"Cisplatine" redirects here. For the Brazilian province that existed from 1821 to 1828, see
Cisplatina. For the conflict in that province, see
Cisplatine War.
The introduction of cisplatin as a standard treatment for testicular cancer improved remission rates from 5-10% before 1974 to 75-85% by 1984.[10]
Side effects
Cisplatin has a number of side effects that can limit its use:
Nephrotoxicity (kidney damage) is the primary dose-limiting side effect and is of major clinical concern. Cisplatin selectively accumulates into the
proximal tubule via basolateral-to-apical transport, where it disrupts mitochondrial energetics and
endoplasmic reticulum Ca2+ homeostasis and stimulates
reactive oxygen species and pro-inflammatory
cytokines.[11] Multiple mitigation strategies are being explored clinically and pre-clinically, including hydration regimens,
amifostine, transporter inhibitors, antioxidants, anti-inflammatories, and
epoxyeicosatrienoic acids and their analogues.[11][12]
Neurotoxicity (nerve damage) can be anticipated by performing
nerve conduction studies before and after treatment. Common neurological side effects of cisplatin include visual perception and hearing disorder, which can occur soon after treatment begins.[13] While triggering apoptosis through interfering with DNA replication remains the primary mechanism of cisplatin, this has not been found to contribute to neurological side effects. Recent studies have shown that cisplatin noncompetitively inhibits an archetypal, membrane-bound mechanosensitive sodium-hydrogen ion transporter known as
NHE-1.[13] It is primarily found on cells of the peripheral nervous system, which are aggregated in large numbers near the ocular and aural stimuli-receiving centers. This noncompetitive interaction has been linked to hydroelectrolytic imbalances and cytoskeleton alterations, both of which have been confirmed in vitro and in vivo. However, NHE-1 inhibition has been found to be both dose-dependent (half-inhibition = 30 μg/mL) and reversible.[13] Cisplatin can increase levels of
sphingosine-1-phosphate in the
central nervous system, contributing to the development of
post-chemotherapy cognitive impairment.[14][15]
Ototoxicity and hearing loss associated with cisplatin can be severe and is considered to be a dose-limiting side effect.[5] Audiometric analysis may be necessary to assess the severity of ototoxicity. Other drugs (such as the
aminoglycoside antibiotic class) may also cause ototoxicity, and the administration of this class of antibiotics in patients receiving cisplatin is generally avoided. The ototoxicity of both the aminoglycosides and cisplatin may be related to their ability to bind to
melanin in the
stria vascularis of the inner ear or the generation of
reactive oxygen species. In September 2022, the U.S.
Food and Drug Administration (FDA) approved
sodium thiosulfate under the brand name Pedmark to lessen the risk of ototoxicity and hearing loss in people receiving cisplatin.[16][17][18] There is ongoing investigation of
acetylcysteine injections as a preventative measure.[5][19]
Electrolyte disturbance: Cisplatin can cause hypomagnesaemia, hypokalaemia and hypocalcaemia. The hypocalcaemia seems to occur in those with low serum magnesium secondary to cisplatin, so it is not primarily due to the cisplatin.
Hemolytic anemia can be developed after several courses of cisplatin. It is suggested that an antibody reacting with a cisplatin-red-cell membrane is responsible for
hemolysis.[20]
Pharmacology
Cisplatin interferes with DNA replication, which kills the fastest proliferating cells, which in theory are cancerous. Following administration, one chloride ion is slowly displaced by water to give the
aquo complexcis-[PtCl(NH3)2(H2O)]+, in a process termed
aquation. Dissociation of the chloride is favored inside the cell because the intracellular chloride concentration is only 3–20% of the approximately 100 mM chloride concentration in the extracellular fluid.[21][22]
The water molecule in cis-[PtCl(NH3)2(H2O)]+ is itself easily displaced by the N-
heterocyclic bases on
DNA.
