Cisplatin

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Cisplatin

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.

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.
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.
Alopecia (hair loss): this is generally not a major problem in patients treated with cisplatin.

History

As a compound cisplatin was first described by M. Peyrone in 1845. The structure was elucidated by Alfred Werner in 1893. It was rediscovered in the 1960s by Rosenberg et al, who discovered that electrolysis products from a platinum electrode inhibited mitosis in Escherichia coli (E. coli) bacteria. The bacteria grow to 300 times their normal length but cell division fails.

In the 1970s, a series of experiments were conducted at Michigan State University to test the effects the cis-diamminedichloroplatinum(II), along with other platinum coordination complexes, on sarcomas artificially implanted in rats. This study found that cis-diamminedichloroplatinum(II) was the most effective out of this group, which started the medicinal career of cisplatin.

Approved for clinical use by the United States Food and Drug Administration (FDA) in 1978, it revolutionized the treatment of certain cancers. Detailed studies on its molecular mechanism of action, using a variety of spectrocopic methods including X-ray, NMR and other physico-chemical methods, revealed its ability to form irreversible crosslinks with bases in DNA.

References

Rosenberg B, Vancamp L, Krigas T. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature 1965;205:698-9. PMID 14287410.
Peyrone M. Ann Chemie Pharm 1845;51:129.

External links

Platinum compounds | Chemotherapeutic agents | IARC Group 2A carcinogens | Coordination compounds