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Cisplatin
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== 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 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>
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