Editing Cisplatin

{{Short description|Chemical compound and pharmaceutical drug}}
{{redirect|Cisplatine|the Brazilian province that existed from 1821 to 1828|Cisplatina|the conflict in that province|Cisplatine War}}
{{cs1 config|name-list-style=vanc}}
{{Use dmy dates|date=June 2023}}
{{Infobox drug
| Verifiedfields     = changed
| Watchedfields      = changed
| verifiedrevid      = 457790642
| drug_name          = 
| type               = 
| IUPAC_name         = [[Polyhedral symbol|(''SP''-4-2)]]-diamminedichloridoplatinum(II)
| image              = CisplatinTR.svg
| image_class        = skin-invert-image
| alt                = 
| caption            = 
| imageL             = Cisplatin-3D-balls.png
| image_classL       = bg-transparent
| widthL             = 140
| imageR             = Cisplatin-3D-vdW.png
| image_classR       = bg-transparent

<!--Clinical data-->| tradename          = Platinol, others
| synonyms           = Cisplatinum, platamin, neoplatin, cismaplat, ''cis''-diamminedichloroplatinum(II) (CDDP)
| Drugs.com          = {{drugs.com|monograph|cisplatin}}
| MedlinePlus        = a684036
| licence_EU         = 
| licence_US         = 
| DailyMedID         = Cisplatin
| pregnancy_AU       = D
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Cisplatin Use During Pregnancy | website=Drugs.com | date=12 September 2019 | url=https://www.drugs.com/pregnancy/cisplatin.html | access-date=25 February 2020}}</ref>
| pregnancy_US       = N
| pregnancy_US_comment = <ref name="Drugs.com pregnancy" />
| pregnancy_category = Contraindicated<ref name="Drugs.com pregnancy" />
| legal_AU           = S4
| legal_CA           = Rx-only
| legal_UK           = POM
| legal_US           = Rx-only
| legal_status       = 
| routes_of_administration = [[Intravenous therapy|Intravenous]]
| ATC_prefix         = L01
| ATC_suffix         = XA01

<!--Pharmacokinetic data-->| bioavailability    = 100% (IV)
| protein_bound      = > 95%
| metabolism         = 
| elimination_half-life = 30–100 hours
| excretion          = Renal

<!--Identifiers-->| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 15663-27-1 <!-- verified against list from Chemical Abstracts Service -->
| PubChem            = 2767
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB00515
| ChemSpiderID_Ref   = {{chemspidercite|changed|chemspider}}
| ChemSpiderID       = 76401
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = Q20Q21Q62J
| KEGG_Ref           = {{keggcite|correct|kegg}}
| KEGG               = D00275
| ChEBI_Ref          = {{ebicite|correct|EBI}}
| ChEBI              = 27899
| ChEMBL_Ref         = {{ebicite|changed|EBI}}
| ChEMBL             = 2068237
| PDB_ligand         = CPT

<!--Chemical data-->| chemical_formula   = [Pt(NH<sub>3</sub>)<sub>2</sub>Cl<sub>2</sub>]
| N                  = 2
| H                  = 6
| Cl                 = 2
| Pt                 = 1
| smiles             = [NH3+][Pt+2](Cl)(Cl)[NH3+]
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChI           = 1S/2ClH.2H3N.Pt/h2*1H;2*1H3;/q;;;;+2/p-2
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = LXZZYRPGZAFOLE-UHFFFAOYSA-L
}}

<!-- Definition and medical uses -->
'''Cisplatin''' is a chemical compound with [[chemical formula|formula]] ''cis''-{{chem2|[Pt(NH3)2Cl2]}}. It is a [[coordination complex]] of [[platinum]] that is used as a [[chemotherapy medication]] used to treat a number of [[cancers]].<ref name=AHFS2016/> These include [[testicular cancer]], [[ovarian cancer]], [[cervical cancer]], [[bladder cancer]], [[head and neck cancer]], [[esophageal cancer]], [[lung cancer]], [[mesothelioma]], [[brain tumors]] and [[neuroblastoma]].<ref name=AHFS2016/> It is given by [[intravenous|injection into a vein]].<ref name=AHFS2016/>

