Cisplatin or cis-diamminedichloroplatinum(II)
(CDDP) is a platinum-based chemotherapy drug used to treat various types
of cancers, including sarcomas, some carcinomas (e.g. small cell lung
cancer and ovarian cancer), lymphomas and germ cell tumors. It was the
first member of its class, which now also includes carboplatin and oxaliplatin.

Pharmacology

Mode of action

Cisplatin acts by crosslinking DNA in several different ways,
making it impossible for rapidly dividing cells to duplicate their DNA
for mitosis. The damaged DNA sets off DNA repair mechanisms, which activate
apoptosis when repair proves impossible. The trans isomer does not have
this pharmacological effect. The chlorine undergoes slow displacement
with water molecules forming a positively charged molecule which then
crosslinks the DNA. Thus the drug need to be administered in saline solution,
to prevent inactivation.

Most notable among the DNA changes are the intrastrand GpG adducts which
form nearly 90% of the adducts. Other adducts include inter-strand crosslinks
and nonfunctional adducts that have been postulated to contribute to its
activity. Interaction with cellular proteins has also been advanced as
a mechanism of interfering with mitosis, although this is probably not
its main action.

Side effects

Cisplatin has a number of side-effects that can limit its use:

* Nephrotoxicity (kidney damage) is a major concern when cisplatin is
prescribed as a chemotherapy agent. The dose is reduced when the patient’s
creatinine clearance (a measure of renal function) is reduced. Adequate
hydration and diuresis is used to prevent renal damage. The nephrotoxicity
of platinum-class drugs seems to be related to reactive oxygen species
and in animal models can be ameliorated by free radical scavenging agents.
This is a dose limiting toxicity.
* Neurotoxicity (nerve damage) can be anticipated by performing nerve
conduction studies before and after treatment.
* Nausea and vomiting. cisplatin is one of the most emetogenic chemotherapy
agents, but this is managed with prophylactic antiemetics (e.g. ondansetron,
granisetron, etc.) in combination with corticosteroids.
* Ototoxicity (hearing loss): unfortunately there is at present no effective
treatment to prevent this side effect, which may be severe. Audiometric
analysis may be necessary to assess the severity of ototoxicity. Other
drugs (such as the aminoglycoside antibiotic class) may also cause ototoxicity,
and the administration of this class of antibiotics in patients receiving
cisplatin is generally avoided. The ototoxicity of both the aminoglycosides
and cisplatin may be related to their ability to bind to melanin in the
stria vascularis of the inner ear or the generation of reactive oxygen
species.
* Alopecia (hair loss): this is generally not a major problem in patients
treated with cisplatin.