Array ( [0] => {{Short description|Medication used for cancer}} [1] => {{Use dmy dates|date=November 2023}} [2] => {{cs1 config |name-list-style=vanc |display-authors=6}} [3] => {{Infobox drug [4] => | Verifiedfields = changed [5] => | verifiedrevid = 458461737 [6] => | image = Taxol.svg [7] => | width = 250 [8] => | alt = [9] => | caption = [10] => | image2 = Paclitaxel-from-hydrate-xtal-Mercury-3D-sk.png [11] => | alt2 = [12] => [13] => [14] => | pronounce = [15] => | tradename = Taxol, Abraxane, others [16] => | Drugs.com = {{drugs.com|monograph|paclitaxel}} [17] => | MedlinePlus = a607070 [18] => | licence_EU = yes [19] => | DailyMedID = Paclitaxel [20] => | licence_US = [21] => | pregnancy_AU = D [22] => | pregnancy_AU_comment = {{cite web | title=Paclitaxel Use During Pregnancy | website=Drugs.com | date=24 January 2019 | url=https://www.drugs.com/pregnancy/paclitaxel.html | access-date=19 May 2020 | archive-date=3 December 2020 | archive-url=https://web.archive.org/web/20201203140443/https://www.drugs.com/pregnancy/paclitaxel.html | url-status=live }} [23] => | pregnancy_category = [24] => | routes_of_administration = [[Intravenous therapy|Intravenous]] [25] => | class = [26] => | ATCvet = [27] => | ATC_prefix = L01 [28] => | ATC_suffix = CD01 [29] => | ATC_supplemental = [30] => [31] => [32] => | legal_AU = S4 [33] => | legal_AU_comment = [34] => | legal_BR = [35] => | legal_BR_comment = [36] => | legal_CA = Rx-only [37] => | legal_CA_comment = [38] => | legal_DE = [39] => | legal_DE_comment = [40] => | legal_NZ = [41] => | legal_NZ_comment = [42] => | legal_UK = POM [43] => | legal_UK_comment = [44] => | legal_US = Rx-only [45] => | legal_US_comment = [46] => | legal_EU = Rx-only [47] => | legal_EU_comment = [48] => | legal_UN = [49] => | legal_UN_comment = [50] => | legal_status = [51] => [52] => [53] => | bioavailability = 6.5% (by mouth){{cite journal | vauthors = Peltier S, Oger JM, Lagarce F, Couet W, Benoît JP | title = Enhanced oral paclitaxel bioavailability after administration of paclitaxel-loaded lipid nanocapsules | journal = Pharmaceutical Research | volume = 23 | issue = 6 | pages = 1243–1250 | date = June 2006 | pmid = 16715372 | doi = 10.1007/s11095-006-0022-2 | s2cid = 231917 }} [54] => | protein_bound = 89 to 98% [55] => | metabolism = [[Liver]] ([[CYP2C8]] and [[CYP3A4]]) [56] => | metabolites = [57] => | onset = [58] => | elimination_half-life = 5.8 hours [59] => | duration_of_action = [60] => | excretion = Fecal and urinary [61] => [62] => [63] => | CAS_number_Ref = {{cascite| correct| ??}} [64] => | CAS_number = 33069-62-4 [65] => | CAS_supplemental = [66] => | PubChem = 36314 [67] => | IUPHAR_ligand = 2770 [68] => | DrugBank_Ref = {{drugbankcite| correct| drugbank}} [69] => | DrugBank = DB01229 [70] => | ChemSpiderID_Ref = {{chemspidercite| correct| chemspider}} [71] => | ChemSpiderID = 10368587 [72] => | UNII_Ref = {{fdacite| correct| FDA}} [73] => | UNII = P88XT4IS4D [74] => | KEGG_Ref = {{keggcite| correct| kegg}} [75] => | KEGG = D00491 [76] => | ChEBI_Ref = {{ebicite| correct| EBI}} [77] => | ChEBI = 45863 [78] => | ChEMBL_Ref = {{ebicite| changed| EBI}} [79] => | ChEMBL = 428647 [80] => | NIAID_ChemDB = [81] => | PDB_ligand = TA1 [82] => | synonyms = PTX [83] => [84] => [85] => | IUPAC_name = (2α,4α,5β,7β,10β,13α)-4,10-Bis(acetyloxy)-13-{[(2''R'',3''S'')-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate [86] => | C = 47| H = 51| N = 1| O = 14 [87] => | SMILES = CC1=C2[C@@]([C@]([C@H]([C@@H]3[C@]4([C@H](OC4)C[C@@H]([C@]3(C(=O)[C@@H]2OC(=O)C)C)O)OC(=O)C)OC(=O)c5ccccc5)(C[C@@H]1OC(=O)[C@H](O)[C@@H](NC(=O)c6ccccc6)c7ccccc7)O)(C)C [88] => | StdInChI_Ref = {{stdinchicite| correct| chemspider}} [89] => | StdInChI = 1S/C47H51NO14/c1-25-31(60-43(56)36(52)35(28-16-10-7-11-17-28)48-41(54)29-18-12-8-13-19-29)23-47(57)40(61-42(55)30-20-14-9-15-21-30)38-45(6,32(51)22-33-46(38,24-58-33)62-27(3)50)39(53)37(59-26(2)49)34(25)44(47,4)5/h7-21,31-33,35-38,40,51-52,57H,22-24H2,1-6H3,(H,48,54)/t31-,32-,33+,35-,36+,37+,38-,40-,45+,46-,47+/m0/s1 [90] => | StdInChI_comment = [91] => | StdInChIKey_Ref = {{stdinchicite| correct| chemspider}} [92] => | StdInChIKey = RCINICONZNJXQF-MZXODVADSA-N [93] => | density = [94] => | density_notes = [95] => | melting_point = [96] => | melting_high = [97] => | melting_notes = [98] => | boiling_point = [99] => | boiling_notes = [100] => | solubility = [101] => | sol_units = [102] => | specific_rotation = [103] => }} [104] => [105] => '''Paclitaxel''', sold under the brand name '''Taxol''' among others, is a [[chemotherapy medication]] used to treat [[ovarian cancer]], [[esophageal cancer]], [[breast cancer]], [[lung cancer]], [[Kaposi's sarcoma]], [[cervical cancer]], and [[pancreatic cancer]]. It is administered by [[intravenous]] injection. There is also an [[protein-bound paclitaxel|albumin-bound formulation]].{{cite web|title=Paclitaxel|url=https://www.drugs.com/monograph/paclitaxel.html|publisher=The American Society of Health-System Pharmacists|access-date=2 January 2015|url-status=live|archive-url=https://web.archive.org/web/20170914125312/https://www.drugs.com/monograph/paclitaxel.html|archive-date=14 September 2017}} [106] => [107] => [108] => Common side effects include [[hair loss]], [[bone marrow suppression]], [[Hypoesthesia|numbness]], [[allergic reactions]], [[Myalgia|muscle pains]], and [[diarrhea]]. Other side effects include heart problems, increased risk of infection, and [[pneumonitis|lung inflammation]]. There are concerns that use during pregnancy may cause [[birth defects]].{{cite journal | vauthors = Berveiller P, Mir O | title = Taxanes during pregnancy: probably safe, but still to be optimized | journal = Oncology | volume = 83 | issue = 4 | pages = 239–240 | date = 2012 | pmid = 22907122 | doi = 10.1159/000341820 | doi-access = free }} Paclitaxel is in the [[taxane]] family of medications.{{cite book| vauthors = Chang AE, Ganz PA, Hayes DF, Kinsella T, Pass HI, Schiller JH, Stone RM, Strecher VO |title=Oncology: An Evidence-Based Approach|date=2007|publisher=Springer Science & Business Media|isbn=9780387310565|page=34|url=https://books.google.com/books?id=vxh6u1-ETk0C&pg=PA34|language=en|url-status=live|archive-url=https://web.archive.org/web/20161221162027/https://books.google.ca/books?id=vxh6u1-ETk0C&pg=PA34|archive-date=21 December 2016}} It works by interference with the normal function of [[microtubule]]s during [[cell division]]. [109] => [110] => [111] => Paclitaxel was isolated in 1971 from the [[Pacific yew]] and approved for medical use in 1993.