<!-- Side effects and mechanisms -->
Common side effects include [[bone marrow suppression]], [[hearing problems]] including severe hearing loss, [[nephrotoxicity|kidney damage]], and [[vomiting]].<ref name=AHFS2016/><ref>{{cite journal | vauthors = Oun R, Moussa YE, Wheate NJ | title = The side effects of platinum-based chemotherapy drugs: a review for chemists | journal = Dalton Transactions | volume = 47 | issue = 19 | pages = 6645–6653 | date = May 2018 | pmid = 29632935 | doi = 10.1039/c8dt00838h }}</ref><ref name="pmid29051464">{{cite journal |vauthors=Callejo A, Sedó-Cabezón L, Juan ID, Llorens J |title=Cisplatin-Induced Ototoxicity: Effects, Mechanisms and Protection Strategies |journal=Toxics |volume=3 |issue=3 |pages=268–293 |date=July 2015 |pmid=29051464 |pmc=5606684 |doi=10.3390/toxics3030268|doi-access=free |bibcode=2015Toxic...3..268C }}</ref> Other serious side effects include numbness, trouble walking, [[allergic reactions]], [[electrolyte problems]], and [[heart disease]].<ref name=AHFS2016/> Use during pregnancy can cause harm to the developing fetus.<ref name="Drugs.com pregnancy" /><ref name=AHFS2016/> Cisplatin is in the [[platinum-based antineoplastic]] family of medications.<ref name=AHFS2016/> It works in part by binding to DNA and inhibiting [[DNA replication|its replication]].<ref name=AHFS2016/>

<!-- History and culture -->
Cisplatin was first reported in 1845 and licensed for medical use in 1978 and 1979.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495|page=513|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA513 |language=en|url-status=live|archive-url=https://web.archive.org/web/20161220163817/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA513 |archive-date=20 December 2016}}</ref><ref name=AHFS2016>{{cite web |title=Cisplatin |url= https://www.drugs.com/monograph/cisplatin.html |publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221012444/https://www.drugs.com/monograph/cisplatin.html|archive-date=21 December 2016}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>

==Medical use==
Cisplatin is administered [[intravenously]] as short-term infusion in normal saline for treatment of solid and haematological malignancies. It is used to treat various types of cancers, including [[sarcoma]]s, some [[carcinoma]]s (e.g., [[lung cancer|small cell lung cancer]], [[squamous cell carcinoma of the head and neck]] and [[ovarian cancer]]), [[lymphoma]]s, [[bladder cancer]], [[cervical cancer]],<ref>{{cite web |publisher=[[National Cancer Institute]] |title=Cisplatin |date=2 March 2007 |url=http://www.cancer.gov/cancertopics/druginfo/cisplatin |access-date=2014-11-13 |url-status=live |archive-url=https://web.archive.org/web/20141008032500/http://www.cancer.gov/cancertopics/druginfo/cisplatin |archive-date=8 October 2014 }}</ref> and [[germ cell tumor]]s.

The introduction of cisplatin as a standard treatment for testicular cancer improved remission rates from 5–10% before 1974 to 75–85% by 1984.<ref name="Treatment of testicular cancer: a n">{{cite journal | vauthors = Einhorn LH | title = Treatment of testicular cancer: a new and improved model | journal = Journal of Clinical Oncology | volume = 8 | issue = 11 | pages = 1777–81 | date = November 1990 | pmid = 1700077 | doi = 10.1200/JCO.1990.8.11.1777 }}</ref>

