Biology Reference
In-Depth Information
TABLE 12.5 DNA Repair and Chemotherapy-Induced Toxicity
Cancer type
Treatment
Repair enzyme
Results
Reference
NSCLC
Platinum
ERCC1
C8092A allele associated with
>
2fold
[
in grade 3 or 4 GI toxicity
131
Glioma
Cx
ERCC1, ERCC2
No association between ERCC C8092A, ERRC2 codon 312 and
codon 751 polymorphisms and toxicity
166
AML
Cx
ERCC1
IVS5
A polymorphisms associated with lung and
metabolic toxicity
þ
34C
230
>
AML
Cx
XRCC3
241 Met variant had
risk of liver toxicity
230
Y
NSCLC
Docetaxel/gemcitabine
XPD
Wild-type genotype at codon 751 associated with
grade 4
171
[
neutropenia
NSCLC
Triplet or doublet Cx
ERCC1
ERCC1 negative adenocarcinoma associated with
risk
231
[
leukopenia, n&v, and neurotoxicity and
QoL
Y
CRC
Oxaliplatin-based
ERCC1
CT genotype of C118T polymorphism associated with earlier
onset of grade 1 neuropathy
232
Abbreviations: NSCLC, non-small-cell lung cancer; CRC, colorectal cancer; AML, acute myeloid leukemia; GI, gastrointestinal; n&v, nausea and vomiting; QoL,
quality of life; Cx, chemotherapy;
increased;
decreased.
[
Y
other normal tissues, such as the liver, lung, nervous
system, are chemotherapy specific.
In NSCLC patients, ERCC1 C8092A allele is associ-
ated with a
The median number of cycles at onset was 6 for these
groups of patients and 7 for individuals with the refer-
ence C/C genotype.
232
2-fold increase in grade 3 or 4 gastrointes-
tinal toxicity to platinating agents.
131
However, another
study found no statistically significant association
between the C8092A polymorphism of ERCC1 and the
codon 312 and codon 751 polymorphisms of ERCC2
and chemotherapy toxicity in patients with glioma
treated with combination chemotherapy.
166
In elderly
patients with acute myeloid leukemia, ERCC1 IVS5
>
DNA REPAIR AND RADIOTHERAPY
RESPONSE (
TABLE 12.6
)
Acute effects of radiotherapy comprise the dose-
limiting normal tissue toxicity during a course of radio-
therapy andmainly involve the mucosa and hemopoietic
system. The loss of reproductive capacity interfering
with the replacement of lost cells is largely responsible
for toxicity to the epithelia of the skin and gut and the
bone marrow. The late effects, on the other hand, occur
predominantly in slowly proliferating tissues such as
the lung, kidney, heart, liver, and central nervous system.
There is considerable inter-patient heterogeneity in
normal tissue tolerance to radiation. Although fraction-
ation schedule, fraction size, volume of treatment field
and total dose of radiation given can account for some
variability, recent studies suggests that genetically deter-
mined intrinsic differences in the response to radiation-
induced cellular damage may significantly contribute
to this effect. DSB repair is the major DNA repair
pathway involved in repair of radiation induced DNA
damage and SNPs within this and other DNA repair
pathways may be expected to alter an individual's
response to radiotherapy.
Several in vitro studies suggest associations between
SNPs in DNA repair genes and radiation
sensitivity.
97,160,233
e
235
However clinical studies are
limited. In head and neck squamous-cell cancer patients
treated with radiotherapy it has been found that the
XPF/ERCC1 SNP at codon 259 and the XPG/ERCC5
þ
34C
A polymorphisms were significantly associated
with lung and metabolic toxicities, and patients with
the XRCC3 241Met variant had reduced risk of liver
toxicity.
230
In advanced NSCLC patients treated with
docetaxel and gemcitabine, the wild-type XPD genotype
at codon 751 was associated with a significantly higher
risk of grade 4 neutropenia.
171
While a significantly improved outcome has been
observed in patients with advanced NSCLC who are
ERCC1-negative, a greater incidence of treatment-
related toxicity has been recorded in these individuals.
An interaction was also seen between ERCC1 status
and adenocarcinomas. Patients were treated with either
triplet or standard doublet chemotherapy. A significant
association between ERCC1-negative adenocarcinomas
and leukopenia, nausea and vomiting, and neurotoxicity
was seen across the entire population. Patient-reported
quality of life was also lower in the whole population
of patients who were ERCC1 negative and in the
subgroup of ERCC1-negative adenocarcinomas.
231
In a Japanese study of adults with colorectal cancer
treated with oxaliplatin-based chemotherapy, grade 1
chronic neuropathy developed earlier in patients with
C/T genotypes of the ERCC1 C118T polymorphism.
>
