Platinum, transition metal, possesses eight electrons in its outer d shell, which are highly polarizable and able to form covalent bonds. Cisplatin is a square planar olecule,
which has two chloride and two ammonia ligands in the cis-configuration. This stearic conformation is important for anti-tumour effect, as the trans-isomer has no activity.
The pharmacological behaviour and activation to a cytotoxic species are determined by the aquation reaction, in which a chloride ion is replaced by a water olecule. This reaction mainly occurs in the cellular cytoplasm, as the low chloride-ion concentration favours driving the formation of the active species. Once in the cell, platinum complexes are able to react with nucleophiles, such as DNA bases, RNA and proteins, to form adducts. These adducts can bridge the strands of DNA in a similar
way to the crosslinks formed by melphalan and chlorambucil. The actual pathway from DNA damage to cell death has not been fully elucidated, but involves many steps, resulting ultimately in apoptosis or programmed cell death. Cisplatin is generally given intravenously and has an initial half-life of 40 minutes and a terminal half-life of greater than 24 hours. It is highly protein bound, and renally excreted, resulting in nephrotoxicity due to a mechanism thought to be related to persisting adducts in renal tissue DNA. Large volumes of fluid are required to ameliorate this renal damage, but significant cumulative doses of cisplatin invariably lead to an irreversible reduction in glomerular filtration rate. Renal wasting of magnesium and potassium can occur, and therefore supplementation is provided during the hydration phases. In addition, cumulative cisplatin dosing produces neurotoxicity, which usually manifests as a sensory peripheral neuropathy or hearing loss. No interventions are known to abrogate this toxicity, and when present it is thought to be only partially reversible over many months or years. Other significant toxicities include emesis, which is routinely managed by prophylactic use of 5-HT3 antagonists in addition to corticosteroids. Myelosuppression is mild to moderate.
Cisplatin has a wide spectrum of activity against solid tumours, and is an integral component of curative regimens for testicular and ovarian cancer. It is also used in the treatment of upper gastrointestinal cancers, head and neck cancer, cervical and endometrial cancer, lung cancer (non-small cell and small cell), bladder cancer and osteosarco-mas. Intraperitoneal cisplatin has been utilized in malignancies such as ovarian cancer and gastrointestinal cancer, with demonstrated activity and a decreased frequency of systemic toxicity. However, optimal pharmaco-kinetic and pharmacodynamic considerations mean that intraperitoneal tumour masses of 1 cm are required to ensure adequate delivery of drug to target.
Carboplatin is a cisplatin analogue that is less potent but more stable, with a longer half-life. Mechanistically, the ultimate reaction products of carboplatin are thought to be chemically identical to those of cisplatin, and the drugs have similar, if not identical, spectra of activity. However, toxicity profiles are different, with carboplatin being much less nephrotoxic and neurotoxic, but causing more bone-marrow suppression. Clearance of carboplatin is also renal, with the majority of the administered dose appearing in the urine during the first 24 hours. Dosing is most accurately performed using the Calvert formula, wherein the required AUC is chosen and the dose in milligrams is calculated by: (glomerular filtration rate + 25) X desired AUC. Carboplatin has virtually replaced cisplatin in combination chemotherapy for ovarian cancer, having demonstrated equivalent efficacy in prospective, randomized trials. However, carboplatin has been shown to be less effective than cisplatin in testicular cancer; therefore cyto-toxic equivalency extrapolations between tumour types is not recommended.
Oxaliplatin is a third-generation platinum analogue, from the 1,2-diaminocyclohexane (DACH) platinum family. Pre-clinical studies have demonstrated at least equivalent potency when compared with cisplatin but, more interestingly, a degree of non-cross-resistance with other platinum compounds. In addition, data from the US NCI COMPARE programme - a screen for functional families of cytotoxics - identified DACH platinum compounds as mechanistically different from cisplatin and carboplatin. Although oxaliplatin engages DNA in a similar way to the other platinum compounds, it seems likely that the specific cellular target and exact mechanism of action are different.
Tumour types sensitive to oxaliplatin include ovarian cancer and colorectal cancer, and there is evidence for synergy with 5-FU. An unusual type of peripheral neurotoxicity has been documented, mainly characterized by reversible paraesthesias or cold-related dysaesthesias. Haematological toxicity is mild.
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