==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]] Ca<sup>2+</sup> homeostasis and stimulates [[reactive oxygen species]] and pro-inflammatory [[cytokines]].<ref name="Miller">{{cite journal |journal = Toxins |date = October 2010| volume = 2|issue = 11|pages = 2490–2518 | title = Mechanisms of Cisplatin Nephrotoxicity. |vauthors = Miller RP, Tadagavadi RK, Ramesh G, Reeves WB | doi=10.3390/toxins2112490| pmid=22069563 | pmc=3153174 | doi-access=free }}</ref> 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.<ref name=Miller/><ref name="Singh">{{cite journal |journal= Chemical Research in Toxicology |date =November 2021| volume=34|issue=12|pages=2579–2591 | title= New Alkoxy- Analogues of Epoxyeicosatrienoic Acids Attenuate Cisplatin Nephrotoxicity In Vitro via Reduction of Mitochondrial Dysfunction, Oxidative Stress, Mitogen-Activated Protein Kinase Signaling, and Caspase Activation. |vauthors=Singh N, Vik A, Lybrand DB, Morisseau C, Hammock BD | doi=10.1021/acs.chemrestox.1c00347|pmid =34817988|pmc =8853703}}</ref>
* [[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.<ref name="Milosavljevic_2010">{{cite journal | vauthors = Milosavljevic N, Duranton C, Djerbi N, Puech PH, Gounon P, Lagadic-Gossmann D, Dimanche-Boitrel MT, Rauch C, Tauc M, Counillon L, Poët M | display-authors = 6 | title = Nongenomic effects of cisplatin: acute inhibition of mechanosensitive transporters and channels without actin remodeling | journal = Cancer Research | volume = 70 | issue = 19 | pages = 7514–22 | date = October 2010 | pmid = 20841472 | doi = 10.1158/0008-5472.CAN-10-1253 | url = https://www.sciencedaily.com/releases/2010/10/101005141117.htm | doi-access = free }}</ref> 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 as [[SLC9A1|NHE-1]].<ref name="Milosavljevic_2010"/> 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&nbsp;μg/mL) and reversible.<ref name="Milosavljevic_2010"/> Cisplatin can increase levels of [[sphingosine-1-phosphate]] in the [[central nervous system]], contributing to the development of [[post-chemotherapy cognitive impairment]].<ref name="pmid36047496">{{cite journal |vauthors=Squillace S, Niehoff ML, Doyle TM, Green M, Esposito E, Cuzzocrea S, Arnatt CK, Spiegel S, Farr SA, Salvemini D |title=Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment |journal=The Journal of Clinical Investigation |volume=132 |issue=17 |date=September 2022 |pmid=36047496 |pmc=9433103 |doi=10.1172/JCI157738}}</ref><ref>{{cite web|url= https://neurosciencenews.com/chemo-brain-drug-21353/|title=Unlocking the Mystery of "Chemo Brain" | work = Neuroscience News |date=2 September 2022}}</ref>
* [[Nausea]] and [[vomiting]]: cisplatin is one of the most emetogenic chemotherapy agents, but this symptom is managed with prophylactic antiemetics ([[ondansetron]], [[granisetron]], etc.) in combination with [[corticosteroids]]. [[Aprepitant]] combined with [[ondansetron]] and [[dexamethasone]] has been shown to be better for highly emetogenic chemotherapy than just [[ondansetron]] and [[dexamethasone]].
* [[Ototoxicity]] and hearing loss associated with cisplatin can be severe and is considered to be a dose-limiting side effect.<ref name="pmid29051464"/> 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 (medical use)|sodium thiosulfate]] under the brand name Pedmark to lessen the risk of ototoxicity and hearing loss in people receiving cisplatin.<ref name="pmid35489339">{{cite journal |vauthors=Orgel E, Villaluna D, Krailo MD, Esbenshade A, Sung L, Freyer DR |title=Sodium thiosulfate for prevention of cisplatin-induced hearing loss: updated survival from ACCL0431 |journal=The Lancet. Oncology |volume=23 |issue=5 |pages=570–572 |date=May 2022 |pmid=35489339 |pmc=9635495 |doi=10.1016/S1470-2045(22)00155-3}}</ref><ref name="Winstead 2022">{{cite web | vauthors = Winstead E |title=Sodium Thiosulfate Reduces Hearing Loss in Kids with Cancer |website=National Cancer Institute |date=6 October 2022 |url=https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-sodium-thiosulfate-cisplatin-hearing-loss-children |access-date=9 March 2023}}</ref><ref name="FDA 2022">{{cite web |title=FDA approves sodium thiosulfate to reduce the risk of ototoxicity associated with cisplatin in pediatric patients with localized, non-metastatic solid tumors |publisher=Food and Drug Administration |date=20 September 2022 |url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sodium-thiosulfate-reduce-risk-ototoxicity-associated-cisplatin-pediatric-patients |archive-url=https://web.archive.org/web/20220920220037/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sodium-thiosulfate-reduce-risk-ototoxicity-associated-cisplatin-pediatric-patients |url-status=dead |archive-date=20 September 2022 |access-date=9 March 2023}}</ref> There is ongoing investigation of [[acetylcysteine]] injections as a preventative measure.<ref name="pmid29051464"/><ref>{{cite journal | vauthors = Sarafraz Z, Ahmadi A, Daneshi A | title = Transtympanic Injections of N-acetylcysteine and Dexamethasone for Prevention of Cisplatin-Induced Ototoxicity: Double Blind Randomized Clinical Trial | journal = The International Tinnitus Journal | volume = 22 | issue = 1 | pages = 40–45 | date = June 2018 | pmid = 29993216 | doi = 10.5935/0946-5448.20180007 }}</ref>
* [[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]].<ref name="pmid6788166">{{cite journal | vauthors = Levi JA, Aroney RS, Dalley DN | title = Haemolytic anaemia after cisplatin treatment | journal = British Medical Journal | volume = 282 | issue = 6281 | pages = 2003–4 | date = June 1981 | pmid = 6788166 | pmc = 1505958 | doi = 10.1136/bmj.282.6281.2003 }}</ref>

