Cisplatin (CAS: 15663-27-1)

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II)(CDDP) is a chemotherapy drug.

It was the first member of a class ofplatinum-containing anti-cancer  medicine, which now also

includes carboplatin and oxaliplatin. These platinum complexes react in vivo, binding to and causing

 crosslinking of DNA, which ultimately triggers apoptosis (programmed cell death).

Usage

Cisplatin is administered intravenously as short-term infusion in normal saline for treatment of solid

malignancies. It is 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 is used in

combinations with bleomycin and vinblastine in testicular cancer.

Cisplatin is particularly effective against testicular cancer; the cure rate was improved from 10% to 85%.

In addition, Cisplatin is used in Auger therapy.

Mechanism of action

Following administration, one of the chloride ligands is slowly displaced by water (an aqua ligand), in a

process termed aquation. The aqua ligand in the resulting [PtCl(H2O)(NH3)2]+ is itself easily displaced,

allowing the platinum atom to bind to bases. Of the bases on DNA, guanine is preferred. Subsequent to

formation of [PtCl(guanine-DNA)(NH3)2]+, crosslinking can occur via displacement of the other chloride

ligand, typically by another guanine. Cisplatin crosslinks DNA in several different 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, researchers were able to show that the apoptosis induced by cisplatin

on human colon cancer cells depends on the mitochondrial serine-protease Omi/Htra2. Since this was only

demonstrated for colon carcinoma cells, it remains an open question if 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. 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.

Note that although cisplatin is frequently designated as an alkylating agent, it has no alkyl group and so cannot carry

out alkylating reactions. It is correctly classified as alkylating-like.

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 and increased DNA

repair.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 unknown.

Transplatin

Transplatin, the trans stereoisomer of cisplatin, has formula trans-[PtCl2(NH3)2] and does not exhibit a

comparably useful pharmacological effect. Its low activity is generally thought to be due to rapid deactivation

of the drug before it can arrive at the DNA.[citation needed] It is toxic, and it is desirable to test batches of 

cis-platin for the absence of the trans isomer. In a procedure by Woollins et al., which is based on the classic

‘Kurnakov test’, thiourea reacts with the sample to give derivatives which can easily be separated and

detected byHPLC.