Cisplatin

Cisplatin
Clinical data
Trade namesPlatinol, others
Other namesCisplatinum, platamin, neoplatin, cismaplat, cis-diamminedichloroplatinum(II) (CDDP)
AHFS/Drugs.comMonograph
MedlinePlusa684036
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Pregnancy
category
  • AU: D
  • Contraindicated
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability100% (IV)
Protein binding> 95%
Elimination half-life30–100 hours
ExcretionRenal
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CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.036.106 Edit this at Wikidata
Chemical and physical data
Formula[Pt(NH3)2Cl2]
Molar mass300.05 g·mol−1
3D model (JSmol)
  • Cl[Pt@SP1](Cl)([NH3])[NH3]
  • InChI=1S/2ClH.2H3N.Pt/h2*1H;2*1H3;/q;;;;+2/p-2 checkY
  • Key:LXZZYRPGZAFOLE-UHFFFAOYSA-L checkY
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Cisplatin is a chemical compound with formula cis-[Pt(NH3)2Cl2]. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain tumors and neuroblastoma. It is given by injection into a vein.

Common side effects include bone marrow suppression, hearing problems including severe hearing loss, kidney damage, and vomiting. Other serious side effects include numbness, trouble walking, allergic reactions, electrolyte problems, and heart disease. Use during pregnancy can cause harm to the developing fetus. Cisplatin is in the platinum-based antineoplastic family of medications. It works in part by binding to DNA and inhibiting its replication.

History

Cisplatin was first reported in 1845 and licensed for medical use in 1978 and 1979. It is on the World Health Organization's List of Essential Medicines. Cisplatin was first synthesized in 1844 by Michele Peyrone and was initially known as Peyrone's chloride. It played an important role in the development of coordination chemistry through the work of Alfred Werner. The original discovery of the cytotoxic effect of platinum complexes in the 1960s was purely accidental. Barnett Rosenberg aimed to investigate the effect of alternating current on the growth of Escherichia coli. Using platinum electrodes, he observed that cell growth was inhibited. Subsequent investigation revealed that the cause was not the alternating current but the metal complex cis-diamminetetrachloridoplatinum(IV), [Pt(NH3)2Cl4], which had formed from the supposedly inert platinum electrodes.

Further experiments with the previously known platinum complex cis-diamminedichloridoplatinum(II), [Pt(NH3)2Cl2], demonstrated the same growth-inhibiting effect. In contrast, studies with the corresponding trans compound showed no such effect. Diamminedichloridoplatinum(II) had already been known since 1844 as Peyrone's salt or Reiset's second chloride. Later investigations established that these compounds exhibit cis-trans isomerism. The existence of these two isomers led Alfred Werner in 1894 to conclude that both complexes possess a planar structure.

In cancer therapy, cisplatin was first used in 1974 in a study at the University Hospital of Indiana for the treatment of testicular cancer and, in the following years, led to significant success in a large number of patients without recurrence. Because antiemetic drugs were not yet widely used at the time, the therapy was associated with exceptionally severe nausea for patients.

Medical use

Cisplatin is administered intravenously as short-term infusion in normal saline for treatment of solid and haematological malignancies. It is used to treat various types of cancers, including sarcomas, some carcinomas (e.g., small cell lung cancer, squamous cell carcinoma of the head and neck and ovarian cancer), lymphomas, bladder cancer, cervical cancer, and germ cell tumors.

The introduction of cisplatin as a standard treatment for testicular cancer improved remission rates from 5–10% before 1974 to 75–85% by 1984.

Side effects

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

Pharmacology

Cisplatin interferes with DNA replication, which kills the fastest proliferating cells, which in theory are cancerous. Following administration, one chloride ion is slowly displaced by water to give the aquo complex cis-[Pt(NH3)2(H2O)Cl]+, in a process termed aquation. Dissociation of the chloride is favored inside the cell because the intracellular chloride concentration is only 3–20% of the approximately 100 mM chloride concentration in the extracellular fluid.

The water molecule in cis-[Pt(NH3)2(H2O)Cl]+ is itself easily displaced by the N-heterocyclic bases on DNA. Guanine preferentially binds. A model compound has been prepared and crystals were examined by X-ray crystallography

Subsequent to formation of [Pt(guanine−DNA)(NH3)2Cl]+, crosslinking can occur via displacement of the other chloride, typically by another guanine. Cisplatin crosslinks DNA in several ways, interfering with cell division by mitosis. The damaged DNA elicits DNA repair mechanisms, which in turn activate apoptosis when repair proves impossible. In 2008, apoptosis induced by cisplatin on human colon cancer cells was shown to depend on the mitochondrial serine-protease Omi/Htra2. Since this was only demonstrated for colon carcinoma cells, it remains an open question whether the Omi/Htra2 protein participates in the cisplatin-induced apoptosis in carcinomas from other tissues.

Most notable among the changes in DNA 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. Coordination chemists have obtained crystals of the products of reacting cisplatin with small models of DNA.

A POVray render of cisplatin bound to a short segment of DNA, the platinum atom is highlighted in yellow.