== 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 complex]] ''cis''-[PtCl(NH<sub>3</sub>)<sub>2</sub>(H<sub>2</sub>O)]<sup>+</sup>, 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&nbsp;mM chloride concentration in the extracellular fluid.<ref name="WangLippard2005">{{cite journal | vauthors = Wang D, Lippard SJ | s2cid = 31357727 | title = Cellular processing of platinum anticancer drugs | journal = Nature Reviews. Drug Discovery | volume = 4 | issue = 4 | pages = 307–320 | date = April 2005 | pmid = 15789122 | doi = 10.1038/nrd1691 }}</ref><ref>{{cite journal | vauthors = Johnstone TC, Suntharalingam K, Lippard SJ | title = The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs | journal = Chemical Reviews | volume = 116 | issue = 5 | pages = 3436–3486 | date = March 2016 | pmid = 26865551 | pmc = 4792284 | doi = 10.1021/acs.chemrev.5b00597 }}</ref>

The water molecule in ''cis''-[PtCl(NH<sub>3</sub>)<sub>2</sub>(H<sub>2</sub>O)]<sup>+</sup> is itself easily displaced by the ''N''-[[Heterocyclic amine|heterocyclic base]]s on [[DNA]]. [[Guanine]] preferentially binds. A model compound has been prepared and crystals were examined by [[X-ray]] crystallography<ref>{{cite journal | vauthors = Orbell JD, Solorzano C, Marzilli LG, Kistenmacher TJ | title = 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. | journal = Inorganic Chemistry | date = October 1982 | volume = 21 | issue = 10 | pages = 3806–3810 | doi = 10.1021/ic00140a041 }}</ref>

Subsequent to formation of [PtCl(guanine-DNA)(NH<sub>3</sub>)<sub>2</sub>]<sup>+</sup>, crosslinking can occur via displacement of the other chloride, typically by another guanine.<ref name = trzaska/> Cisplatin crosslinks DNA in several 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, apoptosis induced by cisplatin on human colon cancer cells was shown to depend on the mitochondrial serine-protease [[HTRA2|Omi/Htra2]].<ref name="pmid18606591">{{cite journal |vauthors=Pruefer FG, Lizarraga F, Maldonado V, Melendez-Zajgla J | s2cid = 11052459 | title = Participation of Omi Htra2 serine-protease activity in the apoptosis induced by cisplatin on SW480 colon cancer cells | journal = Journal of Chemotherapy | volume = 20 | issue = 3 | pages = 348–354 | date = June 2008 | pmid = 18606591 | doi = 10.1179/joc.2008.20.3.348 }}</ref> 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.<ref name="pmid18606591"/>

Most notable among the changes in DNA are the 1,2-intrastrand cross-links with [[purine]] bases. These include 1,2-intrastrand d([[guanine|Gp]]G) adducts, which form nearly 90% of the adducts, and the less common 1,2-intrastrand d([[adenosine|Ap]]G) 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.<ref name="pmid4048939">{{cite journal | vauthors = Sherman SE, Gibson D, Wang AH, Lippard SJ | title = X-ray structure of the major adduct of the anticancer drug cisplatin with DNA: cis-[Pt(NH3)2(d(pGpG))] | journal = Science | volume = 230 | issue = 4724 | pages = 412–7 | date = October 1985 | pmid = 4048939 | doi = 10.1126/science.4048939 | bibcode = 1985Sci...230..412S }}</ref>

[[File:Cisplain adduct with two Gs bonded to ribose and linked by phosphate.png|thumb|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 the [[nucleotide]] excision repair ([[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 [[high mobility group|HMG]] domain proteins, has also been advanced as a mechanism of interfering with mitosis, although this is probably not its primary method of action.<ref name="pmid27688757">{{cite journal |vauthors=Hu J, Lieb JD, Sancar A, Adar S | s2cid = 11052459 | title = Cisplatin DNA damage and repair maps of the human genome at single-nucleotide resolution | journal = PNAS | volume = 113 | issue = 41 | pages = 11507–11512 | date = October 2016 | pmid = 27688757 |doi=10.1073/pnas.1614430113 | pmc = 5068337 | bibcode = 2016PNAS..11311507H | doi-access = free }}</ref>

