Biology Reference
In-Depth Information
mutants against cytotoxic agents.
30,34,74
Similarly trans-
fecting Apn 1-deficient yeast with APE1 also protected
against methyl methane sulfonate (MMS).
75
In HeLa
cells, overexpression of APE1 conferred a protective
effect against alkylating agents.
76
In human embryonal
carcinoma cell lines, over-expression of APE1 conferred
resistance to bleomycin and radiation.
77
These preclin-
ical studies demonstrate that APE1 expression may
modulate responses to cytotoxic therapy and is a prom-
ising predictive biomarker.
In human tumors, APE1 expression is ubiquitous
and exhibits complex and heterogeneous staining.
The biological significance of compartmentalization of
APE1 is not fully known but nuclear localization of
APE1 is thought to indicate its functions in DNA repair
and cytoplasmic localization may relate to its role
in mitochondrial DNA repair or redox regulation of
newly synthesized transcription factors.
55
For exam-
ple, in cervical cancer.
78
non-small-cell lung cancer
(NSCLC),
79,80
rhabdomyosarcomas,
81
and squamous
cell head and neck cancer,
82
a strong upregulation at
the nuclear level of APE1 was always observed. Several
clinical studies provide evidence that APE1 expression
levels and/or subcellular dysregulation may indicate
sensitivity of tumors towards radio- or chemotherapy.
Nuclear expression of APE1 in head and neck cancer
was associated with resistance to chemoradiotherapy
and poor outcome.
82
An inverse relationship between
intrinsic radiosensitivity and the levels of APE1 was
also demonstrated in cervical carcinoma.
83
In semino-
mas, yolk sac tumors, and malignant teratomas, APE1
expression levels and DNA repair ability correlated
and conferred a proportional level of protection from
bleomycin treatment.
77
In non-small-cell lung cancer,
levels of APE1 are correlated with cisplatin resistance.
84
APE1 may also have prognostic
than 60 validated SNPs in XRCC1 have been listed in
the Ensembl database.
99
The Arg194Trp on exon 6,
Arg280Hisonexon9,andArg399Glnonexon10poly-
morphisms have been extensively investigated.
Response rates and survival were both higher in
patients with Arg/Arg genotype in a Korean study
100
and in another study patients with at least one Gln
allele at this location were at a 5.2-fold increased risk
of failing to respond to the chemotherapy.
101
Similarly
in NSCLC, response to platinum based chemotherapy
was significantly higher in patients with the 399 Arg/
ArggenotypethaninpatientswiththeArg/Glnor
Gln/Gln genotype.
102
This study also found an associ-
ation of the Arg194Trp polymorphism with response to
chemotherapy; the response rates in patients with the
194Arg/Trp or Trp/Trp genotype were significantly
higher than those in patients with the Arg/Arg geno-
type.
102
A further study in advanced NSCLC patients
treated with platinum based chemotherapy also found
an increasing number of variant (Gln) alleles at the
Arg399Gln locus was associated with a decreased over-
all survival.
103
A more recent study has however
shown no significant association between XRCC1
Arg194Trp, Arg280His, and Arg399Gln polymor-
phisms and survival in patients with advanced NSCLC
treated with platinum-based chemotherapy.
104
The
XRCC1 T-77C polymorphism has also been shown
not to be associated with survival in patients treated
with platinum-based chemotherapy for advanced
NSCLC.
105
In esophageal cancer patients the variant alleles of
XRCC1 Arg399Gln were significantly associated with
the absence of complete pathological response and
poor survival.
106
In gastric cancer, median overall
survival time was longer in patients with the Arg geno-
type at codon 399 who were treated with platinum-
based chemotherapy.
107
However, a study of colorectal
cancer patients who received adjuvant chemotherapy
for Dukes B and C cancer, who were homozygotes for
the glutamine variant showed a significantly better over-
all survival than the carriers of the arginine allele.
108
In
patients with metastatic colorectal cancer treated with
irinotecan-based regimens, allelic variants of the
XRCC1 gene at codon 399 were also found to be predic-
tive of overall survival. In this study, however, highest
mortality was seen in individuals with the Gln/Gln
genotype.
109
XRCC1 A399G polymorphism has been
shown to be predictive of response to neoadjuvant che-
moradiotherapy in patients with locally advanced rectal
cancer. Response was better in the AG genotype group,
where 53% of patients demonstrated a major response
compared to 22% of patients with homogenous AA or
GG genotypes. No association was observed between
survival and XRCC1 A399G gene polymorphisms.
110
A
further study in patients with advanced colorectal
significance in
cancer.
72,85
e
91,92
Polymorphisms in the human APE1 gene have been
reported that alter DNA repair capacity.
93
APE1 poly-
morphic variants may increase cancer risk.
94
In patients
with pancreatic cancer a significantly reduced overall
survival was associated with the homozygous variant
alleles of the Asp148Glu SNP.
95
The Asp148Glu variant
not only increased lung cancer susceptibility
96
but may
also be associated with ionizing radiation sensitivity.
97
A similar study in lung cancer suggested that
Asp148Glu polymorphism may be associated with
higher complete or partial response rates to chemoradio-
therapy, but not to chemotherapy alone.
98
X-ray Repair Cross-complementing
Group 1 (XRCC1)
XRCC1 interacts with DNA ligase-III, DNA Pol
b
and poly (ADPribose) polymerase (PARP). More
