"Cisplatine" redirects here. For the Brazilian province that existed from 1821 to 1828, seeCisplatina. For the conflict in that province, seeCisplatine War.
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 theproximal tubule via basolateral-to-apical transport, where it disrupts mitochondrial energetics andendoplasmic reticulum Ca2+ homeostasis and stimulatesreactive oxygen species and pro-inflammatorycytokines.[10] Multiple mitigation strategies are being explored clinically and pre-clinically, including hydration regimens,amifostine, transporter inhibitors, antioxidants, anti-inflammatories, andepoxyeicosatrienoic acids and their analogues.[10][11]
Neurotoxicity (nerve damage) can be anticipated by performingnerve 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.[12] 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. Cisplatin noncompetitively inhibits an archetypal, membrane-bound mechanosensitive sodium-hydrogen ion transporter known asNHE-1.[12] 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.[12] Cisplatin can increase levels ofsphingosine-1-phosphate in thecentral nervous system, contributing to the development ofpost-chemotherapy cognitive impairment.[13][14]
Ototoxicity and hearing loss associated with cisplatin can be severe and is considered to be a dose-limiting side effect.[4] The incidence of cisplatin-induced ototoxicity has been estimated at approximately 36% in adult cancer patients and between 40% and 60% in pediatric patients.[15] Audiometric analysis may be necessary to assess the severity of ototoxicity. Other drugs (such as theaminoglycoside 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 tomelanin in thestria vascularis of the inner ear or the generation ofreactive oxygen species. In September 2022, the U.S.Food and Drug Administration (FDA) approvedsodium 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 ofacetylcysteine injections as a preventative measure.[4][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 forhemolysis.[20]
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 theaquo complexcis-[PtCl(NH3)2(H2O)]+, in a process termedaquation. 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 incis-[PtCl(NH3)2(H2O)]+ is itself easily displaced by theN-heterocyclic bases onDNA.Guanine preferentially binds. A model compound has been prepared and crystals were examined byX-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 ways, interfering with cell division bymitosis. The damaged DNA elicitsDNA repair mechanisms, which in turn activateapoptosis when repair proves impossible. In 2008, apoptosis induced by cisplatin on human colon cancer cells was shown to depend on the mitochondrial serine-proteaseOmi/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 withpurine 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 aPOVray plot of the platinum binding to a small model of DNA.[26]
A POVray plot of the atomic coordinates for the cis Pt(NH3)2 and short fragment of DNA which was reported by Stephen J. Lippard in Science 1985
1,3-intrastrand d(GpXpG) adducts occur but are readily excised by thenucleotide 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, particularlyHMG 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 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 ofapoptosis, increasedDNA 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 drugpaclitaxel may be useful in the treatment of cisplatin-resistant cancer; the mechanism for this activity is as yet unknown.[30]
Transplatin, thetrans-stereoisomer of cisplatin, has formulatrans-[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, thetrans 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]
Cisplatin is thesquare planarcoordination complex cis-[Pt(NH3)2Cl2].[32]: 286–8 [33]: 689 The prefixcis indicates thecis isomer in which two similar ligands are in adjacent positions.[32][33]: 550 The systematic chemical name of this molecule iscis–diamminedichloroplatinum,[32]: 286 whereammine with two m's indicates anammonia (NH3)ligand, as opposed to an organicamine 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)
The compoundcis-[Pt(NH3)2Cl2] was first described by Italian chemistMichele Peyrone in 1845, and known for a long time as Peyrone's salt.[34][35] The structure was deduced byAlfred Werner in 1893.[24] In 1965,Barnett Rosenberg, Van Camp et al. ofMichigan State University discovered thatelectrolysis of platinum electrodes generated a soluble platinum complex which inhibited binary fission inEscherichia 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) complexcis-[PtCl4(NH3)2], but not thetrans isomer, was found to be effective at forcing filamentous growth ofE. 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 thatcis-[PtCl2(NH3)2] was indeed highly effective at regressing the mass ofsarcomas inrats.[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 childhoodmedulloblastoma.[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 againsttesticular cancer, where its use improved the cure rate from 10% to 85%.[9]
Syntheses of cisplatin start frompotassium tetrachloroplatinate. Several procedures are available. One obstacle is the facile formation ofMagnus's green salt (MGS), which has the same empirical formula as cisplatin. The traditional way to avoid MGS involves the conversion of K2PtCl4 toK2PtI4, as originally described by Dhara.[46][47] Reaction withammonia forms PtI2(NH3)2 which is isolated as a yellow compound. Whensilver nitrate in water is added insolublesilver iodide precipitates and [Pt(OH2)2(NH3)2](NO3)2 remains in solution. Addition ofpotassium chloride will form the final product which precipitates[47] In the triiodo intermediate the addition of the second ammonia ligand is governed by thetrans effect.[47]
Aone-pot synthesis of cisplatin from K2PtCl4 has been developed. It relies on the slow release of ammonia from ammonium acetate.[48]
Cisplatin has been studied withAuger therapy to increase the therapeutic effects of cisplatin, without increasing normal tissue toxicities.[49] 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.[50] Cisplatin-like molecules ([PtCl(NH3)2] and [Pt(NH3)Cl2]) linked by variable length alkandiamine chains have attracted some interest in cancer chemotherapy.[51][52][53]
^abcdefghi"Cisplatin". The American Society of Health-System Pharmacists.Archived from the original on 21 December 2016. Retrieved8 December 2016.