=== 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.<ref>{{cite journal | vauthors = Cruz-Bermúdez A, Laza-Briviesca R, Vicente-Blanco RJ, García-Grande A, Coronado MJ, Laine-Menéndez S, Palacios-Zambrano S, Moreno-Villa MR, Ruiz-Valdepeñas AM, Lendinez C, Romero A, Franco F, Calvo V, Alfaro C, Acosta PM, Salas C, Garcia JM, Provencio M | display-authors = 6 | title = Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition | journal = Free Radical Biology & Medicine | volume = 135 | pages = 167–181 | date = May 2019 | pmid = 30880247 | doi = 10.1016/j.freeradbiomed.2019.03.009 | hdl-access = free | hdl = 10486/688357 }}</ref><ref name="Stordal_2007">{{cite journal | vauthors = Stordal B, Davey M | title = Understanding cisplatin resistance using cellular models | journal = IUBMB Life | volume = 59 | issue = 11 | pages = 696–699 | date = November 2007 | pmid = 17885832 | doi = 10.1080/15216540701636287 | s2cid = 30879019 | url = http://doras.dcu.ie/2202/1/Stordal-IUBMB-2007.pdf | doi-access = free }}</ref> [[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.<ref name="Stordal_2007"/> The drug [[paclitaxel]] may be useful in the treatment of cisplatin-resistant cancer; the mechanism for this activity is as yet unknown.<ref name="pmid17881133">{{cite journal | vauthors = Stordal B, Pavlakis N, Davey R | title = A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship | journal = Cancer Treatment Reviews | volume = 33 | issue = 8 | pages = 688–703 | date = December 2007 | pmid = 17881133 | doi = 10.1016/j.ctrv.2007.07.013 | url = http://doras.dcu.ie/2190/1/StordalCTR2007-Paclitaxel.pdf | hdl = 2123/4068 }}</ref>

===Transplatin===
[[Trans-Dichlorodiammineplatinum(II)|Transplatin]], the [[Cis–trans isomerism#Coordination complexes|''trans''-stereoisomer]] of cisplatin, has formula [[trans-Dichlorodiammineplatinum(II)|''trans''-[PtCl<sub>2</sub>(NH<sub>3</sub>)<sub>2</sub>]]] 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.<ref>{{cite journal | vauthors = Coluccia M, Natile G | title = Trans-platinum complexes in cancer therapy | journal = Anti-Cancer Agents in Medicinal Chemistry | volume = 7 | issue = 1 | pages = 111–123 | date = January 2007 | pmid = 17266508 | doi = 10.2174/187152007779314080 }}</ref>

==Molecular structure==
Cisplatin is the [[Square planar molecular geometry|square planar]] [[coordination complex]] cis-[Pt(NH<sub>3</sub>)<sub>2</sub>Cl<sub>2</sub>].<ref name= "Miessler_1999">{{cite book | vauthors = Miessler GL, Tarr DA |date=1999 |title=Inorganic Chemistry |edition=2nd |publisher=Prentice Hall |isbn=978-0-13-841891-5 }}</ref>{{rp|286–8}}<ref name = "Housecroft_2005" />{{rp|689}} The prefix ''cis'' indicates the [[Cis–trans isomerism#Coordination complexes|''cis'' isomer]] in which two similar ligands are in adjacent positions.<ref name="Miessler_1999" /><ref name = "Housecroft_2005">{{cite book | vauthors = Housecroft CE, Sharpe AG |date=2005 |title=Inorganic Chemistry |edition=2nd |publisher=Pearson Prentice Hall |isbn=978-0-130-39913-7 }}</ref>{{rp|550}} The systematic chemical name of this molecule is ''cis''–diamminedichloroplatinum,<ref name= "Miessler_1999" />{{rp|286}} where ''ammine'' with two m's indicates an [[ammonia]] (NH<sub>3</sub>) [[ligand]], as opposed to an organic [[amine]] with one m.<ref name= "Miessler_1999" />{{rp|284}}

{{Gallery
|width=160
|height=160
|align=center
|File:Solution structure of Cisplatin-induced Interstrand GG cross-link.png|Solution structure of cisplatin (highlighted) interstrand GG adducts with double-stranded DNA.  ([[Protein Data Bank|PDB]]: [https://www.rcsb.org/structure/1ddp 1DDP])
|File:X-Ray diffraction structure of Cisplatin intra-strand GG adducts.png|2.60Å resolution crystal structure of cisplatin (highlighted) intrastrand GG adducts with double-stranded DNA.  Note: the hydrogens on amine ligands are not shown. ([[Protein Data Bank|PDB]]: [https://www.rcsb.org/structure/1AIO 1AIO])
|whitebg=no}}

