POLB Various
132
pol4
FEN1 Various
133
rad27 104
Synthetic lethalities observed in mammalian cells and the number of synthetic lethal interactions (SLIs) for their Saccharomyces cervisiae homologues are shown.
The genes showing SLIs with DNA repair genes can potentially be used as targets for novel drugs that then may selectively kill cancer cells in monotherapy.
A complete list of the SLIs in S. cervisiae can be found in Supplementary information S1 (table). ATM, ataxia telangiectasia mutated; BER, base-excision repair;
CHK, checkpoint kinase; ERCC, excision repair cross-complementation; FA, Fanconi anaemia-mediated repair; FANC, Fanconi anemia, complementation group;
FEN1, flap structure-specific endonuclease 1; HR, homologous recombination; IR, infrared; MLH, mutL homologue; MMR, mismatch repair; MSH, mutS
homologue; NER, nucleotide-excision repair; NHEJ, non-homologous end joining; PARP, poly(ADP-ribose) polymerase; RecQ, RecQ-mediated repair; SCE, sister
chromatid exchange; UV, ultraviolet; XP, xeroderma pigmentosum.
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Nature Reviews | Cancer
Targeted monotherapy Cancer mutation
Replication lesion
Survival
a Initial cancer mutation
Lethal
b Inhibitor of Top3 in cancer cells
Survival
c Drug-resistant mutation d Second therapy in resistant cells
Lethal
SAE2 mre11
SGS1
TOP3 mre11
SGS1
TOP3
sgs1
Gene function Drug-resistant mutation
Monotherapy Mutation Monotherapy
mre11 mre11 SAE2
sgs1
inherited breast and ovarian cancers that lack wild-type
copies of the BRCA1 or BRCA2 genes
78,79
. BRCA1- and
BRCA2-mutated cells are defective in HR repair
80,81

and show extensive replication-associated lesions
82,83
.
These recombination-defective cells are 1001,000-
fold more sensitive to PARP inhibitors than are the
heterozygote or the wild-type cell lines, indicating
their potential to be exploited as specific treatments of
BRCA1- or BRCA2-defective tumours
78,79
. One explana-
tion for this sensitivity is that PARP inhibitors induce
single-strand breaks that can result in DSBs as a result
of stalled replication forks. Such lesions would normally
be repaired by HR, but this is prohibited in BRCA1- or
BRCA2-deficient cancer cells
79,8486
. PARP activity is also
required for the actions of CHFR (checkpoint protein
with forkhead-associated and ring finger domains)
58
and
the reactivation of stalled replication forks
57
. These func-
tions might also explain the hypersensitivity to PARP
inhibitors of recombination-defective cells. Translation
of these observations has led to phase II clinical trials of
monotherapy using the PARP inhibitor AZD2281
(AstraZeneca) currently recruiting patients with breast
and ovarian cancer who harbour mutations in BRCA1 or
BRCA2 genes. A separate phase II trial with the PARP1
inhibitor AG014699 (Pfizer GRD) is due to open to
recruitment of known carriers of BRCA1 or BRCA2
mutations with locally advanced or metastatic cancers of
the breast or ovaries. It should be noted however that not
all patients with mutations in BRCA1 or BRCA2 respond
to PARP inhibitors as a monotherapy. The reasons for
this are currently under investigation. Cells that are
defective in recombination-related proteins other than
BRCA1 or BRCA2, such as RAD51, RAD54, XRCC2,
XRCC3, DSS1 (also known as SHFM1), replication
protein A1 (RPA1), ATM, ATR, CHK1, CHK2, NBS1
(also known as NBN) and components of the Fanconi
anaemia repair pathway, also show increased sensitivity
to PARP inhibition
79,87,88
. This suggests that PARP inhibi-
tors might also be suitable in treating several types of
tumours with defects in HR.
Another synthetic lethal interaction has recently
been discovered between the Fanconi anaemia repair
pathway and ATM. Two pancreatic tumour lines defec-
tive in the Fanconi anaemia pathway were more sensitive
to the ATM inhibitor KU-55933 than isogenic control
cells
89
. This finding provides a rationale for studying
ATM inhibitors in the treatment of Fanconi anaemia
repair-defective pancreatic cancer.