^Oun R, Moussa YE, Wheate NJ (May 2018). "The side effects of platinum-based chemotherapy drugs: a review for chemists".Dalton Transactions.47 (19):6645–6653.doi:10.1039/c8dt00838h.PMID29632935.
^World Health Organization (2019).World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^World Health Organization (2021).World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization.hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^abEinhorn LH (November 1990). "Treatment of testicular cancer: a new and improved model".Journal of Clinical Oncology.8 (11):1777–81.doi:10.1200/JCO.1990.8.11.1777.PMID1700077.
^Sarafraz Z, Ahmadi A, Daneshi A (June 2018). "Transtympanic Injections of N-acetylcysteine and Dexamethasone for Prevention of Cisplatin-Induced Ototoxicity: Double Blind Randomized Clinical Trial".The International Tinnitus Journal.22 (1):40–45.doi:10.5935/0946-5448.20180007.PMID29993216.
^Orbell JD, Solorzano C, Marzilli LG, Kistenmacher TJ (October 1982). "Preparation and structure of cis-chlorodiammine (N2, N2-dimethyl-9-methylguanine) platinum (II) hexafluorophosphate. A model for the intermediate in the proposed crosslinking mode of action of platinum (II) antitumor agents".Inorganic Chemistry.21 (10):3806–3810.doi:10.1021/ic00140a041.
^abPruefer FG, Lizarraga F, Maldonado V, Melendez-Zajgla J (June 2008). "Participation of Omi Htra2 serine-protease activity in the apoptosis induced by cisplatin on SW480 colon cancer cells".Journal of Chemotherapy.20 (3):348–354.doi:10.1179/joc.2008.20.3.348.PMID18606591.S2CID11052459.
^Sherman SE, Gibson D, Wang AH, Lippard SJ (October 1985). "X-ray structure of the major adduct of the anticancer drug cisplatin with DNA: cis-[Pt(NH3)2(d(pGpG))]".Science.230 (4724):412–7.Bibcode:1985Sci...230..412S.doi:10.1126/science.4048939.PMID4048939.
^Cruz-Bermúdez A, Laza-Briviesca R, Vicente-Blanco RJ, García-Grande A, Coronado MJ, Laine-Menéndez S, et al. (May 2019). "Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition".Free Radical Biology & Medicine.135:167–181.doi:10.1016/j.freeradbiomed.2019.03.009.hdl:10486/688357.PMID30880247.
^Coluccia M, Natile G (January 2007). "Trans-platinum complexes in cancer therapy".Anti-Cancer Agents in Medicinal Chemistry.7 (1):111–123.doi:10.2174/187152007779314080.PMID17266508.
^abcdMiessler GL, Tarr DA (1999).Inorganic Chemistry (2nd ed.). Prentice Hall.ISBN978-0-13-841891-5.
^Kauffman GB, Pentimalli R, Hall MD (2010)."Michele Peyrone (1813–1883), Discoverer of Cisplatin".Platinum Metals Review.54 (4):250–256.doi:10.1595/147106710X534326. Retrieved3 October 2022.This biographical article aims to present, for the first time in the English language, a summary of his life and the achievements that he made during his scientific career.
^Christie DA, Tansey EM (2007). Christie DA, Tansey EM, Thomson AJ (eds.).The Discovery, Use and Impact of Platinum Salts as Chemotherapy Agent for Cancer. Wellcome Trust Witnesses to Twentieth Century Medicine. Vol. 30. pp. 6–15.ISBN978-0-85484-112-7.
^Carpenter DP (2010).Reputation and power: organizational image and pharmaceutical regulation at the FDA. Princeton, NJ: Princeton University Press.ISBN978-0-691-14180-0.
^Packer RJ, Sutton LN, Elterman R, Lange B, Goldwein J, Nicholson HS, et al. (November 1994). "Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy".Journal of Neurosurgery.81 (5):690–8.doi:10.3171/jns.1994.81.5.0690.PMID7931615.
^Packer RJ, Sutton LN, Goldwein JW, Perilongo G, Bunin G, Ryan J, et al. (March 1991). "Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma".Journal of Neurosurgery.74 (3):433–40.doi:10.3171/jns.1991.74.3.0433.PMID1847194.
^Dhara SC (1970). "Cisplatin".Indian J. Chem.8:123–134.
^Teixeira LJ, Seabra M, Reis E, da Cruz MT, de Lima MC, Pereira E, et al. (May 2004). "Cytotoxic activity of metal complexes of biogenic polyamines: polynuclear platinum(II) chelates".Journal of Medicinal Chemistry.47 (11):2917–2925.doi:10.1021/jm0311238.hdl:10316/10605.PMID15139770.
^Omondi RO, Ojwach SO, Jaganyi D (November 2020). "Review of comparative studies of cytotoxic activities of Pt(II), Pd(II), Ru(II)/(III) and Au(III) complexes, their kinetics of ligand substitution reactions and DNA/BSA interactions".Inorganica Chimica Acta.512 119883.doi:10.1016/j.ica.2020.119883.S2CID225575546.
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.
N
Y (what is this?) (verify)
