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'Cisplatin', 'cisplatinum' 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.

Contents

Synthesis

Pharmacology

Mechanism of action

Side effects

History

References

External links

Synthesis

The synthesis of cisplatin is a classic in inorganic chemistry. Starting from tetrachloroplatinate, PtCl₄²⁻, the first NH₃ ligand is added to any of the four equivalent positions, but the second NH₃ could be added cis or trans to the amine ligand. Because Cl⁻ has a larger trans effect than NH₃, the second amine substitutes trans to the chloride ligand, and therefore cis to the first amine. The trans effect of the halides follows the order I^->Br^->Cl^-, therefore the synthesis is conducted using PtI₄²⁻ to ensure high yield and purity of the cis isomer, followed by conversion of the PtI₂(NH₃)₂ into PtCl₂(NH₃)₂, as first described by Dhara.

Pharmacology

Mechanism of action

Upon administration, a chlorine ligand can undergo slow displacement with water (an aqua ligand) molecules, in a process termed aquation. The aqua ligand is highly reactive, allowing cisplatin to coordinate a base in DNA, and a subsequent cross-link is formed after loss of the second chlorine ligand. 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, though this is generally thought to be due to rapid deactivation of the drug before it can arrive at the DNA.
The cis isomer is cytotoxic to the tumor cells whereas the trans isomer does not have an anticancer effect, it is toxic, therefore it is normal to test batches of ''cis''-platin by HPLC for the absence of the trans isomer. This test, based on the classic 'Kurnakov test', uses thiourea as a ligand; cis compounds turn yellow, trans compounds give a white precipitate.^[1]
Most notable among the DNA changes are the 1,2-intrastrand cross-links with purine bases. These include 1,2-intrastrand d(GpG) adducts which form nearly 90% of the adducts and the less common 1,2-intrastrand d(ApG) adducts. 1,3-intrastrand d(GpXpG) adducts occur but are readily excised by the nucleotide excision repair (NER) . Other adducts include inter-strand crosslinks and nonfunctional adducts that have been postulated to contribute to cisplatin's activity. Interaction with cellular proteins, particularly HMG domain proteins, has also been advanced as a mechanism of interfering with mitosis, although this is probably not its primary method of 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 given. 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. Aprepitant combined with ondansetron and dexamethasone has been shown to be better for highly emetogenic chemotherapy than just ondansetron and dexamethasone.

★ 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.

★ Electrolyte disturbance: Cisplatin can cause hypomagnesaemia, hypokalaemia and hypocalcaemia. The hypocalcaemia seems to occur in those with low serum magnesium secondary to cisplatin, so it is not primarily due to the Cisplatin.

History

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

1. Woollins, J. D.; Woollins, A.; Rosenberg, B. ''Polyhedron'', 1983, '2', 175-178.


★ 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.

★ Alderden, Hall and Hambley 'The Discovery and Development of Cisplatin' , Journal of Chemical Education, 2006, 83:728-724 (http://jchemed.chem.wisc.edu/journal/issues/2006/May/abs728.html).

External links

★ Cisplatin: The Invention of an Anticancer Drug by Andri Smith

★ MedlinePlus page on cisplatin

★ Chemical & Engineering News Cisplatin in June 20, 2005

★ NIOSH Pocket Guide to Chemical Hazards

★ IARC Monograph: "Cisplatin"