CisPlatin

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. Platinum complexes are formed in cells, which bind and cause cross-linking of DNA -- ultimately triggering apoptosis, or automated cell death.



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 cisplatin to coordinate to 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. Recently it was shown that the apoptosis induced by Cisplatin on human colon cancer cells depends on the mitochondrial serine-protease Omi/Htra2. If Omi/Htra2 protein participates in the cisplatin induced apoptosis in other carcinomas remains an open question.
Pharmacology
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.
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.

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