== History ==
The compound ''cis''-[Pt(NH<sub>3</sub>)<sub>2</sub>Cl<sub>2</sub>] was first described by Italian chemist [[Michele Peyrone]] in 1845, and known for a long time as Peyrone's salt.<ref>{{cite journal | vauthors = Kauffman GB, Pentimalli R, Hall MD |title=Michele Peyrone (1813–1883), Discoverer of Cisplatin |journal=Platinum Metals Review |date=2010 |volume=54 |issue=4 |pages=250–256 |doi=10.1595/147106710X534326 |url=https://technology.matthey.com/article/54/4/250-256 |access-date=3 October 2022 |quote=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.|doi-access=free }}</ref><ref>{{cite journal | vauthors= Peyrone M | journal = Ann. Chem. Pharm. | year = 1844 | volume = 51 | issue = 1 | pages = 1–29 | doi = 10.1002/jlac.18440510102 | title = Ueber die Einwirkung des Ammoniaks auf Platinchlorür|trans-title=On the action of ammonia on platinum chloride|url=https://zenodo.org/record/1426984 }}</ref> The structure was deduced by [[Alfred Werner]] in 1893.<ref name = trzaska>{{cite journal | url = http://pubs.acs.org/cen/coverstory/83/8325/8325cisplatin.html | title = Cisplatin | vauthors = Trzaska S | journal= [[Chemical & Engineering News]] | volume = 83 | issue = 25 | date = 20 June 2005| page = 52 | doi = 10.1021/cen-v083n025.p052 | url-access = subscription }}</ref> 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.<ref>{{cite journal | vauthors = Rosenberg B, Vancamp L, Krigas T | title = Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode | journal = Nature | volume = 205 | issue = 4972 | pages = 698–9 | date = February 1965 | pmid = 14287410 | doi = 10.1038/205698a0 | bibcode = 1965Natur.205..698R | s2cid = 9543916 }}</ref> The octahedral Pt(IV) complex ''cis''-[PtCl<sub>4</sub>(NH<sub>3</sub>)<sub>2</sub>], 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''-[PtCl<sub>2</sub>(NH<sub>3</sub>)<sub>2</sub>] turned out to be even more effective at forcing filamentous growth.<ref name="pmid5337590">{{cite journal | vauthors = Rosenberg B, Van Camp L, Grimley EB, Thomson AJ | title = The inhibition of growth or cell division in Escherichia coli by different ionic species of platinum(IV) complexes | journal = The Journal of Biological Chemistry | volume = 242 | issue = 6 | pages = 1347–52 | date = March 1967 | doi = 10.1016/S0021-9258(18)96186-7 | pmid = 5337590 | doi-access = free }}</ref><ref>{{cite book | vauthors = Christie DA, Tansey EM | veditors = Christie DA, Tansey EM, Thomson AJ | year = 2007 | title = The Discovery, Use and Impact of Platinum Salts as Chemotherapy Agent for Cancer | series = Wellcome Trust Witnesses to Twentieth Century Medicine | volume = 30| pages = 6–15 | isbn= 978-0-85484-112-7 }}</ref> This finding led to the observation that ''cis''-[PtCl<sub>2</sub>(NH<sub>3</sub>)<sub>2</sub>] was indeed highly effective at regressing the mass of [[sarcoma]]s in [[rat]]s.<ref name="pmid5782119">{{cite journal | vauthors = Rosenberg B, VanCamp L, Trosko JE, Mansour VH | s2cid = 32398470 | title = Platinum compounds: a new class of potent antitumour agents | journal = Nature | volume = 222 | issue = 5191 | pages = 385–6 | date = April 1969 | pmid = 5782119 | doi = 10.1038/222385a0 | bibcode = 1969Natur.222..385R }}</ref> 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.<ref name = trzaska/><ref name="isbn0-691-14180-0">{{cite book | vauthors = Carpenter DP | title = Reputation and power: organizational image and pharmaceutical regulation at the FDA | publisher = Princeton University Press | location = Princeton, NJ | year = 2010 | isbn = 978-0-691-14180-0  }}</ref><ref>{{cite web|url=http://www.accessdata.fda.gov/scripts/cder/onctools/summary.cfm?ID=73 |title=Approval Summary for cisplatin for Metastatic ovarian tumors |access-date=2009-07-15 |date=19 December 1978 |work= FDA Oncology Tools |publisher=[[Food and Drug Administration (United States)|Food and Drug Administration]], Center for Drug Evaluation and Research |archive-url= https://web.archive.org/web/20080208232952/http://www.accessdata.fda.gov/scripts/cder/onctools/summary.cfm?ID=73 |archive-date=8 February 2008 }}</ref> and in the UK (and in several other European countries) in 1979.<ref>{{cite journal | vauthors = Wiltshaw E | title = Cisplatin in the treatment of cancer | journal = Platinum Metals Review | volume = 23 | issue = 3 | pages = 90–8 | year =1979| doi = 10.1595/003214079X2339098 | s2cid = 267470502 }}</ref> 
Cisplatin was the first to be developed.<ref name=Kelland>{{cite journal | vauthors = Kelland L | title = The resurgence of platinum-based cancer chemotherapy | doi = 10.1038/nrc2167 | journal = Nature Reviews Cancer | volume = 7 | issue = 8 | pages = 573–584 | year = 2007 | pmid =  17625587| s2cid = 205468214 }}</ref> 
In 1983 pediatric oncologist Roger Packer began incorporating cisplatin into adjuvant chemotherapy for the treatment of childhood [[medulloblastoma]].<ref>{{cite journal | vauthors = Packer RJ, Sutton LN, Elterman R, Lange B, Goldwein J, Nicholson HS, Mulne L, Boyett J, D'Angio G, Wechsler-Jentzsch K | display-authors = 6 | title = Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy | journal = Journal of Neurosurgery | volume = 81 | issue = 5 | pages = 690–8 | date = November 1994 | pmid = 7931615 | doi = 10.3171/jns.1994.81.5.0690 }}</ref> The new protocol that he developed led to a marked increase in disease-free survival rates for patients with medulloblastoma, up to around 85%.<ref>{{cite journal | vauthors = Packer RJ, Sutton LN, Goldwein JW, Perilongo G, Bunin G, Ryan J, Cohen BH, D'Angio G, Kramer ED, Zimmerman RA | display-authors = 6 | title = Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma | journal = Journal of Neurosurgery | volume = 74 | issue = 3 | pages = 433–40 | date = March 1991 | pmid = 1847194 | doi = 10.3171/jns.1991.74.3.0433 }}</ref> 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%.<ref name="Treatment of testicular cancer: a n"/>

