Chemistry Reference
In-Depth Information
could trigger a cell death response. Thus, MMR recognition of cisplatin adducts on
DNA may trigger a programmed cell death pathway rendering MMR-profi cient
cells more sensitive to DNA modifi cation by cisplatin than MMR-defi cient cells. In
other words, loss of MMR would then increase the cell's ability to tolerate lesions
formed on DNA by cisplatin. The MMR is likely to act mainly in the postreplicative
phase, when the highest concentration of mispairs is expected in the newly synthe-
sized DNA. This would be in contrast to NER, which probably acts independently
of the cell cycle. Thus, rapidly proliferating tumour cells would be more prone to
futile repair attempts capable of triggering cell death. Although the level of resist-
ance to cisplatin that accompanies loss of MMR is relatively small, loss of MMR
has been shown to be suffi cient to account for the failure of treatment with cisplatin
in several model systems.
135 - 137
Nevertheless, a direct connection between the MMR
pathway and cytotoxicity of cisplatin has not been established.
6.4.4 Nonhomologous End - Joining
Radiation exposure can produce many types of DNA damage, including double-
strand breaks. In a local multiply damaged site, where an adduct of cisplatin occurs
close to a single-strand break, the damage may be initially repaired by NER.
However, during the dual incision step, a double-strand break, which is the most
lethal type of a cell damage, is produced. Alternatively, if an adduct of cisplatin is
close to a double-strand break, it could physically block cisplatin removal and repair
by the NER pathway, or the cisplatin adduct could hinder the double-strand break
repair pathways by restricting the access of the protein complexes involved. Another
possibility is that the NER and proteins involved in repair of double-strand breaks
may compete for access to the local multiply damaged site. Investigations into the
effi ciency of NER have shown that NER is less effi cient if cisplatin adducts are near
to a double-strand break due to binding of the heterodimer Ku70/80 at the DNA
ends.
138
In addition, a decreased amount of NER proteins binds to the lesion if a
double - strand break is present.
139,140
Double - strand break NHEJ, which requires
DNA-PK, is also inhibited by cisplatin-damaged DNA in cell extracts.
26,27
This
process may in part explain the radiosensitizing effect of cisplatin administered
during concurrent chemoradiation.
6.4.5 Homologous Recombination Repair
Several studies have shown that HRR plays a role in the repair of DNA damage
by cisplatin in mammalian cells.
21,141,142
HRR of unrepaired cisplatin adducts at
stalled replication forks appears to be a mechanism of cellular resistance to cisplatin
in NER - defi cient and MMR-defi cient cells. In addition to its function in NER and
its ability to uncouple cisplatin interstrand crosslinks, the ERCC1/XPF structure-
specifi c nuclease has a role in the repair of cisplatin adducts related to recombina-
tion processing.
143
Homologous recombination might be initiated prior to excision
of interstrand crosslinks of cisplatin. Because of its probable role in HRR of DNA
adducts of cisplatin, ERCC1 is an attractive therapeutic target, especially in MMR-
defi cient cancers, where increased recombinational bypass of cisplatin lesions
