Biology Reference
In-Depth Information
demonstrate that ionizing radiation or administration of
anticancer drugs in doses equivalent to those that
patients receive reduces behaviors associated with
learning and memory.
21,74
e
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Of the multiple cancer therapies that cause DNA
damage, cognitive dysfunction is well documented in
patients receiving radiation, in patients administered
platinum compounds, in those treated with the alkylat-
ing drugs, especially cyclophosphamide, and in those
receiving antibiotics such as doxorubicin. It is important
to note, however, that in most instances, patient treat-
ment paradigms are not limited to a single drug or to
only radiation, but involve administration of multiple
drug combinations or of drugs and radiation. Thus, it
is difficult to ascertain the degree of neurotoxicity attrib-
utable to a single agent. Complementary data using
animal models and isolated neurons, therefore, provides
valuable insight as to which specific agents directly
produce neurotoxicity and to potential mechanism(s)
for the toxicity.
It is well established that ionizing radiation produces
cognitive impairment (see reviews in
6,77
e
78
). A number
of studies show that children with acute lymphoblastic
leukemia who receive cranial irradiation with intra-
thecal and/or intravenous methotrexate have more
severe cognitive impairment than those who received
just chemotherapy.
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e
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Similar findings were observed
in children receiving irradiation for brain tumors.
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e
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The dependent variables for the level of impairment
include the age of the patients (with younger children
at greater risk) and the dose of radiation used.
78
Loss
of cognitive function also is seen in adults treated with
ionizing radiation.
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e
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Although evaluation of the effects of ionizing radia-
tion on cognitive function in patients is often compli-
cated by the disease process and the use of multiple
therapies, a number of studies in animals support the
notion that ionizing radiation results in neuronal
damage that is associated with cognitive dysfunction.
Damage to the nervous system by irradiation can occur
secondary to the effects on the vasculature,
89
compro-
mise of the blood
endpoints of neuronal function, including uptake of
glutamate;
100
decreases in calcium uptake
101
and alter-
ations in excitability.
102
The importance of these effects
in cognitive function has yet to be determined. Irradia-
tion also results in increased activation of microglia,
57
and these observations, along with other studies
showing activation of the immune system with radia-
tion,
103
suggest an interaction between neurons and
immunocompetent cells that could alter neuronal func-
tion. Sorting out the causes of diminished cognitive
function and thus finding interventions that will effec-
tively block the toxicity remains a challenge.
The general consensus from studies measuring
cognitive function in patients receiving chemotherapy
is that the drugs are a contributing factor in the neuro-
toxicity.
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e
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Many of the reported studies to date
examine cognitive function in women receiving adju-
vant therapy for breast cancer, and in a majority of
these studies the patients showed reduced cognitive
function compared to controls.
70,106
e
111
In some of
the cross-sectional or prospective studies, however,
little if any influence of chemotherapy on cognitive
function is observed.
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e
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Variable factors that could
influence the outcomes in these studies include: base-
line cognitive function in the patients, the study
design, the type of testing performed, the hormonal
status of the patient, and the controls used. In some
instances, cognitive assessment was compared with
healthy controls,
106
e
107,116
whereas in other studies
patients who received systemic chemotherapy were
compared to those receiving local therapies.
70,109
The
reduced cognition is often observed during therapy
106
and in some cases remains for years after therapy is
terminated.
70,106
Although the agents employed and
the number of cycles of adjuvant therapy vary, most
dosing includes drugs that cause DNA damage, cyclo-
phosphamide, epirubicine, and doxorubicin and/or
the antimetabolites, methotrexate and fluorouracil.
Studies also show that administration of cisplatin
produces CNS toxicity including encephalopathy in
patients.
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e
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Evidence from a majority of the clinical observations
suggests that various anticancer drugs produce signifi-
cant toxicity in the central nervous system, and this
toxicity can manifest as reduced cognitive abilities in
patients. Since therapy often involves multiple drugs,
however, studies in animals or in isolated neuronal prep-
arations can address the question of which individual
anticancer drugs are causal in producing cognitive
impairment (see review in
21
). It is important to note
that a number of anticancer drugs do not readily cross
the blood
brain barrier,
90
and/or alterations
in glial function.
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e
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Direct application of relatively
low doses of ionizing radiation onto neuronal cells
grown in culture also causes DNA damage
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and
significant apoptosis.
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Similarly, exposing the
spinal cord to radiation results in apoptosis of neurons
and glia.
97
The cell death in neurons occurs after
neonatal exposure to radiation, while in adult rats the
cell death is largely in glial cells.
97
Of significance is
the observation that irradiation which results in
decreased performance of cognitive behaviors in
animals is associated with a significant decline in neu-
rogenesis in the hippocampus.
57,98
e
99
Animal studies
also show that
e
brain barrier, suggesting that toxicity in the
central nervous system is secondary to off-target
actions.
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e
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Data from animal studies, however,
show that relatively low amounts of anticancer drugs
e
irradiation can affect a number of
