1.(MeSH)An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle.
definition of Wikipedia
D01.210.375, D01.625.125, D01.710.100, Biocisplatinum (MeSH), cis-Diamminedichloroplatinum (MeSH), cis-Diamminedichloroplatinum(II) (MeSH), cis-Dichlorodiammineplatinum(II) (MeSH), cis-Platinum (MeSH), Dichlorodiammineplatinum (MeSH), NSC-119875 (MeSH), Platidiam (MeSH), Platino (MeSH), Platinol (MeSH), Platinum Diamminodichloride (MeSH)
Cisplatin (n.) [MeSH]
|Systematic (IUPAC) name|
|Pregnancy cat.||D (US)|
|Legal status||℞-only (US)|
|Protein binding||> 95%|
|Mol. mass||301.1 g/mol|
| (what is this?)
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II) (CDDP) (trade name Cisplatin,brand name Platin marketed by Cadila Healthcare according to FDA Orange Book) is a chemotherapy drug. 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 was the first member of a class of platinum-containing anti-cancer drugs, 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).
The compound cis-PtCl2(NH3)2 was first described by M. 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 PtCl4(NH3)2, 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 PtCl2(NH3)2 turned out to be even more effective at forcing filamentous growth. This finding led to the observation that cis PtCl2(NH3)2 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 December 19, 1978.
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. Recently it was shown 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 is administered intravenously as short-term infusion in normal saline for treatment of solid malignancies.
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, 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. 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 by HPLC.
||This date March 2010 needs additional citations for verification. (April 2010)|
Cisplatin has a number of side-effects that can limit its use:
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 spectroscopic methods including X-ray, NMR spectroscopy, and other physico-chemical methods, revealed its ability to form irreversible crosslinks with bases in DNA.
The synthesis of cisplatin is a classic in inorganic chemistry. Starting from potassium tetrachloroplatinate(II), K2[PtCl4], 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 bound amine ligand. Because Cl− has a larger trans effect than NH3, the second amine preferentially substitutes trans to a chloride ligand, and therefore cis to the original amine. The trans effect of the halides follows the order I->Br->Cl-, therefore the synthesis is conducted using [PtI4]2− 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.
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