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Cisplatin

Cisplatinum, trade names Platinol and Platinol-AQ 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).

Cisplatin was approved for use in testicular and ovarian cancers by the U.S. Food and Drug Administration on December 19, 1978.

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.

An interesting quote “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”.  [ie They don’t know how it works]

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'.  And “The drug Paclitaxel may be useful in the treatment of cisplatin-resistant cancer; the mechanism for this activity is unknown”

A bit more “Transplatin, the trans stereoisomer of cisplatin, is toxic, and it is desirable to test batches of cis-platin for the absence of the trans isomer”.

Side effects

Cisplatin has a number of side-effects ‘that can limit its use’:

• Kidney damage - Nephrotoxicity is 'a major concern'. The dose is reduced when the patient's creatinine clearance (a measure of renal function) is reduced.

• Nerve damage - Neurotoxicity can be anticipated.

• Nausea and vomiting: cisplatin is one of the most emetogenic chemotherapy agents

• Deafness - Ototoxicity: 'unfortunately there is at present no effective treatment to prevent this side effect, which may be severe'.

• Electrolyte disturbance: Cisplatin can cause hypomagnesaemia, hypokalaemia and hypocalcaemia. The hypocalcaemia seems to occur in those with low serum magnesium secondary to 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 spectroscopic methods including X-ray, NMR spectroscopy, and other physico-chemical methods, revealed its ability to form irreversible crosslinks with bases in DNA”.