Biology Reference
In-Depth Information
CHAPTER
13
The Role of DNA Damage and Repair
in Neurotoxici
ty Caused by Can
cer Therapies
Djane Braz Duarte, Michael R. Vasko
Indiana University School of Medicine, Indianapolis, IN
INTRODUCTION
The reasons for focusing on DNA damage inducing
neurotoxicity are three-fold. First, multiple studies in
cancer patients and in animal models demonstrate
that cancer therapies that produce oxidative stress
and/or DNA damage in neurons result in significant
neurotoxicity. Second, DNA repair mechanisms are
critically important in maintaining the normal function
of neurons in the central and peripheral nervous sys-
tems.
13
e
15
Third, growing evidence suggests that modi-
fying DNA repair mechanisms in neurons alters
neurotoxicity induced by cancer therapies. Assuming
that DNA damage is an important mechanism for
neurotoxicity, then enhancing DNA repair mechanisms
represents a novel target for improving outcomes in
patients. Although beyond the scope of this chapter, it
should be noted that cancer therapies can affect
neuronal function indirectly through effects on non-
neuronal targets such as the immune system, glia,
etc.
16
e
18
In addition, a number of cancer therapies
produce neurotoxicity by direct actions on neurons
but not by producing direct DNA damage. For
example, the drugs paclitaxel and vincristine cause
peripheral neuropathy in patients, presumably through
stabilizing microtubules.
19
Furthermore, a number of
antimetabolites such as methotrexate and fluorouracil
produce significant neurotoxicity, presumably by
blocking transcription (see reviews in
4,20
e
21
).
With anticancer drugs that damage DNA and with
cancer therapies not targeting DNA directly, major
neurotoxicity can occur. This is now recognized as an
important side effect that impacts therapy and quality
of life in patients and survivors. Two major types of
neurotoxicity are prevalent side effects of cancer
therapy: alterations in cognitive function
1
e
3
and
peripheral neuropathy
4
(
Figure 13.1
). The severity of
symptoms and duration of these neurotoxic effects
vary depending on the patient, the therapeutic agent
or agents used, the dosing regimen, and a number of,
as yet, unrecognized factors.
1,4
e
5
Neurotoxicity
secondary to cancer therapies represents a unique chal-
lenge to clinicians and basic medical scientists because
of the prevalence of the toxicity, the lack of under-
standing of the mechanisms mediating the toxicity,
and the lack of therapies to alleviate the toxicity.
For the purpose of this chapter, we will focus on
cancer therapies that produce neurotoxic effects as
a result of DNA damage in neurons. These therapies
include ionizing radiation, the platinum compounds,
alkylating agents such as cyclophosphamide and temo-
zolomide, and the topoisomerase interacting agent
doxorubicin. Ionizing radiation produces reactive
oxygen species (ROS) which in turn can cause oxidative
DNA damage.
6
Platinum compounds interact with
DNA to form cross-linking adducts.
7
e
8
Recent evidence
also suggests that platinum compounds increase
production of ROS which can damage DNA and
contribute to neurotoxicity.
9
e
10
Alkylating agents form
covalent bonds with DNA strands, thus preventing
cell replication,
11
whereas anticancer antibiotics interca-
late into the DNA molecule and this blocks transcrip-
tion, but also stabilizes the topoisomerase II-DNA
complex.
12
DNA R
EPAIR MECHANISM IN NE
URONS
In recent years much evidence has accumulated sup-
porting the idea that DNA repair mechanisms are crit-
ical in helping to maintain neuronal function in the
central and peripheral nervous systems. Indeed,
evidence to support this notion has been eloquently
reviewed by others.
13,15,22
Briefly, it is clear that DNA