{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=512|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA512|language=en|url-status=live|archive-url=https://web.archive.org/web/20161221092059/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA512|archive-date=21 December 2016}}{{cite web|publisher=National Cancer Institute|url=http://dtp.nci.nih.gov/timeline/flash/success_stories/S2_taxol.htm|title=Taxol® (NSC 125973)|access-date=14 February 2016|url-status=live|archive-url=https://web.archive.org/web/20150905144824/https://dtp.nci.nih.gov/timeline/flash/success_stories/S2_Taxol.htm|archive-date=5 September 2015 }} [https://web.archive.org/web/20111015000818/http://dtp.cancer.gov/timeline/flash/success_stories/S2_taxol.htm Wayback machine] It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].{{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 }} It has been made from precursors, and more recently through [[cell culture]]. [112] => [113] => ==Medical use== [114] => Paclitaxel is approved in the UK for ovarian, breast, lung, [[Bladder cancer|bladder]], [[Prostate cancer|prostate]], [[melanoma]], esophageal, and other types of solid tumor cancers as well as [[Kaposi's sarcoma]].{{cite journal | vauthors = Saville MW, Lietzau J, Pluda JM, Feuerstein I, Odom J, Wilson WH, Humphrey RW, Feigal E, Steinberg SM, Broder S | title = Treatment of HIV-associated Kaposi's sarcoma with paclitaxel | journal = Lancet | volume = 346 | issue = 8966 | pages = 26–28 | date = July 1995 | pmid = 7603142 | doi = 10.1016/S0140-6736(95)92654-2 | url = https://zenodo.org/record/1259817 | access-date = 28 October 2018 | url-status = dead | type = Submitted manuscript | s2cid = 44624033 | archive-url = https://web.archive.org/web/20190626185333/https://zenodo.org/record/1259817 | archive-date = 26 June 2019 }} [115] => [116] => It is recommended in [[National Institute for Health and Care Excellence]] (NICE) guidance of June 2001 for [[Non-small-cell lung carcinoma|non-small-cell lung cancer]] in patients unsuitable for curative treatment, and in first-line and second-line treatment of ovarian cancer. In September 2001, NICE recommended paclitaxel for the treatment of advanced breast cancer after the failure of [[Anthracycline|anthracyclic chemotherapy]], but that its first-line use should be limited to clinical trials. In September 2006, NICE recommended paclitaxel should ''not'' be used in the [[adjuvant treatment]] of early node-positive breast cancer.{{cite web|url=http://www.bnf.org/bnf/bnf/current/21850.htm|title=British National Formulary|access-date=7 August 2007|archive-date=14 March 2020|archive-url=https://web.archive.org/web/20200314040938/https://about.medicinescomplete.com/|url-status=dead}} [117] => [118] => {{asof|2018}}, it is approved in the United States for the treatment of breast, pancreatic, ovarian, Kaposi's sarcoma and non-small-cell lung cancers.{{cite web|url = http://www.cancer.org/treatment/treatmentsideeffects//guidetocancerdrugs/paclitaxel-protein-bound-suspension|title = Paclitaxel, Protein-Bound Suspension|date = 6 January 2015|access-date = 24 January 2015|website = Paclitaxel, Protein-Bound Suspension|publisher = Cancer.Org}}{{dead link|date=March 2018|bot=InternetArchiveBot|fix-attempted=yes }}Product Information: TAXOL(R) IV injection, paclitaxel IV injection. Bristol-Myers Squibb Company, Princeton, NJ, 2013. Accessed from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020262s051lbl.pdf {{Webarchive|url=https://web.archive.org/web/20170210214138/http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020262s051lbl.pdf |date=10 February 2017 }} on 4 October 2018. [119] => [120] => ===Similar compounds=== [121] => {{Further|Protein-bound paclitaxel|Docetaxel}} [122] => Albumin-bound paclitaxel (brand name [[Abraxane]], also called nab-paclitaxel) is an alternative formulation where paclitaxel is bound to [[Human serum albumin|albumin]] nanoparticles. Much of the clinical toxicity of paclitaxel is associated with the solvent [[Cremophor EL]] in which it is dissolved for delivery.{{cite journal | vauthors = Gelderblom H, Verweij J, Nooter K, Sparreboom A | title = Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation | journal = European Journal of Cancer | volume = 37 | issue = 13 | pages = 1590–1598 | date = September 2001 | pmid = 11527683 | doi = 10.1016/S0959-8049(01)00171-X }} [123] => [124] => [[Abraxis BioScience]] developed Abraxane, in which paclitaxel is bonded to [[Human serum albumin|albumin]] as an alternative delivery agent to the often toxic solvent delivery method. This was approved by the FDA in January 2005 for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy."[https://www.fda.gov/cder/foi/label/2005/021660lbl.pdf Abraxane Drug Information] {{webarchive|url=https://web.archive.org/web/20050526050715/https://www.fda.gov/cder/foi/label/2005/021660lbl.pdf|date=2005-05-26 }}." ''[[Food and Drug Administration]].'' 7 January 2005. Retrieved on 9 March 2007. It has since been approved for locally advanced or metastatic non-small cell lung cancer and metastatic [[adenocarcinoma of the pancreas]] as well.Product Information: ABRAXANE(R) intravenous injection suspension, paclitaxel protein-bound particles intravenous injection suspension. Celgene Corporation (per FDA), Summit, NJ, 2018. Accessed from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021660s045lbl.pdf {{Webarchive|url=https://web.archive.org/web/20190626204817/https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021660s045lbl.pdf |date=26 June 2019 }} on 4 October 2018. [125] => [126] => Synthetic approaches to paclitaxel production led to the development of [[docetaxel]]. Docetaxel has a similar set of clinical uses to paclitaxel, and it is marketed under the brand name Taxotere. [127] => [128] => [[Taxane]]s, including paclitaxel, [[10-deacetylbaccatin III]], [[baccatin III]], paclitaxel C, and 7-epipaclitaxel, have been found in the leaves and shells of [[hazel]].{{cite journal | vauthors = Ottaggio L, Bestoso F, Armirotti A, Balbi A, Damonte G, Mazzei M, Sancandi M, Miele M | title = Taxanes from Shells and Leaves of Corylus avellana | journal = Journal of Natural Products | volume = 71 | issue = 1 | pages = 58–60 | date = January 2008 | pmid = 18163585 | doi = 10.1021/np0704046 }} The finding of these compounds in shells, which are considered discarded material and are mass-produced by many food industries, is of interest for the future availability of paclitaxel.