Finding new synthetic lethal DNA repair-based partner-
ships. As mutations in checkpoint and DNA repair
pathways are associated with cancer (TABLE 2), it should
be straightforward to exploit DNA repair inhibitors
for the treatment of tumours carrying specific defects
in DNA repair or damage signalling (FIG. 2). Genome-
wide screens in model organisms, such as the bud-
ding yeast Saccharomyces cerevisiae, have helped to
identify protein interaction networks, which serve to
elucidate protein functions within highly complex cel-
lular processes. Such knowledge can prove extremely
useful in identifying suitable targets for monotherapy,
but perhaps more significantly those that could be used
in combination therapies. We have compiled a list of
reported mutations in DNA damage response genes
found in human tumours and homologous synthetic
lethal interactions that have been demonstrated in
Figure 2 | Synthetic lethal interactions to identify molecular targets for inhibitors of DNA repair. A mutation in a
single tumour suppressor gene can result in genetic instability that can accelerate tumour progression
90
. Here, we use
synthetic lethal interactions in Saccharomyces cerevisiae to illustrate a hypothetical scenario. a | We start with an
Mre11 mutation that is found in mismatch repair-defective tumours
108
. b | The yeast mre11 is synthetic lethal with
topoisomerase III (Top3 3)
109
. If the synthetic lethal interaction is conserved from yeast to man, inhibitors of Top3 would,
in theory, kill Mre11-mutated tumour cells. Top3-mutated yeast cells are viable, albeit with genetic instability
110
,
and thus Top3 inhibitors may specifically kill Mre11-mutated cancer cells while being tolerated in normal cells.
c | Replication repair networks are complex and an additional mutation might override synthetic lethal interactions. In
yeast, an additional mutation in sgs1, upstream of the hypothetically targeted TOP3 pathway, reverses the synthetic
lethal phenotype
109
. Thus, in this scenario, an additional tumour mutation in the human homologue of SGS1, BLM, might
result in resistance to Top3 inhibitors. d | sae2 is in turn synthetic lethal with sgs1 in yeast
111
. If this synthetic lethal
interaction is conserved, the human SAE2 homologue CtIP (also known as retinoblastoma binding protein 8 (RBBP8))
might, in theory, then be targeted as a second-line therapy in Top3 inhibitor-resistant tumours that gained resistance
owing to a BLM mutation. In summary, understanding of DNA repair networks is important to identify pathways to
target and to circumvent resistance mechanisms.
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Biomarkers
A molecule or substance
whose detection indicates a
particular disease state or
treatment response.
Hypoxia
A subnormal concentration of
oxygen. In cancer tissue,
hypoxia is often the result of
abnormal vasculature.
S. cerevisiae (Supplementary information S1 (table)).
This information could be used to identify proteins
encoded by the human homologues of genes showing
synthetic lethal interactions that may represent good
targets for specific treatment of cancers carrying muta-
tions in DNA repair genes. Unfortunately, the poorly
defined biochemical properties of these proteins are
still a significant barrier to the exploitation of these
proteins as potential targets for drug intervention in
the immediate future.
A further limitation to exploiting these pathways
is the lack of reliable biomarkers to aid the selection of
patients that might respond to such treatments. This is
particularly important as cancers in patients that have no
DNA repair defect will not respond. The most reliable
biomarkers will probably be those that identify loss of
specific post-translational modifications present in the
DNA damage response and repair pathways, or those
that indicate increased activity of the targeted pathway.
Future directions
Current chemotherapy regimens demonstrate that pro-
duction of excessive replication lesions is a successful
means of killing cancer cells. It has been observed that
tumour cells themselves exhibit a high level of endogenous
replication lesions that result in genetic instability
32,33,90
.
In theory, DNA repair inhibitors could be used to impair
the repair of replication lesions that are present in tumour
cells and convert them into fatal replication lesions that
specifically kill cancer cells. For example, there is evidence
that the increased expression or activity of oncogenes can
induce replication stress
32,33,91,92
. In such tumours it might
be possible to use DNA repair inhibitors to make existing
cancer-specific replication lesions more toxic, resulting
in fatal replication lesions selectively killing oncogene-
expressing cancer cells
32,33,91972
(BOX 3).
More advanced cancers are exposed to another source
of replication stress owing to the tumour microenviron-
ment. Tumours are often hypoxic, which has been shown
to disrupt DNA synthesis
98
. These conditions cause repli-
cation lesions that activate the ATM- and ATR-mediated
checkpoint response
99101
. Furthermore, DNA repair is
downregulated in hypoxic cells
102
, which cumulatively
contributes to the genetic instability observed in these
cells
103,104
. In hypoxic cancer cells, therefore, inhibitors of
the checkpoint response could prove to be more efficient
than inhibitors of DNA repair
105
.
Conclusions
The potential of inhibitors of DNA repair in the future
of cancer therapy is starting to become apparent.
Although selective inhibition of DNA repair pathways
can be used to enhance current chemotherapy, the
most attractive use of DNA repair inhibitors might be
in using cancer defects for selective cell killing. DNA
Box 2 | Advantages and limitations using DNA repair inhibitors as single agents in treatment of cancers
DNA repair inhibitors can exploit tumour-specific defects in checkpoint signalling and DNA repair to convert
endogenous DNA lesions into fatal replication lesions that selectively kill tumour cells.
A general problem for novel cancer therapies is that they are not sufficiently efficient at killing cancer cells to
replace current cytotoxic therapies. As a result, some enzyme inhibitors (that do not target DNA repair) have failed
in late clinical trial development owing to a general lack of anti-tumour efficacy. Inhibition of DNA repair amplifies
toxic replication-associated DNA lesions that directly result in cell death. DNA repair inhibitors might therefore be
highly efficient at killing tumours.