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.

Cisplatin resistance

Cisplatin combination chemotherapy is the cornerstone of treatment of many cancers. Initial platinum responsiveness is high, but the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Many mechanisms of cisplatin resistance have been proposed, including changes in cellular uptake and efflux of the drug, increased detoxification of the drug, inhibition of apoptosis, increased DNA repair or changes in metabolism. Oxaliplatin is active in highly cisplatin-resistant cancer cells in the laboratory; however, there is little evidence for its activity in the clinical treatment of patients with cisplatin-resistant cancer. The drug paclitaxel may be useful in the treatment of cisplatin-resistant cancer; the mechanism for this activity is as yet unknown. In prostate cancer models, increased reliance on fatty acid oxidation has been associated with cisplatin resistance. A cisplatin-based prodrug, Platin-L, has been investigated preclinically for overcoming this resistance by inhibiting CPT1A-dependent fatty acid oxidation.

Transplatin

Transplatin, the trans-stereoisomer of cisplatin, has formula trans-[Pt(NH3)2]Cl2 and does not exhibit a comparably useful pharmacological effect. Two mechanisms have been suggested to explain the reduced anticancer effect of transplatin. Firstly, the trans arrangement of the chloro ligands is thought to confer transplatin with greater chemical reactivity, causing transplatin to become deactivated before it reaches the DNA, where cisplatin exerts its pharmacological action. Secondly, the stereo-conformation of transplatin is such that it is unable to form the characteristic 1,2-intrastrand d(GpG) adducts formed by cisplatin in abundance.

Molecular structure

Cisplatin is the square planar coordination complex cis-[Pt(NH3)2Cl2].: 286–8 : 689  The prefix cis indicates the cis isomer in which two similar ligands are in adjacent positions.: 550  The systematic chemical name of this molecule is cis–diamminedichloroplatinum,: 286  where ammine with two m's indicates an ammonia (NH3) ligand, as opposed to an organic amine with one m.: 284 

History

The compound cis-[Pt(NH3)2Cl2] was first described by Italian chemist Michele Peyrone in 1845, and known for a long time as Peyrone's salt. The structure was deduced by Alfred Werner in 1893. In 1965, Barnett Rosenberg, Van Camp et al. of Michigan State University discovered that electrolysis of platinum electrodes generated a soluble platinum complex which inhibited binary fission in Escherichia coli (E. coli) bacteria. Although bacterial cell growth continued, cell division was arrested, the bacteria growing as filaments up to 300 times their normal length. The octahedral Pt(IV) complex cis-[Pt(NH3)2Cl4], but not the trans isomer, was found to be effective at forcing filamentous growth of E. coli cells. The square planar Pt(II) complex, cis-[Pt(NH3)2Cl2] turned out to be even more effective at forcing filamentous growth. This finding led to the observation that cis-[Pt(NH3)2Cl2] was indeed highly effective at regressing the mass of sarcomas in rats. Confirmation of this discovery, and extension of testing to other tumour cell lines launched the medicinal applications of cisplatin. Cisplatin was approved for use in testicular and ovarian cancers by the U.S. Food and Drug Administration on 19 December 1978. and in the UK (and in several other European countries) in 1979. Cisplatin was the first to be developed. In 1983 pediatric oncologist Roger Packer began incorporating cisplatin into adjuvant chemotherapy for the treatment of childhood medulloblastoma. The new protocol that he developed led to a marked increase in disease-free survival rates for patients with medulloblastoma, up to around 85%. The Packer Protocol has since become a standard treatment for medulloblastoma. Likewise, cisplatin has been found to be particularly effective against testicular cancer, where its use improved the cure rate from 10% to 85%.

Synthesis

A commercial route starts from potassium tetrachloroplatinate, a standard Pt(II) reagent. The reaction of this tetrachloride with ammonia gives Magnus's green salt (MGS), which has the same empirical formula as cisplatin but is an intractable solid. A traditional way to avoid MGS involves the conversion of K2PtCl4 to K2PtI4, as originally described by Dhara. Reaction of the tetraiodide with ammonia forms Cis-diamminediiodoplatinum(II), [Pt(NH3)2I2], which can be isolated as a yellow solid. Treatment of the diammine diiodide with aqueous silver nitrate gives the diaquo complex [Pt(NH3)2(H2O)2]2+, concomitant with precipitation of silver iodide. Addition of potassium chloride to the solution of the diaquo complex precipitates cisplatin.

A one-pot synthesis of cisplatin from K2PtCl4 relies on the slow release of ammonia from ammonium acetate.

Research

Cisplatin has been studied with Auger therapy to increase the therapeutic effects of cisplatin, without increasing normal tissue toxicities. However, due to significant side effects, the search for structurally novel Pt(II) and Pd(II) compounds exhibiting antineoplastic activity is extremely important and aims to develop more effective and less toxic drugs. Cisplatin-like molecules ([Pt(NH3)2Cl]+ and [Pt(NH3)Cl2]) linked by variable length alkandiamine chains have attracted some interest in cancer chemotherapy.

References

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Further reading