Sunday 12 March 2006
Cisplatin, a platinating agent commonly used to treat several cancers, is associated with nephrotoxicity, neurotoxicity, and ototoxicity, which has hindered its utility.
Cisplatin is similar to the bifunctional alkylating agents. It covalently binds to DNA and disrupts DNA function. After cisplatin enters the cells, the chloride ligands are replaced by water molecules. This reaction results in the formation of positively charged platinum complexes that react with the nucleophilic sites on DNA.
These platinum complexes covalently bind to DNA bases using intra-strand and inter-strand cross-links creating cisplatin-DNA adducts thus preventing DNA, RNA and protein synthesis. This action is cell cycle phase-nonspecific.
Cisplatin acts by crosslinking DNA in various different ways, making it impossible for rapidly dividing cells to duplicate their DNA for mitosis. The damaged DNA sets off DNA repair mechanisms, which activate apoptosis when repair proves impossible. The trans isomer does not have this pharmacological effect.
Most notable among the DNA changes are the intrastrand GpG adducts which form nearly 90% of the adducts. Other adducts include inter-strand crosslinks and nonfunctional adducts that have been postulated to contribute to its activity. Interaction with cellular proteins has also been advanced as a mechanism of interfering with mitosis, although this is probably not its main action.
Cisplatin also has immunosuppressive, radiosensitizing, and antimicrobial properties.
In the 1960s, while studying the effects of electric fields on Escherichia coli bacteria, the physicist Barnett Rosenberg serendipitously discovered that a platinum-based compound, cis-diamminedichloroplatinum(II) or cisplatin, markedly inhibited the proliferation of bacteria cells and induced filamentous cell growth.
Cisplatin primarily binds covalently to adjacent guanines in the major groove of DNA and as a result bends DNA in the direction of the major groove.
It is this distortion of DNA - while allowing access to DNA-binding proteins in the minor groove - that stabilizes the interactions between DNA and its binding proteins.
Although the repercussions of cisplatin binding to DNA provide intriguing concepts to explain how drug toxicity could be mediated, they do not readily explain the extraordinary sensitivity of some cancers (for example, testicular cancer) to this drug.
As with DNA-interactive drugs such as doxorubicin, other molecular targets (DNA or otherwise) might be important in enhancing the susceptibility of particular cancers.
It is intriguing that many drugs, including cisplatin, interact preferentially with guanines in DNA. The human telomeric sequence (TTAGGG)n is guanine rich and is a particularly good target for cisplatin.
Perhaps the coincident damage to non-telomeric regions and critically short telomeres, interfaced with protein hijacking and inefficient NER, leads to preferential cell killing in certain cancer cells.
CisPlatin: Mechanism of Action
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Huang RS, Duan S, Shukla SJ, Kistner EO, Clark TA, Chen TX, Schweitzer AC, Blume JE, Dolan ME. Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach. Am J Hum Genet. 2007 Sep;81(3):427-37. PMID: 17701890