Biology Reference
In-Depth Information
tumor suppressor, you have a better chance of effectively
attacking all the tumor cells.
25
As attractive as this
sounds, such less-selective CDK inhibitors must be
screened for toxicity in animal models, due to the impor-
tance of these enzymes in other cell types. Monospecific
CDK inhibitors also have their place, but they seem to
be better suited to conditions where primarily one kinase
is deregulated, as in certain cardiovascular disorders.
25
One common thread that is emerging in using
inhibitors of DNA repair proteins and DNA checkpoints
is that the inhibitors enhance the toxicities of the anti-
cancer agents given with them, requiring downward
dosage adjustments to the traditional chemotherapeu-
tics. Myelosuppression remains the most common
dose-limiting toxicity, even with these more “targeted”
approaches.
15
This raises yet-unanswered questions:
OVERVI
EW OF DNA REPAIR PAT
HWAYS
Every cell in the body employs an intricate system of
repair, damage tolerance, and checkpoint pathways to
counteract DNA damage and maintain genome stability.
DNA damage induces more than 900 distinct phos-
phorylation events involving more than 700 proteins.
5
The manner in which the repairs are made is predicated
on the type and extent of the damage done. Six major
DNA repair pathways, each with distinct (but some-
times overlapping) modes of action, dispatch the
damage caused by endogenous and exogenous DNA-
damaging agents, including chemotherapy and radio-
therapy.
6,17,26
It is those DNA repair pathways, and
how they are influencing emerging treatments for
cancer, that is the focus of this topic. Separate chapters
are dedicated to each pathway, as well as select repair
proteins and signaling targets within those pathways
that are being culled for clinical development as thera-
peutics. This topic ends with discussions of the role of
DNA repair in cancer therapeutic toxicities and future
directions for development of therapeutics.
A short description of each DNA repair pathway
follows. (See also
Figure 1.6
).
What dosing approach is optimal: combination,
intermittent, sequential?
What combinations of treatment approaches can yield
true synthetic lethality (with less toxic results)?
These questions continue to remain uppermost in the
minds of everyone working in translational research of
DNA repair and damage response inhibitors.
FIGURE 1.6
Summary of the DNA repair pathways. The filled ovals and rectangle represent DNA repair proteins that are being studied for
development of inhibitors as future therapeutics in the fight against cancer.
Mary Ann Liebert, Inc. publishers. Reproduced with permission.
