Platinum-based anti-cancer agents, which include cisplatin, carboplatin and oxaliplatin,
are an important class of drugs used in clinical setting to treat a variety of cancers.
The cytotoxic efficacy of these drugs is mediated by the formation of inter-strand and intrastrand
crosslinks, or platinum adducts on nuclear DNA. There is also evidence demonstrating
that mitochondrial DNA is susceptible to platinum-adduct damage in dorsal root ganglia neurons.
Although all platinum-based agents form similar DNA adducts, they are quite different
in terms of activation, systemic toxicity and tolerance. Platinum-based agents are well known
for their neurotoxicity and gastrointestinal side-effects which are major causes for dose limitation
and treatment discontinuation compromising the efficacy of anti-cancer treatment.
Accumulating evidence in non-neuronal cells shows that the copper transport system is associated
with platinum drug sensitivity and resistance. There is minimal research concerning the
role of copper transporters within the central and peripheral nervous systems. It is unclear
whether neurons are more sensitive to platinum-based drugs, are insufficient in drug clearance,
or whether platinum accumulation affects intracellular copper status and coppermediated
functions. Understanding these mechanisms is important as neurotoxicity is the predominant
side-effect of platinum-based chemotherapy.
This review highlights the role of copper transpor
ters in drug influx, differences in drug activation
and side-effects caused by platinum-based agents, as well as their association with central
and peripheral neuropathies and gastrointestinal toxicities.