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Cisplatin, cisplatinum or cis-diamminedichloridoplatinum(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.
Upon administration, a chloride ligand undergoes slow displacement with water (an aqua ligand) molecules, in a process termed aquation. The aqua ligand in the resulting [PtCl(H2O)(NH3)2]+ is easily displaced, allowing cisplatin to coordinate a basic site in DNA. Subsequently, the platinum cross-links two bases via displacement of the other chloride ligand. 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.
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.
Note that although cisplatin is frequently designated as an alkylating agent, it has no alkyl group and cannot carry out alkylating reactions. It is correctly classified as alkylating-like.
The trans-[PtCl2(H2O)(NH3)2 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 are easily separated and detected by HPLC.
Cisplatin has a number of side-effects that can limit its use:
The compound cis-PtCl2(NH3)2 was first described by M. Peyrone in 1845 (known as Peyrone's salt). The structure was deduced by Alfred Werner in 1893. In the 1960s, Barnett Rosenberg and van Camp et al at Michigan State University discovered that electrolysis of a platinum electrode produced cisplatin, which inhibited binary fission in Escherichia coli (E. coli) bacteria. The bacteria grow to 300 times their normal length but cell division fails. Rosenberg then conducted a series of experiments to test the effects various platinum coordination complexes on sarcomas artificially implanted in rats. This study found that cis-diamminedichloridoplatinum(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 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 tetrachloridoplatinate, K2PtCl42−, 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 a 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.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Cisplatin". A list of authors is available in Wikipedia.|