==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 K<sub>2</sub>PtCl<sub>4</sub> to [[Potassium tetraiodoplatinate|K<sub>2</sub>PtI<sub>4</sub>]], as originally described by Dhara.<ref>{{cite journal|title=Cisplatin| vauthors = Dhara SC |journal=Indian J. Chem. |date=1970|volume= 8|pages= 123–134}}</ref><ref name=Alderden>{{cite journal|title=The Discovery and Development of Cisplatin| vauthors = Alderden RA, Hall MD, Hambley TW |s2cid= 29546931 |journal=[[J. Chem. Educ.]]|date= 2006|volume= 83 |issue=5 |page=728 |doi=10.1021/ed083p728|bibcode=2006JChEd..83..728A}}</ref> Reaction with [[ammonia]] forms PtI<sub>2</sub>(NH<sub>3</sub>)<sub>2</sub> which is isolated as a yellow compound. When [[silver nitrate]] in water is added insoluble [[silver iodide]] precipitates and [Pt(OH<sub>2</sub>)<sub>2</sub>(NH<sub>3</sub>)<sub>2</sub>](NO<sub>3</sub>)<sub>2</sub> remains in solution. Addition of [[potassium chloride]] will form the final product which precipitates<ref name=Alderden /> In the triiodo intermediate the addition of the second ammonia ligand is governed by the [[trans effect]].<ref name=Alderden />

:[[File:Cisplatin synthesis.svg|class=skin-invert-image|600px]]

A [[one-pot synthesis]] of cisplatin from K<sub>2</sub>PtCl<sub>4</sub> has been developed.  It relies on the slow release of ammonia from ammonium acetate.<ref>{{cite book|doi=10.1002/9780470132630.ch23|title=Facile Synthesis of Isomerically Pure cis -Dichlorodiammineplatinum(II), Cisplatin|series=Inorganic Syntheses|year=2007| vauthors = Kukushikin VY, Oskarsson Å, Elding LI, Farrell N |chapter=Facile Synthesis of Isomerically Pure ''cis'' -Dichlorodiammineplatinum(II), ''Cisplatin'' |pages=141–144|volume=32|isbn=9780470132630}}</ref>
{{clear}}