{{cite journal | vauthors = Zhang C, Yin G | title = Safety of paclitaxel-coated devices in the femoropopliteal arteries: A systematic review and meta-analysis | journal = PLOS ONE | volume = 17 | issue = 10 | pages = e0275888 | date = 2022 | pmid = 36227807 | pmc = 9560511 | doi = 10.1371/journal.pone.0275888 | bibcode = 2022PLoSO..1775888Z | doi-access = free }} [129] => [130] => ===Restenosis=== [131] => Paclitaxel is used as an antiproliferative agent for the prevention of [[restenosis]] (recurrent narrowing) of coronary and peripheral [[stent]]s; locally delivered to the wall of the [[artery]], a paclitaxel coating limits the growth of [[neointima]] (scar tissue) within stents.{{cite journal | vauthors = Heldman AW, Cheng L, Jenkins GM, Heller PF, Kim DW, Ware M, Nater C, Hruban RH, Rezai B, Abella BS, Bunge KE, Kinsella JL, Sollott SJ, Lakatta EG, Brinker JA, Hunter WL, Froehlich JP | title = Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis | journal = Circulation | volume = 103 | issue = 18 | pages = 2289–2295 | date = May 2001 | pmid = 11342479 | doi = 10.1161/01.CIR.103.18.2289 | doi-access = free }} Paclitaxel [[drug-eluting stent]]s for coronary artery placement are sold under the trade name Taxus by [[Boston Scientific]] in the United States. Paclitaxel drug-eluting stents for femoropopliteal artery placement are also available. [132] => [133] => ==Side effects== [134] => Common side effects include nausea and vomiting, [[Anorexia (symptom)|loss of appetite]], [[Dysgeusia|change in taste]], thinned or brittle hair, [[Arthralgia|pain in the joints]] of the arms or legs lasting two to three days, changes in the color of the nails, and [[Paresthesia|tingling]] in the hands or toes.{{cite book | vauthors = Abou-Donia M |title=Mammalian Toxicology |date=5 February 2015 |publisher=John Wiley & Sons |isbn=978-1-118-68285-2 |page=626 |language=en}} More serious side effects such as unusual bruising or bleeding, pain, redness or swelling at the injection site, [[hand-foot syndrome]], change in normal bowel habits for more than two days, fever, chills, cough, [[sore throat]], [[Dysphagia|difficulty swallowing]], dizziness, [[shortness of breath]], severe exhaustion, [[Rash|skin rash]], [[Flushing (physiology)|facial flushing]], [[female infertility]] by ovarian damage, and [[chest pain]] can also occur. [[Neuropathy]] may also occur. [135] => [136] => [[Dexamethasone]] is given prior to paclitaxel infusion to mitigate some of the side effects.{{cite book | vauthors = Hoskins WJ |title=Principles and Practice of Gynecologic Oncology |date=2005 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-4689-2 |page=531 |language=en}} [137] => [138] => A number of these side effects are associated with the [[excipient]] used, Cremophor EL, a polyoxyethylated [[castor oil]]. Allergies to [[Ciclosporin|cyclosporine]], [[teniposide]], and other drugs delivered in polyoxyethylated castor oil may increase the risk of adverse reactions to paclitaxel."{{cite web | url = https://www.nlm.nih.gov/medlineplus/druginfo/meds/a607070.html | work = Medline Plus | publisher = U.S. National Library of Medicine | title = Paclitaxel Injection | archive-url = https://web.archive.org/web/20100212114958/http://www.nlm.nih.gov/medlineplus/druginfo/meds/a607070.html| archive-date=12 February 2010 }} [139] => [140] => ==Mechanism of action== [141] => [[File:Tubulin&paclitaxel-2HXF.png|thumb|Complex of α, β tubulin subunits and paclitaxel. Paclitaxel is shown as yellow stick.]] [142] => Paclitaxel is one of several [[cytoskeletal drugs]] that target [[tubulin]]. Paclitaxel-treated cells have defects in [[mitotic spindle]] assembly, [[chromosome segregation]], and [[cell division]]. Unlike other tubulin-targeting drugs, such as [[colchicine]], that inhibit [[microtubule]] assembly, paclitaxel stabilizes the microtubule polymer and protects it from disassembly. Chromosomes are thus unable to achieve a [[metaphase]] spindle configuration. This blocks the progression of [[mitosis]] and prolonged activation of the [[mitotic checkpoint]] triggers [[apoptosis]] or reversion to the [[G0 phase|G0-phase]] of the cell cycle without cell division.{{cite journal | vauthors = Bharadwaj R, Yu H | title = The spindle checkpoint, aneuploidy, and cancer | journal = Oncogene | volume = 23 | issue = 11 | pages = 2016–2027 | date = March 2004 | pmid = 15021889 | doi = 10.1038/sj.onc.1207374 | s2cid = 11114877 | doi-access = }}{{cite journal | vauthors = Brito DA, Yang Z, Rieder CL | title = Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied | journal = The Journal of Cell Biology | volume = 182 | issue = 4 | pages = 623–629 | date = August 2008 | pmid = 18710927 | pmc = 2518701 | doi = 10.1083/jcb.200805072 }} [143] => [144] => The ability of paclitaxel to inhibit spindle function is generally attributed to its suppression of microtubule dynamics,{{cite journal | vauthors = Jordan MA, Wilson L | title = Microtubules as a target for anticancer drugs | journal = Nature Reviews. Cancer | volume = 4 | issue = 4 | pages = 253–265 | date = April 2004 | pmid = 15057285 | doi = 10.1038/nrc1317 | s2cid = 10228718 }} but other studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. At the higher therapeutic concentrations, paclitaxel appears to suppress microtubule detachment from [[centrosome]]s, a process normally activated during mitosis.{{cite journal | vauthors = Ganguly A, Yang H, Cabral F | title = Paclitaxel-dependent cell lines reveal a novel drug activity | journal = Molecular Cancer Therapeutics | volume = 9 | issue = 11 | pages = 2914–2923 | date = November 2010 | pmid = 20978163 | pmc = 2978777 | doi = 10.1158/1535-7163.MCT-10-0552 }} Paclitaxel binds to the beta-tubulin subunits of microtubules.{{cite journal | vauthors = Löwe J, Li H, Downing KH, Nogales E | title = Refined structure of alpha beta-tubulin at 3.5 A resolution | journal = Journal of Molecular Biology | volume = 313 | issue = 5 | pages = 1045–1057 | date = November 2001 | pmid = 11700061 | doi = 10.1006/jmbi.2001.5077 | url = https://zenodo.org/record/1229896 | access-date = 29 August 2020 | archive-date = 22 January 2021 | archive-url = https://web.archive.org/web/20210122161041/https://zenodo.org/record/1229896 | url-status = live }} [145] => [146] => == Chemistry == [147] => [148] => The [[Chemical nomenclature|nomenclature]] for paclitaxel is structured on a [[bicyclic|tetracyclic]] 17-atom skeleton. There are a total of 11 stereocenters. The active [[stereoisomer]] is (−)-paclitaxel (shown here). [149] => [150] => {{multiple image|align = center|image1 = TaxolNomenClature.svg|width1 = 315|caption1 = Position numbering|image2 = TaxolStereochemistry.svg|width2 = 303|caption2 = Absolute stereochemistry|footer = (1''S'',2''S'',3''R'',4''S'',7''R'',9''S'',10''S'',12''R'',15''S'')-4,12-Diacetoxy-15-{{(}}[(2''R'',3''S'')-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl rel-benzoate [151] => }} [152] => [153] => ==Production== [154] => [[Image:PacificYew 8566.jpg|thumb|Undisturbed Pacific yew bark contains paclitaxel and related chemicals.]] [155] => [156] => === Bark processing === [157] => [[Image:Yew bark Taxol PD.jpg|thumbnail|The bark is peeled and processed to provide paclitaxel.]] [158] => [159] => From 1967 to 1993, almost all paclitaxel produced was derived from bark of the Pacific yew, ''[[Taxus brevifolia]]'', the harvesting of which kills the tree in the process.