Biology Reference
In-Depth Information
TABLE 1.2 Examples of How Direct Repair (MGMT) Activity
Overlaps with other DNA Repair Pathways
TABLE 1.3 Progression in Paradigms of Treating Cancers
Selectively
Overlap
Mechanism
Model/technique
Approach/activity
In DR, if O
6
-methylguanine-DNA
methyltransferase (MGMT) is unsuccessful in
removing the O
6
-alkyl group from guanine, the
MMR pathway can recognize and fix O
6
-
methylguanine mispairs
26
DR/MMR
1
Infectious disease
Match 1 specific drug to 1 type of cancer
DR/MMR
When MGMT repairs guanine after replication
occurs, MGMT can leave behind guanine/thymine
mismatches that MMR can repair.
13
Alternately,
MMR-mediated signaling can arrest the cell cycle
and induce apoptosis (see Chapter 9)
2
Scatter technique
Damage DNA but without tumor
selectivity
DR/BER
Mismatch pairs and other alkylation adducts that
DR doesn't repair are repaired by BER
26,28
Larger adducts at the O
6
-position of guanine that
MGMT cannot repair are repaired by NER
13
DR/NER
3
Additive technique
Treat cancer non-selectively but
with more than one agent at a time
(chemo
IR; chemo
chemo, etc.)
þ
þ
DR/NER/
HR or
NHEJ
If interstrand crosslinks form before MGMT can
make repairs, the intramolecular rearrangement of
O
6
-chloroethylguanine can be repaired by NER or
one of the DSB repair pathways
13
Abbreviations: BER, base excision repair; DR, direct repair; DSB, double-strand
break; HR, homologous recombination; MMR, mismatch repair; NER, nucleotide
excision repair; NHEJ, non-homologous end joining.
4
Chemosensitization
Chemo
þ
MAb; chemo
þ
DNA repair
inhibitor
therapeutic use to sensitize tumors to chemotherapy in
an attempt to overcome treatment resistance. However,
inhibition of MGMT did not occur only in the tumor
cells; it also sensitized normal cells to alkylating agents.
In some cases, this resulted in an obligatory reduction in
dose of alkylator therapy, which compromised the
agent's efficacy. Therefore, despite MGMT's contribu-
tion, scientists again faced the question of how to selec-
tively kill tumors while sparing normal cells. That
question remains today.
Virtually all of today's anticancer drugs, including the
“targeted” ones, still target fundamental cellular
processes (such as DNA replication) that transpire in
both healthy and mutagenic cells.
10
But researchers are
coming closer to an answer in the continuing quest of
how to selectively kill cancer cells (
Table 1.3
).
If key processes in the continuum of cancer transfor-
mation and progression can be interrupted, then it
should be possible to stop cancer in its tracks. The key
processes that have manifested themselves to date are
primarily deficiencies. As mutations progress, loss of
heterozygosity occurs, also called “genetic streamlin-
ing”
3
(
Figure 1.1
). With respect to DNA repair pathways,
deficiencies in a particular pathway can lead to
increased levels of other DNA repair proteins, either in
the same pathway or a different one. Compensating
for a deficiency is paramount to efficient DNA repair,
and by extension, cancer survival. These altered levels
of DNA repair proteins contribute to acquired or
5
Synthetic lethality
Treat a weakness with an agent that will
turn the weakness into induced cell
death
6
Individualized
Therapy
Functional assays for DNA repair
competence and oncogenic mutation
status; customized treatment plans based
on molecular profiling
intrinsic cellular resistance to DNA-damaging agents.
17
Capitalizing on cancer-cell deficiencies to turn them
against themselves is the conceptual framework for
synthetic lethality
e
a new approach being pursued in
the war against cancer.
SYNTHETIC LETHALITY
Synthetic lethality is a situation in which a mutation
in one of two genes separately still supports cellular
viability, but the combination of the two mutations leads
to cell death. If one of those genes is important to
