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apoptosis after various genotoxic agents.
195
e
198
Since
a role of GADD45
a
in MMR-dependent G
2
cell cycle
checkpoint arrest responses was reported,
91,137,199
we
examined the role of GADD45
a
in MMR-dependent
apoptotic responses. MMR-dependent apoptosis was
partially suppressed in GADD45
a
knockout MEF cells,
or in MMR-proficient RKO7 cells knocked down for
GADD45
a
expression.
90
We also observed suppressed
expression levels of GADD45
a
after STI571-induced
inhibition of c-Abl or shRNA-knockdown of c-Abl.
These data put GADD45
a
as a downstream gene regu-
lated by c-Abl. Surprisingly, our data showed no
evidence for a functional relationship between
GADD45
a
and p73
a
in MMR-dependent apoptotic
responses after MNNG treatments. We demonstrated
that two separate c-Abl-p73
a
and c-Abl-GADD45
a
signaling pathways independently involved in MMR-
dependent apoptosis or G
2
cell cycle checkpoint arrest
responses after MNNG exposure (see
Figure 9.2
).
However, further studies are needed to clarify the roles
of GADD45
a
in MMR-c-Abl-mediated apoptosis after
various chemotherapeutic agents. Understanding these
signaling events could lead to new ways to overcome
chemoresistance or unwanted normal tissue responses
that occur during MMR-dependent cell stress responses.
these early studies suffered from both inappropriate
sample selection and insufficient sample size. Recently,
more extensive retrospective and prospective studies
have demonstrated that colorectal cancer patients with
MMR deficiencies do not receive significant benefit
from 5-FU-based adjuvant chemotherapy,
79,200,204,205
and strongly suggest that treatments with 5-FU are
particularly ineffective in the treatments of MMR-defi-
cient HNPCC patients. Based on large sample size and
appropriate control groups, Ribic and his colleagues
79
demonstrated that patients with stage II and III colon
cancer benefited from 5-FU-based adjuvant chemo-
therapy only when their tumors were MMR-competent.
In contrast, patients in the same study with tumors that
lack of MMR activity, received no benefit from 5-FU
adjuvant therapies. Additional prospective studies
further confirmed the retrospective reports suggesting
that adjuvant 5-FU-based chemotherapy may not be
useful in stages II and III microsatellite-instable (MIN)
colorectal cancers.
200,205
Taken together, accumulated
evidence (summarized in
Table 9.3
) strongly demon-
strated that therapies using 5-FUdo not provide a benefit
to MMR-deficient patients.
These clinical data reinforce our prior findings that
MMR-deficient cell lines were less responsive than
MMR-proficient cell lines to 5-FU treatments;
92,94
resis-
tance to 5-FU in MMR-deficient compared to MMR-
proficient colon cancer cells was originally reported by
us in the 1994 Annual Report of the American Associa-
tion for Cancer Research and later confirmed by Richard
Boland's laboratory.
216
Additional and comprehensive
studies of the responses of MMR to fluoropyrimidines
were later reported by us.
92
e
94,97
MMR-DEFICIENT CANCERS ARE
RESISTANT TO VARIOUS
CH
EMOTHERAPEUTIC AGEN
TS
Inactivation of MMR by a hMLH1, hMSH2, or
hMSH6 mutation, or hypermethylation of hMLH1,
leads to a MMR deficiency in the population, resulting
in ~5
14% hereditary or ~20% sporadic gastric, colorec-
tal, endometrial, and ovarian cancers.
77
e
79,81
e
86,200
These MMR-deficient cancers not only show MSI (MIN
phenotype), but also exhibit aggressive and uncon-
trolled growth as well as resistance to various anti-
cancer agents. Three clinically important agents will be
discussed: 5-fluorouracil (5-FU), temozolomide (TMZ),
and cisplatin.
e
MMR-Dependent Sensitivities to TMZ
The dependence of MMR in TMZ-induced apoptosis
was originally characterized in 1998.
217
Since that time,
TMZ has become the gold standard care for patients
with glioblastoma. Early studies found that a small
subset of patients with newly diagnosed malignant
glioma displayed TMZ resistance that Friedman and
colleagues
218
identified as a simultaneous elevation of
expression of O
6
-alkylguanine-DNA alkyltransferase
(AGT, the protein encoded by the MGMT gene) with
concomitantly reduced expression of MMR proteins.
Later reports from other groups observed that the loss
of MMR by mutation or hypermethylation of the
hMSH6 gene contributed to chemoresistance of glioblas-
toma to TMZ therapies.
219
e
221
However, conflicting
results reported from Maxwell et al.,
222
showed that
MMR deficiency does not mediate clinical resistance to
TMZ in malignant glioma, since none of the 52 samples
showed the presence of high MSI (biomarker of MMR
MMR Deficiencies Confer Resistance
to 5-fluorouracil (5-FU)
5-FU has been used in cancer chemotherapy for more
than 40 years, and still remains primary “standard of
care” as an adjuvant chemotherapeutic regimen for the
treatment of colorectal cancer. Early studies reported
that stage II and III colorectal cancer patients had
improved overall survival from 5-FU adjuvant chemo-
therapy regardless of MSI status,
201
e
203
suggesting that
MMR status was not important for therapy. However,