{{cite news| vauthors = Gersmann H, Aldred J |title=Medicinal tree used in chemotherapy drug faces extinction|url=https://www.theguardian.com/environment/2011/nov/10/iucn-red-list-tree-chemotherapy|access-date=15 February 2017|work=The Guardian|date=10 November 2011|url-status=live|archive-url=https://web.archive.org/web/20170216143120/https://www.theguardian.com/environment/2011/nov/10/iucn-red-list-tree-chemotherapy|archive-date=16 February 2017}} The processes used were descendants of the original isolation method of [[Monroe Eliot Wall|Monroe Wall]] and [[Mansukh C. Wani|Mansukh Wani]]; by 1987, the U.S. [[National Cancer Institute]] (NCI) had contracted Hauser Chemical Research of [[Boulder, Colorado]], to handle bark on the scale needed for [[Phases of clinical research|phase]] II and III trials.{{citation needed|date=June 2014}} While both the size of the wild population of the Pacific yew and the magnitude of the eventual demand for paclitaxel were uncertain, it was clear that an alternative, sustainable source of the [[natural product]] would be needed. Initial attempts to broaden its sourcing used needles from the tree, or material from other related ''[[Taxus]]'' species, including cultivated ones,{{citation needed|date=June 2014}} but these attempts were challenged by the relatively low and often highly variable yields obtained. Early in the 1990s, coincident with increased sensitivity to the ecology of the forests of the [[Pacific Northwest]], paclitaxel was successfully extracted on a clinically useful scale from these sources.{{sfn|Goodman|Walsh|2001|pp=172–5}} [160] => [161] => === Semisynthesis === [162] => Concurrently, synthetic chemists in the U.S. and France had been interested in paclitaxel, beginning in the late 1970s.{{citation needed|date=June 2014}} As noted, by 1992 extensive efforts were underway to accomplish the [[total synthesis]] of paclitaxel, efforts motivated by the desire to generate new chemical understanding rather than to achieve practical commercial production. In contrast, the French group of [[Pierre Potier]] at the [[Centre national de la recherche scientifique]] (CNRS) addressed the matter of overall process yield, showing that it was feasible to isolate relatively large quantities of the compound [[10-deacetylbaccatin]] from the European yew, ''[[Taxus baccata]]'', which grew on the CNRS campus and whose needles were available in large quantity.{{citation needed|date=June 2014}} By virtue of its structure, 10-deacetylbaccatin was seen as a viable starting material for a short [[semisynthesis]] to produce paclitaxel. By 1988, Poitier and collaborators had published a semisynthetic route from needles of the European yew to paclitaxel.{{sfn|Goodman|Walsh|2001|pp=100–1}} [163] => [164] => The view of the NCI, however, was that even this route was not practical.{{citation needed|date=June 2014}} The group of [[Robert A. Holton]] had also pursued a practical semisynthetic production route; by late 1989, Holton's group had developed a semisynthetic route to paclitaxel with twice the yield of the Potier process.{{cite book | vauthors = Holton RA, Biediger RJ, Boatman PD | chapter = Semisynthesis of taxol and taxotere | veditors = Suffness M | title = Taxol: Science and Applications | date = 1999 | pages = 97–121 | location = Boca Raton | publisher = CRC press | isbn = 978-0-13-873736-8 }} The main innovation was "Ojima−Holton coupling", a ring-opening method independently discovered by Holton and Ojima.{{cite journal | vauthors = Ojima I, Wang X, Jing Y, Wang C | title = Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery | journal = Journal of Natural Products | volume = 81 | issue = 3 | pages = 703–721 | date = March 2018 | pmid = 29468872 | doi = 10.1021/acs.jnatprod.7b01012 | pmc = 5869464 | doi-access = free }} [[Florida State University]], where Holton worked, signed a deal with [[Bristol-Myers Squibb]] (BMS) to license their semisynthesis and future patents.{{citation needed|date=June 2014}} In 1992, Holton patented an improved process with an 80% yield, and BMS took the process in-house and started to manufacture paclitaxel in Ireland from 10-deacetylbaccatin isolated from the needles of the European yew.{{citation needed|date=June 2014}} In early 1993, BMS announced that it would cease reliance on Pacific yew bark by the end of 1995, effectively terminating ecological controversy over its use.{{citation needed|date=June 2014}} This announcement also made good their commitment to develop an alternative supply route, made to the NCI in their [[cooperative research and development agreement]] (CRADA) application of 1989. [165] => [166] => As of 2013, BMS was using the semisynthetic method utilizing needles from the European yew to produce paclitaxel.{{cite web|url=http://wgcriticalcare.com/injectable-pharmaceuticals/wp-content/uploads/2014/01/WGCC-Paclitaxel-PI-June-2013.pdf|title=Paclitaxel Injection, USP|website=Injectable Pharmaceuticals|language=en-US|access-date=22 April 2016|url-status=dead|archive-url=https://web.archive.org/web/20160918114404/http://wgcriticalcare.com/injectable-pharmaceuticals/wp-content/uploads/2014/01/WGCC-Paclitaxel-PI-June-2013.pdf|archive-date=18 September 2016}} Another company which worked with BMS until 2012,{{cite web|url=http://www.phytonbiotech.com/history/|title=History|access-date=22 April 2016|url-status=live|archive-url=https://web.archive.org/web/20160524143938/http://www.phytonbiotech.com/history/|archive-date=24 May 2016}} Phyton Biotech, Inc., uses plant cell fermentation (PCF) technology.{{cite web|url=http://www.phytonbiotech.com/paclitaxel/|title=Phyton BioTech Paclitaxel|access-date=22 April 2016|url-status=live|archive-url=https://web.archive.org/web/20160807223136/http://www.phytonbiotech.com/paclitaxel/|archive-date=7 August 2016}} By cultivating a specific ''Taxus'' [[cell line]] in fermentation tanks, they no longer need ongoing sourcing of material from actual yew tree plantations.