Biology Reference
In-Depth Information
produce neuronal apoptosis, inhibit neurogenesis, and
alter glial function.
2,121
Animal studies using cisplatin clearly demonstrate
that concentrations similar to those achieved in therapy
produce neuronal cell death in isolated neuronal
cultures and in the central nervous system of rodents.
Exposing cortical neurons from embryonic rats to
5
behavioral results were observed with administration
of doxorubicin alone using inhibitory avoidance
tasks
75
and using a combination of doxorubicin and
cyclophosphamide with fear conditioning tasks.
76
Administration of cyclophosphamide alone also
decreases learning and memory in mice using avoid-
ance testing.
130
e
131
In contrast, Lee and coworkers
found no impairment of memory tests after recovery
from long-term cyclophosphamide treatment in female
rats.
132
Both long-term potentiation and learning were
improved after 7
M cisplatin causes dose-dependent cell
death.
122
Analogous results are observed in cultures
of cerebellar granule neurons harvested from 8-day-
old rat pups after treatment with 20
100
e
m
M cisplatin.
123
Exposure of rat cortical neurons to a concentration of
0.5
e
80
m
9 weeks of recovery. The conflicting
results of these studies suggest that alterations in
learning may be related to the cyclophosphamide
dosing schedule and the recovery period. Since some
patients on adjunct therapy have sustained cognitive
problems for years, it is interesting to speculate that
combinations of drugs that each affect the nervous
system may have additive or synergistic actions that
augment chemobrain.
To date, we are aware of only one study examining
effects of cisplatin administration on learning and
memory. Three systemic injections of cisplatin
(5mg/kg) resulted in a significant decrease in memory
using passive and active avoidance testing.
124.
This
dosing also increased lipid peroxidation and decreased
the GSH/GSSG ratio in the brains of treated mice sug-
gesting that the cisplatin treatment was increasing ROS
in the brain. It is important to note that other anticancer
drugs that do not act by direct interactions with
DNA (e.g. the antimetabolites, methotrexate, and fluoro-
uracil) also impair cognitive behaviors in animal
models.
133
e
134
e
M cisplatin inhibits neurite outgrowth,
124
whereas
in neuronal and glial precursor cells from embryonic
rats cisplatin in concentrations as low as 0.1
m
M
produces significant cell death.
121
Interestingly, the
low concentrations of cisplatin produce more cell death
in neuronal and glial progenitors than in cancer cell
lines. When systemically injected into rodents, cisplatin
also kills cells in the subventricular zone of the hippo-
campus
121
and causes lesions of various nuclei in the
rat brain.
122
Similar results are observed with cyclo-
phosphamide and carmustine, with methotrexate and
cytosine arabinoside, and with vinblastine. Doxoru-
bicin also causes cell death in cerebellar granule cells
grown in culture.
125
When administered intravenously
to mice, this drug also causes neuronal damage in areas
of the brain where the drug distributes
126
suggesting
that with access to the CNS, doxorubicin is neurotoxic.
One mechanism for this toxicity could be oxidative
damage since systemic administration of doxorubicin
elevates levels of protein oxidation and lipid peroxida-
tion in the brains of mice
47
and decreases levels of
glutathione peroxidase, superoxide dismutase, and
catalase.
127
Oxidative damage in the brains of mice
also has been reported after systemic administration
of cyclophosphamide.
128
e
129
It remains to be seen if
this oxidative damage also causes DNA damage. The
importance of these data, however, is that they provide
evidence supporting the notion that specific anticancer
drugs that are associated with loss of cognitive function
in patients are neurotoxic in both in vitro and in vivo
animal studies.
The question remains whether the CNS toxicity
observed with anticancer drugs is related to the loss
of cognitive function. To date, limited studies have
been performed using animal models to address this
important issue. Studies with doxorubicin support the
notion that this drug causes cognitive dysfunction in
rats. Using passive avoidance tests, Konat and
coworkers showed that a once a week systemic admin-
istration of doxorubicin (2.5 mg/kg) and cytoxan
(25 mg/kg) for 4 weeks impaired memory function in
female rats.
74
This impairment correlated with
a decrease in neurogenesis in the hippocampus. Similar
m
PERIPHERAL NEUROPATHY INDUCED
BY CANCER THERAPIES
Peripheral neuropathy secondary to cancer therapy is
the second major neurotoxicity observed in patients
during and after treatment.
4
e
5
This toxicity, which is
often called chemotherapy-induced neuropathy (CIN)
or chemotherapy-induced peripheral neuropathy
(CIPN), usually presents as a sensory neuropathy and
symptoms may include distal paresthesia (tingling,
numbness, and burning sensations), altered propriocep-
tion, coldness in extremities, and acute or chronic
pain
4,135
(
Figure 13.1
). Effects of therapies on motor
neurons have been observed but occur less frequently
than sensory neuropathy. Rarely, patients exhibit symp-
toms of autonomic nervous system dysfunction such as
orthostatic hypotension, palpitations, or impotence. In
recent years, increased attention has focused on the
ability of various cancer therapies to produce acute or
chronic pain, which can be severe enough to result in
termination
therapy.
136
of
Indeed,
investigators