== Research ==
Cisplatin has been studied with [[Auger therapy]] to increase the therapeutic effects of cisplatin, without increasing normal tissue toxicities.<ref>{{cite journal | vauthors = Ku A, Facca VJ, Cai Z, Reilly RM | title = Auger electrons for cancer therapy - a review | journal = EJNMMI Radiopharmacy and Chemistry | volume = 4 | issue = 1 | pages = 27 | date = October 2019 | pmid = 31659527 | pmc = 6800417 | doi = 10.1186/s41181-019-0075-2 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Fiuza SM, Amado AM, Oliveira PJ, Sardão VA, De Carvalho LB, Marques MP |title=Pt(II) vs Pd(II) Polyamine Complexes as New Anticancer Drugs: A Structure- Activity Study |url=https://www.eurekaselect.com/article/1846 |journal=Letters in Drug Design & Discovery |date=2006 |language=en |volume=3 |issue=3 |pages=149–151 |doi=10.2174/157018006776286989|hdl=10316/45139 |hdl-access=free }}</ref> Cisplatin-like molecules ([PtCl(NH<sub>3</sub>)<sub>2</sub>] and [Pt(NH<sub>3</sub>)Cl<sub>2</sub>]) linked by variable length alkandiamine chains have attracted some interest in cancer chemotherapy.<ref>{{cite journal | vauthors = Teixeira LJ, Seabra M, Reis E, da Cruz MT, de Lima MC, Pereira E, Miranda MA, Marques MP | display-authors = 6 | title = Cytotoxic activity of metal complexes of biogenic polyamines: polynuclear platinum(II) chelates | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 11 | pages = 2917–2925 | date = May 2004 | pmid = 15139770 | doi = 10.1021/jm0311238 | hdl = 10316/10605 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Vinci D, Chateigner D |date=2022-12-01 |title=Synthesis and structural characterization of a new dinuclear platinum(III) complex, [Pt 2 Cl 4 (NH 3 ) 2 {μ-HN=C(O)Bu t } 2 ] |url=https://scripts.iucr.org/cgi-bin/paper?S2052520622009660 |journal=Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials |volume=78 |issue=6 |pages=835–841 |doi=10.1107/S2052520622009660 |issn=2052-5206 |pmc=9728019}}</ref><ref>{{cite journal | vauthors = Omondi RO, Ojwach SO, Jaganyi D |date= November 2020 |title=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 |journal=Inorganica Chimica Acta |language=en |volume=512 |pages=119883 |doi=10.1016/j.ica.2020.119883|s2cid= 225575546 }}</ref>

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite book |last1=Dabrowiak |first1=James C. |chapter = Cisplatin |title=Metals in Medicine |date= 2009 |isbn=978-0-470-68196-1 |edition=1 |doi=10.1002/9780470684986.ch3 | pages =73–107 |publisher= John Wiley & Sons|language=en}}
* {{cite book | vauthors = Riddell IA, Lippard SJ | veditors = Sigel A, Sigel H, Freisinger E, Sigel RK | title = Metallo-Drugs: Development and Action of Anticancer Agents | series = Metal Ions in Life Sciences | volume = 18 | date = 2018 | publisher = de Gruyter GmbH | location = Berlin | isbn = 978-3-11-046984-4 | doi = 10.1515/9783110470734-007 | pmid = 29394020 | pages = 1–42 | chapter = Cisplatin and Oxaliplatin: Our Current Understanding of Their Actions }}
{{refend}}

== External links ==
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/cisplatin | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Cisplatin }}
* [https://publications.iarc.fr/_publications/media/download/3339/e9c601280dccaa5a877bbc1ef1bd8e4a683ec189.pdf IARC Monograph: "Cisplatin"]
* Wikiversity page for the International Ototoxicity Management Group: https://en.wikiversity.org/wiki/International_Ototoxicity_Management_Group_(IOMG)

{{Chemotherapeutic agents}}
{{Platinum compounds}}

{{portal bar|Medicine}}

[[Category:Ammine complexes]]
[[Category:Bioinorganic chemistry]]
[[Category:Chemotherapy| ]]
[[Category:Chloro complexes]]
[[Category:IARC Group 2A carcinogens]]
[[Category:Medicinal inorganic chemistry]]
[[Category:Metal-containing drugs]]
[[Category:Nephrotoxins]]
[[Category:Platinum complexes]]
[[Category:Platinum-based antineoplastic agents]]
[[Category:Platinum(II) compounds]]
[[Category:World Health Organization essential medicines]]
[[Category:Wikipedia medicine articles ready to translate]]