Biology Reference
In-Depth Information
TABLE 9.3 Efficacy of Chemotherapy in Colorectal Cancer Patients with MMR Deficiencies (MSI)
References
Study design
Number of patients
MSI-H (%)
Effects of 5-FU in MSI patients
Elsaleh et al. (2000)
206
Consecutive patients
656
8.5
Yes
Hemminki et al. (2000)
203
Prospective study
95
11.6
Yes
Liang et al. (2002)
207
Prospective study
244
21.3
Yes
Ribic et al. (2003)
79
Randomized controlled study
570
16.7
No
Carethers et al. (2004)
204
Consecutive patients
204
17.6
No
Storojeva et al. (2005)
208
Randomized controlled study
160
13.1
No
Benatti et al. (2005)
209
Consecutive patients
1263
20.3
No
Popat et al. (2005)
210
Pooled data from multiple studies
7642
16.7
No
Lanza et al. (2006)
211
Consecutive patients
718
15.9
No
Jover et al. (2006)
205
Consecutive patients
754
8.8
No
Kim et al. (2007)
212
Prospective study
542
18.1
No
Des Guetz et al. (2009)
213
Meta-analysis
3690
14.0
No
Bertagnolli et al. (2009)
214
Randomized controlled study
723
13.3
No
Jover et al. (2009)
80
Prospective study
754
10.1
No
Sargent et al. (2010)
215
Randomized controlled study
457
15.3
No
MSI-H: Five markers (BAT25, BAT26, D5S346, D17S250, and D2S123) have been recommended by the National Cancer Institute to screen for MSI in HNPCC tumors
(often called Bethesda markers). Generally, MSI detection in two of the markers is considered a positive result or high probability of MSI (MSI-H).
deficiency) by hMSH6 mutation or loss of hMSH6
protein expression even though TMZ resistance exists.
They further suggested that over-expression of AGT is
the primary reason for TMZ resistance. Further research
into the role(s) of MMR proteins and the processes of
developing of resistance to TMZ therapies in the treat-
ments of glioblastoma are required to better improve
the outcome for patients with this disease.
inactivation and deficiency in MMR results in greater
cisplatin resistance.
229
An intact p73 pathway has also been shown to be an
important determinant of cellular sensitivity to
cisplatin-related anticancer agents. Cells lacking p73
expression proved remarkably resistant to cisplatin-
induced cytotoxicity.
230
Irwin et al.
186
further demon-
strated that trans activation p73 (TAp73) was induced
by a large variety of chemotherapeutic agents, such as
camptothecin, etoposide, cisplatin, doxorubicin, and
Taxol
. Preventing TAp73 function using expression
of dominant-negative p73 or specific siRNA knockdown
strategies led to enhanced chemoresistance of human
tumor cells and engineered transformed cells regardless
of their p53 status. Furthermore, detailed analyses of
a series of ovarian cancers further showed that domi-
nant-negative p73 isoforms contribute to drug resis-
tance.
231
The importance of c-Abl kinase-dependent
p73 induction and stabilization has been proposed as
a regulating factor in MMR-dependent apoptosis
90,101
after cisplatin and other anticancer agent treatments.
Although fewer clinical studies have been performed
to examine the role of GADD45
a
in chemotherapy sensi-
tivity/resistance, abrogation of MMR-dependent G
2
arrest and apoptotic responses as a result of GADD45
a
knockdown and/or knockout of GADD45
a
gene expres-
sion highly suggested that this protein was a key mole-
cule that regulates chemosensitivity. Taken together,
MMR Detection, Cellular Responses, and
Resistance to Cisplatin
Cisplatin-related chemotherapeutic agents have been
broadly used for the treatment of many different types
of cancers. As a class of chemotherapeutic compounds,
they exhibited significant broad-based anticancer activi-
ties for the treatment of small-cell and non-small-cell
lung cancers, as well as for cervical, head and neck, colo-
rectal, and bladder cancers.
223
Similar to MNNG,
attempted repair of DNA lesions caused by cisplatin
drug exposure results in lethality. MMR is a major
DNA repair pathway that contributes to the responses
of tumors to the cisplatin class of chemotherapeutic
agents.
224
Accumulated evidence indicates that cells
deficient in MMR have increased cisplatin resistance
(i.e., “damage tolerance”) with concomitantly reduced
apoptosis,
225
e
228
and that a combination of p53