Cross-talk between DNA repair pathways in normal cells minimizes side effects from the inhibition of a single DNA
repair pathway.
Tumour inactivation of DNA damage signalling and DNA repair are often relatively early events during carcinogenesis,
suggesting that non-toxic DNA repair inhibitors may be considered in the treatment of patients with pre-malignant or
early neoplastic lesions, such as those arising in patients with inherited mutations in BRCA1 or BRCA2 genes, or
intestinal lesions in patients with defects in MLH1 and MSH2 genes or their methylation status.
Cross-talk between DNA repair pathways, such as the cross-talk between homologous recombination and non-
homologous end joining in the repair of DNA double-strand breaks or the cross-talk between base-excision repair,
alkyltransferases and DNA dioxygenases in the repair of alkylation damage, is likely to result in acquisition of
resistance mechanisms in tumours, which is a limitation for killing more advanced tumours.

Box 3 | Targetting oncogene-induced replication stress
The transformation of normal cells to a cancerous state is often initiated by the
activation of oncogenes, which provide excessive growth signals
106
. It was recently
shown that such oncogene activation can induce replication-associated DNA
lesions
32,33,91,92
, including increased replication origin firing, re-replication and
impaired fork progression
32,107
. These replication-associated lesions trigger a cell-cycle
checkpoint response that stops the proliferation of pre-cancerous cells early during
neoplastic transformation
32,33,9193
. This involves checkpoint proteins, such as p53 and
CHK2, that can induce apoptosis or senescence
94,95
,
Genes encoding proteins in the checkpoint pathways are often mutated during
cancer development
96
, allowing cells to evade checkpoints and continue to
proliferate. Taken together, these observations suggest that a key feature of cancer
cells that overexpress oncogenes might be higher levels of endogenous replication-
associated lesions than those present in normal cells. This in turn would contribute to
genetic instability
97
that would assist the tumour to induce the genetic changes
required for continuing transformation to malignant phenotypes
90
. More importantly,
the replication lesions caused by oncogene activation have been found to resemble
those produced by anticancer treatments
32
, and, like the latter, these lesions would
require repair for the cancer cells to survive. We therefore propose that future DNA
repair inhibitors should be used to make existing cancer-specific replication lesions
more toxic, resulting in fatal replication lesions selectively killing oncogene-
expressing cancer cells. The nature of the replication lesions that are produced
following chemotherapy or oncogene-induced stress are poorly understood.
Although several replication repair pathways have been identified, we currently have
little information regarding their complex interplay. Indeed, more intense basic
research is required in this area to identify novel anticancer targets.
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Acknowledgements
We would like to thank the Medical Research Council, The
Swedish Research Council, The Swedish Cancer Society,
The Swedish Childrens Cancer Foundation, The Swedish Pain
Relief Foundation and Cancer Research UK for financial sup-
port. We recognize that we were unable to cover all aspects of
DNA repair in cancer in this Review. We apologize to those
whom we have been unable to cite owing to space constraints.
Competing interests statement
The author declares competing financial interests: see web
version for details.
DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
ALKBH2 | ALKBH3 | ATM | ATR | BLM | BRCA1 | BRCA2 |
BRIP1 | CHK1 | CHK2 | DCLRE1C| DDB1 | ERCC1 | ERCC2 |
ERCC3 | ERCC4 | ERCC5 | FANCA | FANCB | FANCC |
FANCD2 | FANCE | FANCF | FANCG | FANCL | FANCM |
FEN1 | LIG4 | MGMT | MLH1 | MLH3 | Mre11 | MSH2 | MSH6 |
MUS81 | NBN | p53 | PARP1 | PARP2 | PMS1 | PMS2 | POLB |
POLH | PRKDC | RAD51 | RAD51L1 | RBBP8 |
RECQL4 | RPA1 | sgs1 | SHFM1 | top3 | WRN | XPA | XPC |
XRCC2 | XRCC3
ClinicalTrials.gov: http://clinicaltrials.gov/
NCT00475917 | NCT00526617
National Cancer Institute: http://www.cancer.gov/
breast cancer | ovarian cancer
National Cancer Institute Drug Dictionary:
http://www.cancer.gov/drugdictionary/
5-fluorouracil | 6-thioguanine | bleomycin | carboplatin |
chlorambucil | cisplatin | cyclophosphamide | dacarbazine |
decitabine | etoposide | gemcitabine | hydroxyurea | melphalan |
mitomycin C | oxaliplatin | temozolomide | UCN-01 | XL844
FURTHER INFORMATION
Thomas Helledays homepage: http://www.rob.ox.ac.uk/
research/researchgroups/thomas-helleday/
Decitabine and Carboplatin in Relapsed Ovarian Cancer:
http://pfsearch.ukcrn.org.uk/StudyDetail.aspx?TopicID=1&S
tudyID=2192
SUPPLEMENTARY INFORMATION
See online article: S1 (table)
ALL LINKS ARE ACTIVE IN THE ONLINE PDF
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