Biology Reference
In-Depth Information
associated with improved disease response to alkylat-
ing agent chemotherapy and this is associated with
improved survival independent of treatment.
175,176
Correlation of tumor MGMT levels with survival of
malignant astrocytoma patients treated with bis-chlor-
oethylnitrosourea was addressed in a Southwest
Oncology Group study. Low MGMT level in tumor
tissue specimens was a predictive marker of survival
in patients with malignant astrocytoma.
177
In a pivotal
randomized control trial comparing radiotherapy
alone or radiotherapy with concurrent and adjuvant
temozolomide in brain tumors, a benefit from temozo-
lomide was only seen in patients with methylation of
the MGMT promoter.
178
e
180
Polymorphisms in the
MGMT gene
181
e
186
that alter MGMT activity levels
might also be expected to influence response to treat-
ment with methylating and chloroethylating agents.
There is little evidence confirming a role for MGMT
polymorphisms as predictive factors for anticancer
treatments.
108,160,187
However, there is evidence that
polymorphisms may affect sensitivity to MGMT inhib-
itors.
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e
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The Ile143Val/Lys178Arg polymorphism
reduces the activity of MGMT towards low molecular
weight pseudo-substrates including O
6
-benzylguanine
and O
6
-(4-bromothenyl)guanine, both of which are in
clinical trials as MGMT inactivating agents.
191
MGMT promoter methylation was associated with
longer survival in patients in a recently published clin-
ical study testing concomitant and adjuvant temozolo-
mide and radiation.
179
Better tumor response to
temozolomide was seen in glioblastoma (GBM) patients
with hypermethylation in another trial involving inop-
erable patients.
176
These observations are consistent
with the role of MGMT in repair of O
6
meG, the critical
toxic lesion caused by temozolomide. MGMT promoter
methylation has also been shown to be predictive of
radiotherapy response in GBM patients treated with
radiotherapy but not adjuvant alkylating chemotherapy.
In low grade (WHO Grade 2) glioma patients treated
with temozolomide, MGMT promoter methylation was
found to be associated with radiological response to
chemotherapy and time to progression.
192
MGMT expression level has been shown to be associ-
ated with disease stabilization, progression-free and
overall survival in patients with advanced melanoma
treated with dacarbazine chemotherapy.
193
In mela-
noma, MGMT gene promoter methylation has been
shown to correlate with tolerance to temozolamide
chemotherapy; patients with methylated MGMT
promoter experienced more severe adverse events and
were significantly more likely to require a dose reduc-
tion or to discontinue treatment.
194
The TT genotype
of MGMT
oxaliplatin-based chemotherapy than in patients with
the combined GG
GT genotypes.
151
In summary, although the current data do not appear
to suggest an important role for SNPs within MGMT
alone as predictive factors in cancer, MGMT promoter
methylation and silencing is an important predictor of
resistance to temozolomide in patients.
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MISMATCH REPAIR (MMR
)
MMR is responsible for the removal of nucleotides
mispaired by DNA polymerases and insertion/deletion
loops that result from slippage during replication of
repetitive sequences or during recombination.
11,15,20
Several in vitro studies have shown that MMR-deficient
cells are resistant to a variety of chemotherapeutic
agents.
195
e
199
However, to date there are no published
studies showing that polymorphisms within the MMR
genes impact upon response to chemotherapy or radio-
therapy. MMR contributes significantly to genomic
stability by eliminating single-base mismatches and
insertion
e
deletion loops that might arise during DNA
replication. MMR proteins are also involved in the
repair of DNA damage caused by reactive oxygen
species and alkylating agents. MMR proteins interact
with components of other repair pathways, including
NER, BER, and HR. DNA mismatch repair deficiency
in sporadic tumors is seen in colonic, gastric, endome-
trial, and other solid tumors. In addition, germline defi-
ciency in MMR accounts for the Lynch syndrome.
Several clinical studies indicate that MMR deficiency is
a good prognostic marker and MMR deficient tumors
exhibit enhanced responses to chemotherapy.
200
e
209
The relationship between microsatellite instability
(MSI), expression of hMLH1 and hMSH2, treatment
response and survival in patients with colorectal cancer
(CRC) undergoing first-line treatment with weekly
24-hour infusion (24-h inf.) of high-dose 5-fluorouracil
(5-FU) and folinic acid (FA) has shown that MSI status
is an independent predictive marker for survival.
Patients whose tumors were highly unstable (MSI-H)
had a better response and survival after chemotherapy
than tumors that were microsatellite-stable (MSS).
210
Patients with lymph-node-positive breast cancer and
a low hMLH1-IS were more likely to be resistant to
CMF chemotherapy than those having a high hMLH1-
IS.
211
Over-expression of p53 and low expression of
hMSH2 was associated with poor treatment response
and cancer death in non-small-cell lung cancer
patients.
212
Though many preclinical studies suggest
mismatch repair (MMR)-deficient cells are resistant to
alkylating agents,
213
the only published clinical study
found no association between MMR deficiency and
response to temozolomide in malignant glioma.
214
T polymorphism has been found to
correlate with a worse progression-free survival in
patients with metastatic colorectal cancer treated with
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