Guanine preferentially binds. A model compound has been prepared and crystals were examined by
X-ray crystallography[23]
Subsequent to formation of [PtCl(guanine-DNA)(NH3)2+, crosslinking can occur via displacement of the other chloride, typically by another guanine.[24] 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. In 2008, researchers were able to show that the apoptosis induced by cisplatin on human colon cancer cells depends on the mitochondrial serine-protease
Omi/Htra2.[25] Since this was only demonstrated for colon carcinoma cells, it remains an open question whether the Omi/Htra2 protein participates in the cisplatin-induced apoptosis in carcinomas from other tissues.[25]
Most notable among the changes in DNA 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. Coordination chemists have obtained crystals of the products of reacting cisplain with small models of DNA. Here is a
POVray plot of the platinum binding to a small model of DNA.[26]
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.[27]
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 , increased
DNA repair or changes in metabolism.[28][29]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.[29] The drug
paclitaxel may be useful in the treatment of cisplatin-resistant cancer; the mechanism for this activity is as yet unknown.[30]
Transplatin
Transplatin, the
trans-stereoisomer of cisplatin, has formula
trans-[PtCl2(NH3)2 and does not exhibit a comparably useful pharmacological effect. Two mechanisms have been suggested to explain the reduced anticancer effect of transplatin. Firstly, the trans arrangement of the chloro ligands is thought to confer transplatin with greater chemical reactivity, causing transplatin to become deactivated before it reaches the DNA, where cisplatin exerts its pharmacological action. Secondly, the stereo-conformation of transplatin is such that it is unable to form the characteristic 1,2-intrastrand d(GpG) adducts formed by cisplatin in abundance.[31]
Molecular structure
Cisplatin is the
square planarcoordination complex cis-[Pt(NH3)2Cl2].[32]: 286–8 [33]: 689 The prefix cis indicates the
cis isomer in which two similar ligands are in adjacent positions.[32][33]: 550 The systematic chemical name of this molecule is cis–diamminedichloroplatinum,[32]: 286 where ammine with two m's indicates an
ammonia (NH3)
ligand, as opposed to an organic
amine with one m.[32]: 284
Solution structure of cisplatin (highlighted) interstrand GG adducts with double-stranded DNA. (
PDB:
1DDP)
2.60Å resolution crystal structure of cisplatin (highlighted) intrastrand GG adducts with double-stranded DNA. Note: the hydrogens on amine ligands are not shown. (
PDB:
1AIO)
History
The compound cis-[Pt(NH3)2Cl2] was first described by Italian chemist
Michele Peyrone in 1845, and known for a long time as Peyrone's salt.[34][35] The structure was deduced by
Alfred Werner in 1893.[24] In 1965,
Barnett Rosenberg, Van Camp et al. of
Michigan State University discovered that
electrolysis of platinum electrodes generated a soluble platinum complex which inhibited binary fission in Escherichia coli (E. coli) bacteria. Although bacterial cell growth continued, cell division was arrested, the bacteria growing as filaments up to 300 times their normal length.[36] The octahedral Pt(IV) complex cis-[PtCl4(NH3)2], but not the trans isomer, was found to be effective at forcing filamentous growth of E. coli cells. The square planar Pt(II) complex, cis-[PtCl2(NH3)2] turned out to be even more effective at forcing filamentous growth.[37][38] This finding led to the observation that cis-[PtCl2(NH3)2] was indeed highly effective at regressing the mass of
sarcomas in
rats.[39] Confirmation of this discovery, and extension of testing to other tumour cell lines launched the medicinal applications of cisplatin. Cisplatin was approved for use in testicular and ovarian cancers by the U.S. Food and Drug Administration on 19 December 1978.[24][40][41] and in the UK (and in several other European countries) in 1979.[42]
Cisplatin was the first to be developed.[43]
In 1983 pediatric oncologist Roger Packer began incorporating cisplatin into adjuvant chemotherapy for the treatment of childhood
medulloblastoma.[44] The new protocol that he developed led to a marked increase in disease-free survival rates for patients with medulloblastoma, up to around 85%.[45] The Packer Protocol has since become a standard treatment for medulloblastoma. Likewise, cisplatin has been found to be particularly effective against
testicular cancer, where its use improved the cure rate from 10% to 85%.[10]
Recently, some researchers have investigated at the preclinical level new forms of cisplatin
prodrugs in combination with
nanomaterials in order to localize the release of the
drug in the target.[46][47]
Synthesis
Syntheses of cisplatin start from
potassium tetrachloroplatinate. Several procedures are available. One obstacle is the facile formation of
Magnus's green salt (MGS), which has the same empirical formula as cisplatin. The traditional way to avoid MGS involves the conversion of K2PtCl4 to K2PtI4, as originally described by Dhara.[48][49] Reaction with
ammonia forms PtI2(NH3)2 which is isolated as a yellow compound. When
silver nitrate in water is added insoluble
silver iodide precipitates and [Pt(OH2)2(NH3)2](NO3)2 remains in solution. Addition of
potassium chloride will form the final product which precipitates[49] In the triiodo intermediate the addition of the second ammonia ligand is governed by the
trans effect.[49]
A
one-pot synthesis of cisplatin from K2PtCl4 has been developed. It relies on the slow release of ammonia from ammonium acetate.[50]
Research
Cisplatin has been studied with
Auger therapy to increase the therapeutic effects of cisplatin, without increasing normal tissue toxicities.[51] However, due to significant side effects, the search for structurally novel Pt(II) and Pd(II) compounds exhibiting antineoplastic activity is extremely important and aims to develop more effective and less toxic drugs.[52] Metal complexes comprising cisplatin-like molecules ([PtCl(NH3)2] or [Pt(NH3)Cl2]) linked by variable length alkandiamine chains have attracted great interest in the last few years as next-generation alternatives drugs in cancer chemotherapy.[53][54][55]
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Further reading
Riddell IA, Lippard SJ (2018). "Cisplatin and Oxaliplatin: Our Current Understanding of Their Actions". In Sigel A, Sigel H, Freisinger E, Sigel RK (eds.). Metallo-Drugs: Development and Action of Anticancer Agents. Metal Ions in Life Sciences. Vol. 18. Berlin: de Gruyter GmbH. pp. 1–42.
doi:
10.1515/9783110470734-007.
ISBN978-3-11-046984-4.
PMID29394020.
External links
"Cisplatin". Drug Information Portal. U.S. National Library of Medicine.