{{cite book|chapter=Suspension Culture of Plant Cells under Heterotrophic Conditions | vauthors = Imseng N, Schillberg S, Schürch C, Schmid D, Schütte K, Gorr G, Eibl D, Eibl R | date = 2014 | veditors = Meyer HP, Schmidhalter D |title=Industrial Scale Suspension Culture of Living Cells|publisher=Wiley-Blackwell |isbn=978-3-527-33547-3 |pages=224–257 }} Paclitaxel is then captured directly from the suspension broth by a resin allowing concentration to highly enriched powder containing about 40% paclitaxel. The compound is then purified by one [[Chromatography|chromatographic]] step followed by [[crystallization]].Gilbert Gorr and Roland Franke. Commercial Pharmaceutical Production of Complex APIs via Plant Cell Fermentation (PCF®) Technology. Presentation at CPhI 2015, 13 Oct.. Compared to the semisynthesis method, PCF eliminates the need for many hazardous chemicals and saves a considerable amount of energy.{{cite web|url=http://www.epa.gov/greenchemistry/pubs/pgcc/winners/gspa04.html|title=2004 Greener Synthetic Pathways Award: Bristol-Myers Squibb Company: Development of a Green Synthesis for TAXOL Manufacture via Plant Cell Fermentation and Extraction|url-status=live|archive-url=https://web.archive.org/web/20061002105234/http://www.epa.gov/greenchemistry/pubs/pgcc/winners/gspa04.html|archive-date=2 October 2006}} [167] => [168] => In 1993, paclitaxel was discovered as a natural product in ''Taxomyces andreanae'', a newly described [[Endophyte|endophytic]] [[fungus]] living in the yew tree.{{cite journal | vauthors = Stierle A, Strobel G, Stierle D | title = Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew | journal = Science | volume = 260 | issue = 5105 | pages = 214–216 | date = April 1993 | pmid = 8097061 | doi = 10.1126/science.8097061 | bibcode = 1993Sci...260..214S }} It has since been reported in a number of other endophytic fungi, including ''Nodulisporium sylviforme'',{{citation needed|date=November 2019}} ''Alternaria taxi'', ''Cladosporium cladosporioides'' MD2, ''[[Metarhizium anisopliae]]'', ''Aspergillus candidus'' MD3, ''Mucor rouxianus'', ''Chaetomella raphigera'', ''Phyllosticta tabernaemontanae'', ''[[Phomopsis]]'', ''Pestalotiopsis pauciseta'', ''[[Phyllosticta citricarpa]]'', ''[[Podocarpus]]'' sp., ''[[Fusarium solani]]'', ''Pestalotiopsis terminaliae'', ''Pestalotiopsis breviseta'', ''Botryodiplodia theobromae'', ''Gliocladium'' sp., ''Alternaria alternata'' var. ''monosporus'', ''[[Cladosporium cladosporioides]]'', ''Nigrospora'' sp. and ''[[Pestalotiopsis versicolor]]''. However, there has been contradictory evidence for its production by endophytes, with other studies finding independent production is unlikely.{{cite journal | vauthors = Staniek A, Woerdenbag HJ, Kayser O | title = Taxomyces andreanae: a presumed paclitaxel producer demystified? | journal = Planta Medica | volume = 75 | issue = 15 | pages = 1561–1566 | date = December 2009 | pmid = 19809969 | doi = 10.1055/s-0029-1186181 | s2cid = 260283080 }}{{cite journal|doi=10.1007/s13225-013-0228-7|title=Getting to the bottom of taxol biosynthesis by fungi|year=2013|vauthors = Heinig U, Scholz S, Jennewein S|journal=Fungal Diversity|volume=60|pages=161–170|s2cid=18642421|url=https://link.springer.com/content/pdf/10.1007%2Fs13225-013-0228-7.pdf |archive-url=https://ghostarchive.org/archive/20221009/https://link.springer.com/content/pdf/10.1007%2Fs13225-013-0228-7.pdf |archive-date=9 October 2022 |url-status=live|doi-access=free }} [169] => [170] => ===Biosynthesis=== [171] => [[File:Biosynthesis of Taxol.png|thumb|Biosynthesis of Taxol]] [172] => Taxol is a tetracyclic [[diterpene]], and the biosynthesis of diterpenes starts with an FPP molecule being elongated by the addition of an IPP molecule in order to form geranylgeranyl diphosphate ([[GGPP]]).{{cite book| vauthors = Dewick PM |title=Medicinal Natural Products|date=6 February 2009|publisher=John Wiley & Sons, Ltd|isbn=978-0-470-74276-1|location=Chichester, UK |language=en |doi=10.1002/9780470742761 }} The biosynthesis of Taxol contains nineteen steps.{{cite journal | vauthors = Howat S, Park B, Oh IS, Jin YW, Lee EK, Loake GJ | title = Paclitaxel: biosynthesis, production and future prospects | journal = New Biotechnology | volume = 31 | issue = 3 | pages = 242–245 | date = May 2014 | pmid = 24614567 | doi = 10.1016/j.nbt.2014.02.010 }} These 19 steps can be considered in several steps, with the first step being the formation of the taxane skeleton, which then undergoes a series of oxygenations. Following the oxygenations, two acetylations and a benzoylation occur on the intermediate. The oxygenation of the taxane core is believed to occur on C5 and C10, C2 and C9, C13 followed by C7, and a C1 hydroxylation later on in the pathway. Later in the pathway, an oxidation at C9 forms a ketone functional group and an oxetane, forming the intermediate baccatin III. The final steps of the pathway include the formation of a C13-side chain which is attached to baccatin III.{{cite journal | vauthors = Croteau R, Ketchum RE, Long RM, Kaspera R, Wildung MR | title = Taxol biosynthesis and molecular genetics | journal = Phytochemistry Reviews | volume = 5 | issue = 1 | pages = 75–97 | date = February 2006 | pmid = 20622989 | pmc = 2901146 | doi = 10.1007/s11101-005-3748-2 | bibcode = 2006PChRv...5...75C }} The biosynthesis of Taxol is illustrated in more detail in the figure, with steps 1-7 all occurring in the enzyme [[taxadiene synthase]] (TS on the figure). Taxol's biosynthesis begins with E,E,E-GGPP losing pyrophosphate via an [[SN1 reaction|SN1]] mechanism (step 1 in the figure). The double-bond attacks the cation via electrophilic addition, yielding a tertiary cation and creating the first ring closure (step 2). Another electrophilic attack occurs, further cyclizing the structure by creating the first 6-membered ring and creating another tertiary cation (step 3). An intramolecular proton transfer occurs, attacking the verticillyl cation (step 4) and creating a double bond, yielding a tertiary cation. An electrophilic cyclization occurs in step 5, and an intramolecular proton transfer attacks the taxenyl cation (step 6). This forms the fused ring structure intermediate known as taxadiene. Taxadiene then undergoes a series of 10 oxidations via [[NADPH]], forming the intermediate taxadiene-5α-acetoxy-10β-ol (multiple steps later in the figure). A series of hydroxylations and esterficiations occur, forming the intermediate 10-deacetyl-baccatin III, which undergoes a further series of esterifications and a side-chain hydroxylation. This finally yields the product taxol. [173] => [174] => ===Total synthesis=== [175] => {{Main|Paclitaxel total synthesis}} [176] => [177] => [[Image:Taxol number.svg|thumb|Paclitaxel, with rings labeled and accepted numbering scheme shown.]] [178] => By 1992, at least thirty academic research teams globally were working to achieve a [[total synthesis]] of this [[natural product]], with the synthesis proceeding from simple natural products and other readily available starting materials.