Biology Reference
In-Depth Information
of neurons.
10
The platinum compounds, cisplatin, car-
boplatin, and oxaliplatin produce neuronal DNA
damage by forming platinum-DNA adducts that can
result in apoptotic cell death.
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e
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e
62
Adducts can
be divided into three different types: monoadducts,
intrastrand crosslinks, or interstrand crosslinks.
Furthermore, a complex platinum-DNA-protein cross-
link can be formed and these complexes can inhibit
DNA replication.
63
Cisplatin-DNA adducts may be
repaired by different components of the DNA repair
system, including NER and mismatch repair, but the
NER pathway appears to be the major pathway in vitro
and in vivo.
64
As mentioned above, growing evidence
suggests that cisplatin exposure generates ROS,
9
e
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producing oxidative DNA damage that is primarily
removed by the BER pathway.
65
Alkylating anticancer agents such as temozolomide
and cyclophosphamide produce DNA damage through
their ability to alkylate nucleotides.
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e
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Adducts can be
formed with oxygen and nitrogen in DNA bases, as well
as on oxygen in phosphodiesters.
67
DNA damage
caused by these agents is repaired by multiple pathways
that remove alkylated bases and/or repair secondary
damage.
11
Thus it seems feasible that changes in DNA
repair pathways could directly influence toxicity of
alkylating agents.
in XP patients include peripheral neuropathy, deafness,
and loss of reflexes,
43
symptoms similar to those pre-
sented by patients treated with chemotherapeutic agents
(see below). In another inherited developmental
disorder, Cockayne syndrome, cells are deficient in
their ability to repair DNA damage in transcribed
regions.
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e
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Brains of patients with Cockayne's
syndrome have demyelination and these individuals
exhibit multiple developmental problems,
including
mental retardation.
46
NEURONAL DNA DAMAGE AFTER
CANCER THERAPY
The mechanisms causing neurotoxicity after cancer
therapies remain unknown, but radiation and a number
of anticancer drugs have in common that they produce
DNA damage by interacting directly with mitochondrial
or nuclear DNA or by increasing the production of ROS
in cells; both cause oxidative DNA damage.
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e
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Presumably, the DNA damage could result in apoptotic
cell death in neurons or could result in production of
mutated proteins that could affect neuronal function.
13
Since the therapeutic efficacy of these cancer treatments
is through DNA damage, the drugs cannot distinguish
between tumor cells and normal cells. Thus, the chal-
lenge remains to determine whether unique mecha-
nisms of DNA damage and/or repair occurs in cancer
cells compared to neurons.
As discussed in some detail below, ionizing radia-
tion and anticancer drugs cause nuclear DNA damage
in neurons. This can result in alterations in function or
cell death. Damage to DNA after chemotherapy also
occurs in the neuronal mitochondrial DNA
49
and mito-
chondrial damage in neurons can result in deregula-
tion of calcium,
51
increased excitability,
52
loss of
function, and/or cell death.
53
Although a major conse-
quence of DNA damage in neurons is likely to be
altered function, high levels of DNA damage in
neurons can lead to apoptosis.
54
The DNA damage
includes formation of apurinic/apyrimidinic (AP)
sites, DNA-adducts, single-strand breaks (SSBs),
double-strand breaks (DSBs), DNA-protein cross-links,
and insertion/deletion mismatches. Each of the
chemotherapeutic agents discussed below can induce
one or a combination of different
COGNITIVE IMPAIRMENT INDUCED BY
CANCER THERAPIES
Cognitive impairment, also called “chemobrain” or
“chemofog,” is a major neurotoxic side effect of
a number of chemotherapeutic agents and of ionizing
radiation.
1,3,68
The symptoms of “chemobrain” vary
from fatigue, decreased attention, and inability to focus,
to severe impairment in learning and memory
1,3
(
Figure 13.1
). Although chemotherapy induced loss of
cognition may resolve over time,
69
in a significant
subgroup of individuals cognitive changes persist long
after treatment is terminated and in some cases may
be permanent.
70
The incidence of long-term adverse
neurocognitive effect of chemotherapy appears to be
increasing as survival rates increase for cancer patients.
In the past, the recognition of this neurotoxicity was
limited in part because of a lack of clinical evaluation
of cognitive function in patients before and after
receiving cancer therapy. As more testing occurs,
however, accumulating evidence supports the notion
that cancer therapy (radiation and/or chemotherapy)
is a causative factor in reduced cognition in patients
(see below). In addition, imaging studies performed on
patients who receive anticancer drugs show changes in
brain structure and function associated with reduced
cognition.
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Finally, studies in experimental animals
types of DNA
damage.
Exposing cells to ionizing radiation increases
production of ROS and causes damage to DNA in
various types of cancer cells and in post-mitotic cells.
55
Ionizing radiation produces breaks in DNA as well as
increasing the number of AP sites.
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The increase in
DNA damage can lead to apoptosis (especially in cells
involved in neurogenesis
57
) and to a reduced function
