Biology Reference
In-Depth Information
of patients, acute administration produces reversible
symptoms of cold-induced paresthesia, focal weakness,
and pain. These symptoms are dose-dependent and
often appear after a single cycle of treatment.
163
e
166
Chronic sensory neuropathy that develops progres-
sively after multiple exposures to the drug also is
observed in more than half of the patients receiving
the drug.
163
e
164,167
e
168
Symptoms of chronic neuropathy
are similar to those observed in patients receiving
cisplatin. With chronic administration of oxaliplatin,
sensory neuronal function as measured by amplitude
of action potentials and/or conduction velocity is signif-
icantly reduced.
164,168
For the most part, results generated in animal studies
parallel the observations regarding neuropathy in
patients. Indeed, several lines of evidence support the
notion that sensory neurons with cell bodies in the
dorsal root ganglia are the primary target of platinum
compounds. After systemic administration of cisplatin,
platinum-DNA adducts accumulation in rat DRG is
higher than in other tissues,
61
and the amount of these
adducts correlates with sensory neurotoxicity.
48,62
Systemic administration of multiple doses of cisplatin
to rats and mice results in damage to sensory nerve
cell bodies and/or apoptosis, depending on the dosing
regimen used.
59
e
60,169
e
171
Exposing isolated sensory
neurons grown in culture to cisplatin also produces
significant apoptosis.
10,60,172
Chronic administration of
cisplatin also reduces sensory nerve conduction velocity
and the amplitude of action potentials,
48,169,171,173
e
174
which are electrophysiological indices of nerve function.
Most of the electrophysiological data suggest that
cisplatin toxicity occurs on large diameter myelinated
fibers, and behavioral studies show that cisplatin
reduces behavioral responses in tests of proprioception
and nociception.
169,171,175
Cisplatin also has toxic effects on small diameter
sensory neurons. Systemic administration of cisplatin
decreases the amounts of the neuropeptides substance
P and CGRP in peripheral endings of small di-
ameter sensory neurons.
169,171,175
e
176
In one study, the
levels of these peptides in the dorsal root ganglia
increased while the levels in the periphery decreased,
suggesting that cisplatin could be affecting axonal trans-
port to the peripheral endings of sensory neurons.
169
We
have recently shown that exposure of sensory neurons
in culture to cisplatin for 24 hours decreases the evoked
release of CGRP from sensory neurons (see
Figure 13.5
below). This change in CGRP release occurred at
cisplatin concentrations that did not alter the content
of the peptide. Another indication of the involvement
of small diameter sensory neurons is the data showing
that cisplatin treatment affects the ability of animals to
perceive noxious stimuli. Repeated administration
to rodents of relatively low doses of cisplatin resulted
in an enhanced sensitivity to noxious mechanical and
cold stimuli.
173,177
In a number of other studies using
higher cumulative doses of cisplatin, behavioral
responses to noxious stimuli were reduced.
169,171
These
alterations in nociception in animal models parallel
observations in patients of increased or decreased pain
perception.
Long term administration of oxaliplatin and carbo-
platin also produced neuropathy in animal models as
demonstrated by changes in sensory neuron
morphology, decreased nerve conduction, and altered
nociceptive responses.
177
e
179
In isolated sensory
neurons grown in culture, however, oxaliplatin
produced less cell death and less formation of DNA
adducts than equivalent concentrations of cisplatin.
62
Acute administration of oxaliplatin produced hyperno-
ciception.
177,180
This effect paralleled the enhanced
pain perception observed in a majority of patients
receiving a single dose of this drug. The mechanism
for this acute nociceptive effect may involve an increase
in excitability of small diameter sensory neurons since
Adelsberger et al.
181
observed an increase in size and
duration of action potentials in cells treated with the
platinum compound. Presumably the increased excit-
ability occurs in part through altering voltage gated
ion channels. Moreover, it had been suggested that oxa-
liplatin affects excitability through its metabolite
oxalate, which chelates calcium ions and consequently
could affect ion channels.
182
MODIFYING DNA REPAIR
ALTERS NEUROTOXICITY INDUCED
BY CANCER THERAPIES
The literature reviewed above provides strong
correlative evidence suggesting that DNA damage
after cancer therapy is a major mechanism for neuro-
toxicity. Indeed, it is clear that ionizing radiation and
anticancer drugs that produce neurotoxicity also can
cause significant DNA damage in neurons. In addition,
neurons contain DNA repair pathways, and these
pathways can be modified by injury to the central
nervous system or by neurodegenerative diseases. A
major unanswered question, however, is whether
modifying DNA repair mechanisms have a significant
impact on neurotoxicity induced by cancer therapies.
If repair pathways are an important target for prevent-
ing either cognitive dysfunction or CIPN after cancer
therapies, then inhibiting repair pathways should
worsen the neurotoxicity, whereas augmenting repair
should attenuate the toxic effects. Two caveats are
important to consider. First, the data showing muta-
tions of DNA repair mechanisms in neurodegenerative
diseases such as Alzheimer's disease, ALS, and XP