{{cite journal | vauthors = Hall N | title = Creating complexity--the beauty and logic of synthesis | journal = Chemical Communications | issue = 6 | pages = 661–664 | date = March 2003 | pmid = 12703766 | doi = 10.1039/b212248k }} This total synthesis effort was motivated primarily by the desire to generate new chemical understanding, rather than with an expectation of the practical commercial production of paclitaxel. The first laboratories to complete the total synthesis from much less complex starting materials were the research groups of [[Robert A. Holton]], who had the [[Holton taxol total synthesis|first article to be accepted for publication]], and of [[K. C. Nicolaou]] who had the [[Nicolaou Taxol total synthesis|first article to appear in print]] (by a week, on 7 February 1994). Though the Holton submission preceded the Nicolaou by a month (21 December 1993 versus 24 January 1994),See N. Hall, ibid. See also the [[American Chemical Society]] publication [[Chemical and Engineering News]] (C&EN), 21 February 1994, page 32, and primary citations appearing at Holton and Nicolaou taxol total synthesis articles. the near coincidence of the publications arising from each of these massive, multiyear efforts—11–18 authors appearing on each of the February 1994 publications—has led the ending of the race to be termed a "tie"{{cite journal | vauthors = Flam F | title = Race to synthesize taxol ends in a tie | journal = Science | volume = 263 | issue = 5149 | pages = 911 | date = February 1994 | pmid = 7906053 | doi = 10.1126/science.7906053 | author-link = Faye Flam | bibcode = 1994Sci...263..911F }} or a "photo finish", though each group has argued that their synthetic strategy and tactics were superior. [179] => [180] => As of 2006, five additional research groups had reported successful total syntheses of paclitaxel: [[Wender Taxol total synthesis|Wender et al.]] in 1997, and [[Kuwajima Taxol total synthesis|Kuwajima et al.]] and [[Mukaiyama Taxol total synthesis|Mukaiyama et al.]] in 1998 with further [[linear synthesis|linear syntheses]], and [[Danishefsky Taxol total synthesis|Danishefsky et al.]] in 1996 and [[Takahashi Taxol total synthesis|Takahashi et al.]] in 2006 with further [[convergent synthesis|convergent syntheses]].{{update inline|date=March 2017}} As of that date, all strategies had aimed to prepare a 10-deacetylbaccatin-type core containing the ABCD ring system, followed generally by last stage addition of the "tail" to the 13-[[Hydroxy group|hydroxyl group]]. [181] => [182] => While the "political climate surrounding [paclitaxel] and [the Pacific yew] in the early 1990s ... helped bolster [a] link between total synthesis and the [paclitaxel] supply problem," and though total synthesis activities were a requisite to explore the [[structure-activity relationship]]s of paclitaxel via generation of analogs for testing, the total synthesis efforts were never seen "as a serious commercial route" to provide significant quantities of the natural product for medical testing or therapeutic use.{{sfn|Goodman|Walsh|2001|pp=179–182}} [183] => [184] => ==History== [185] => The discovery of paclitaxel began in 1962 as a result of a NCI-funded screening program. A number of years later it was isolated from the bark of the Pacific yew, ''Taxus brevifolia'', hence its name "taxol". [186] => [187] => The discovery was made by [[Monroe E. Wall]] and [[Mansukh C. Wani]] at the [[Research Triangle Institute]], [[Research Triangle Park]], North Carolina, in 1971.{{cite journal | vauthors = Wall ME, Wani MC | title = Camptothecin and taxol: discovery to clinic--thirteenth Bruce F. Cain Memorial Award Lecture | journal = Cancer Research | volume = 55 | issue = 4 | pages = 753–760 | date = February 1995 | pmid = 7850785 | url = http://cancerres.aacrjournals.org/content/55/4/753.long | url-status = live | archive-url = https://web.archive.org/web/20161124171818/http://cancerres.aacrjournals.org/content/55/4/753.long | archive-date = 24 November 2016 }} These scientists isolated the natural product from the bark of the Pacific yew tree, determined its structure and named it "taxol", and arranged for its first biological testing.{{cite journal |last=Donehower |first=Ross C. |date=1996 |title=The Clinical Development of Paclitaxel: A Successful Collaboration of Academia, Industry and the National Cancer Institute |url=https://academic.oup.com/stmcls/article/14/1/25-28/6390626 |journal=Stem Cells |language=en |volume=14 |issue=1 |pages=25–28 |doi=10.1002/stem.140025 |pmid=8820947 |issn=1066-5099}} The compound was then developed commercially by BMS, who had the generic name assigned as "paclitaxel".{{citation needed|date=June 2014}} [188] => [189] => ===Plant screening program=== [190] => In 1955, the NCI in the United States set up the Cancer Chemotherapy National Service Center (CCNSC) to act as a public screening center for anticancer activity in compounds submitted by external institutions and companies.{{sfn|Goodman|Walsh|2001|p=17}} Although the majority of compounds screened were of synthetic origin, one chemist, Jonathan Hartwell, who was employed there from 1958 onwards, had experience with natural product derived compounds, and began a plant screening operation.{{sfn|Goodman|Walsh|2001|p=22}} After some years of informal arrangements, in July 1960, the NCI commissioned the [[United States Department of Agriculture]] (USDA) botanists to collect samples from about 1,000 plant species per year.{{sfn|Goodman|Walsh|2001|pp=25,28}} On 21 August 1962, one of those botanists, Arthur S. Barclay, collected bark from a single Pacific yew tree in a forest north of the town of [[Packwood, Washington]], as part of a four-month trip to collect material from over 200 different species. The material was then processed by a number of specialist CCNSC subcontractors, and one of the tree's samples was found to be [[Cytotoxicity|cytotoxic]] in a cellular assay on 22 May 1964.{{sfn|Goodman|Walsh|2001|p=51}} [191] => [192] => Accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by Monroe E. Wall in Research Triangle Park, North Carolina, began work on fresh ''Taxus'' samples, isolating the active ingredient in September 1966 and announcing their findings at an April 1967 [[American Chemical Society]] meeting in [[Miami Beach, Florida|Miami Beach]].{{cite journal | vauthors = Wall ME, Wani MC | title = Camptothecin and taxol: discovery to clinic--thirteenth Bruce F. Cain Memorial Award Lecture | journal = Cancer Research | volume = 55 | issue = 4 | pages = 753–760 | date = February 1995 | pmid = 7850785 }} They named the pure compound taxol in June 1967.{{sfn|Goodman|Walsh|2001|p=51}} Wall and his colleague Wani published their results, including the chemical structure, in 1971.{{cite journal | vauthors = Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT | title = Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia | journal = Journal of the American Chemical Society | volume = 93 | issue = 9 | pages = 2325–2327 | date = May 1971 | pmid = 5553076 | doi = 10.1021/ja00738a045 }} [193] => [194] => The NCI continued to commission work to collect more ''Taxus'' bark and to isolate increasing quantities of taxol. By 1969, {{Cvt|28|kg|}} of crude extract had been isolated from almost {{Cvt|1200|kg|}} of bark, although this ultimately yielded only {{Cvt|10|g|}} of pure material,{{sfn|Goodman|Walsh|2001|p=81}} but for several years, no use was made of the compound by the NCI. In 1975, it was shown to be active in another ''[[in vitro]]'' system; two years later, a new department head reviewed the data and finally recommended taxol be moved on to the next stage in the discovery process.{{sfn|Goodman|Walsh|2001|pp=79,81}} This required increasing quantities of purified taxol, up to {{Cvt|600|g|}}, and in 1977 a further request for {{Cvt|7000|lb|}} of bark was made. [195] => [196] => In 1978, two NCI researchers published a report showing taxol was mildly effective in leukaemic mice. [197] => {{cite journal | vauthors = Fuchs DA, Johnson RK | title = Cytologic evidence that taxol, an antineoplastic agent from Taxus brevifolia, acts as a mitotic spindle poison | journal = Cancer Treatment Reports | volume = 62 | issue = 8 | pages = 1219–1222 | date = August 1978 | pmid = 688258 }} In November 1978, taxol was shown to be effective in [[xenograft]] studies.{{sfn|Goodman|Walsh|2001|p=95}} Meanwhile, taxol began to be well known in the cell biology, as well as the cancer community, with a publication in early 1979 by [[Susan Band Horwitz|Susan B. Horwitz]], a molecular pharmacologist at [[Albert Einstein College of Medicine]], showing taxol had a previously unknown mechanism of action involving the stabilization of microtubules. Together with formulation problems, this increased interest from researchers meant that, by 1980, the NCI envisaged needing to collect {{Cvt|20000|lb|}} of bark.{{harvnb|Goodman|Walsh|2001|p=97}} Animal toxicology studies were complete by June 1982, and in November NCI applied for the [[Investigational New Drug|IND]] necessary to begin clinical trials in humans. [198] => [199] => ===Early clinical trials, supply and the transfer to BMS=== [200] => [[phases of clinical research|Phase I]] clinical trials began in April 1984, and the decision to start [[phases of clinical research|Phase II]] trials was made a year later.{{sfn|Goodman|Walsh|2001|p=115}} These larger trials needed more bark and collection of a further 12,000 pounds was commissioned, which enabled some phase II trials to begin by the end of 1986. But by then it was recognized that the demand for taxol might be substantial and that more than 60,000 pounds of bark might be needed as a minimum. This unprecedentedly large amount brought ecological concerns about the impact on yew populations into focus for the first time, as local politicians and foresters expressed unease at the program. [201] => [202] => The first public report from a phase II trial in May 1988 showed promising effects in melanoma and refractory ovarian cancer.{{cite journal|vauthors = Rowinsky EK, Donehower RC, Rosenshein NB, Ettinger DS, McGuire WP|title = Phase II study of taxol in advanced epithelial malignancies|journal = Proceedings of the Association of Clinical Oncology|volume = 7|pages = 136|year = 1988 }} At this point, Gordon Cragg of the NCI's Natural Product Branch calculated the synthesis of enough taxol to treat all the ovarian cancer and melanoma cases in the US would require the destruction of 360,000 trees annually. For the first time, serious consideration was given to the problem of supply. [203] => Because of the practical and, in particular, the financial scale of the program needed, the NCI decided to seek association with a pharmaceutical company, and in August 1989, it published a [[Cooperative Research and Development Agreement]] (CRADA) offering its current stock and supply from current bark stocks, and proprietary access to the data so far collected, to a company willing to commit to providing the funds to collect further raw material, isolate taxol, and fund a large proportion of clinical trials. In the words of Goodman and Welsh, authors of a substantial scholarly book on taxol, "The NCI was thinking, not of collaboration, ... but of a hand-over of taxol (and its problems)".{{harvnb|Goodman|Walsh|2001|p=120}} [204] => [205] => Although the offer was widely advertised, only four companies responded to the CRADA, including the American firm [[Bristol-Myers Squibb]] (BMS), [206] => which was selected as the partner in December 1989. The choice of BMS later became controversial and was the subject of Congressional hearings in 1991 and 1992. While it seems clear the NCI had little choice but to seek a commercial partner, there was also controversy about the terms of the deal, eventually leading to a report by the [[General Accounting Office]] in 2003, which concluded the NIH had failed to ensure value for money.{{cite web|url=http://wyden.senate.gov/leg_issues/reports/taxol.pdf|title=Technology Transfer: NIH-Private Sector Partnership in the Development of Taxol|url-status=dead|archive-url=https://web.archive.org/web/20070726000303/http://wyden.senate.gov/leg_issues/reports/taxol.pdf|archive-date=26 July 2007|access-date=17 July 2016}} In related CRADAs with the [[USDA]] and [[Department of the Interior]], Bristol-Myers Squibb was given exclusive first refusal on all Federal supplies of ''Taxus brevifolia''. [207] => This exclusive contract lead to some criticism for giving BMS a "cancer [[monopoly]]".{{cite web| vauthors = Nader R, Love J |url = http://www.findarticles.com/p/articles/mi_m1295/is_n2_v57/ai_13417481|title = Looting the medicine chest: how Bristol-Myers Squibb made off with the public's cancer research|work = [[The Progressive]]|date = February 1993|archive-url = https://web.archive.org/web/20040924184528/http://www.findarticles.com/p/articles/mi_m1295/is_n2_v57/ai_13417481|archive-date = 24 September 2004 }} [208] => Eighteen months after the CRADA, BMS filed a [[new drug application]] (NDA), which was given FDA approval at the very end of 1992. [209] => [210] => Although there was no patent on the compound, the provisions of the [[Waxman-Hatch Act]] gave Bristol-Myers Squibb five years exclusive marketing rights. [211] => [212] => In 1990, BMS applied to trademark the name taxol as ''Taxol(R)''. This was controversially approved in 1992. At the same time, paclitaxel replaced taxol as the generic ([[International Nonproprietary Name|INN]]) name of the compound. Critics, including the journal ''[[Nature (journal)|Nature]]'', argued the name taxol had been used for more than two decades and in more than 600 scientific articles and suggested the trademark should not have been awarded and the BMS should renounce its rights to it.{{cite journal | vauthors = | title = Names for hi-jacking | journal = Nature | volume = 373 | issue = 6513 | pages = 370 | date = February 1995 | pmid = 7830775 | doi = 10.1038/373370a0 | s2cid = 31510966 | bibcode = 1995Natur.373..370. | doi-access = free }} BMS argued changing the name would cause confusion among oncologists and possibly endanger the health of patients. BMS has continued to defend its rights to the name in the courts.{{sfn|Goodman|Walsh|2001|p=170}} [213] => BMS has also been criticized for misrepresentation by Goodman and Walsh, who quote from a company report saying "It was not until 1971 that ... testing ... enabled the isolation of paclitaxel, initially described as 'compound 17".Bristol-Myers Squibb, The development of TAXOL (paclitaxel), March 1997, as cited in {{harvnb|Goodman|Walsh|2001|p=2}} This quote is, strictly speaking, accurate: the objection seems to be that this misleadingly neglects to explain that it was the scientist doing the isolation who named the compound taxol and it was not referred to in any other way for more than twenty years. Annual sales peaked in 2000, reaching [[US$]]1.6 billion; paclitaxel is now available in generic form. [214] => [215] => == Society and culture == [216] => [217] => === Legal status === [218] => Paclitaxel was approved for medical use in the European Union in 2008. [219] => [220] => In November 2023, the [[Committee for Medicinal Products for Human Use]] of the [[European Medicines Agency]] adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Naveruclif, intended for the treatment of metastatic breast cancer, metastatic adenocarcinoma of the pancreas and non-small cell lung cancer. The applicant for this medicinal product is Accord Healthcare S.L.U.{{cite web | title=Naveruclif EPAR | website=[[European Medicines Agency]] (EMA) | date=9 November 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/naveruclif | access-date=28 December 2023}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. [221] => [222] => === Economics === [223] => {{as of|2006}}, the cost to the NHS per patient in early breast cancer, assuming four cycles of treatment, was about £4,000 (approx. $6,000).{{cite web|title=NICE Guidance TA108|date=27 September 2006 |url=http://guidance.nice.org.uk/TA108/guidance/pdf/English|url-status=live|archive-url=https://web.archive.org/web/20070630182944/http://guidance.nice.org.uk/TA108/guidance/pdf/English|archive-date=30 June 2007}} [224] => [225] => ==Research== [226] => {{cleanup section|reason=Huge paragraph needs to be split and sorted|date=September 2023}} [227] => [[Caffeine]] has been speculated to inhibit paclitaxel-induced apoptosis in colorectal cancer cells.{{cite journal | vauthors = Mhaidat NM, Alzoubi KH, Al-Azzam SI, Alsaad AA | title = Caffeine inhibits paclitaxel‑induced apoptosis in colorectal cancer cells through the upregulation of Mcl‑1 levels | journal = Molecular Medicine Reports | volume = 9 | issue = 1 | pages = 243–248 | date = January 2014 | pmid = 24173825 | doi = 10.3892/mmr.2013.1763 | url = http://www.spandidos-publications.com/mmr/9/1/243 | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20150622015153/http://www.spandidos-publications.com/mmr/9/1/243 | archive-date = 22 June 2015 }} [228] => [229] => Aside from its direct clinical use, paclitaxel is used extensively in biological and biomedical research as a [[microtubule]] stabilizer. In general, [[in vitro]] assays involving microtubules, such as motility assays, rely on paclitaxel to maintain microtubule integrity in the absence of the various nucleating factors and other stabilizing elements found in the cell. For example, it is used for in vitro tests of drugs that aim to alter the behavior of microtubule [[motor proteins]], or for studies of mutant motor proteins. Moreover, Paclitaxel has been used in vitro to inhibit insulin fibrillation; in a molar ratio of 10:1 (insulin:paclitaxel), it hindered insulin fibrillation near 70%. Iso-thermal titration calorimetry (ITC) findings indicated a spontaneous tendency of paclitaxel to interact with insulin through hydrogen bonds and van der Waal's forces.{{cite journal | vauthors = Kachooei E, Moosavi-Movahedi AA, Khodagholi F, Mozaffarian F, Sadeghi P, Hadi-Alijanvand H, Ghasemi A, Saboury AA, Farhadi M, Sheibani N | title = Inhibition study on insulin fibrillation and cytotoxicity by paclitaxel | journal = Journal of Biochemistry | volume = 155 | issue = 6 | pages = 361–373 | date = June 2014 | pmid = 24535601 | doi = 10.1093/jb/mvu012 }} Also, the inhibitory role of paclitaxel is attributed to its impact on the colloidal stability of protein solution, as it was observed that paclitaxel inhibited lysozyme fibrillation by inducing the formation of "off-pathway" oligomeric intermediates and increasing the colloidal stability subsequently.{{cite journal | vauthors = Kachooei E, Mozaffarian F, Khodagholi F, Sadeghi P, Karami L, Ghasemi A, Vahdat E, Saboury AA, Sheibani N, Moosavi-Movahedi AA | title = Paclitaxel inhibited lysozyme fibrillation by increasing colloidal stability through formation of "off-pathway" oligomers | journal = International Journal of Biological Macromolecules | volume = 111 | pages = 870–879 | date = May 2018 | pmid = 29352977 | doi = 10.1016/j.ijbiomac.2018.01.072 | doi-access = free }} Paclitaxel is sometimes used for [[in vivo]] studies as well; it can be fed to test organisms, such as [[Drosophila melanogaster|fruit flies]], or injected into individual cells, to inhibit microtubule disassembly or to increase the number of microtubules in the cell. Paclitaxel induces remyelination in a demyelinating mouse in vivo{{cite journal | vauthors = Moscarello MA, Mak B, Nguyen TA, Wood DD, Mastronardi F, Ludwin SK | title = Paclitaxel (Taxol) attenuates clinical disease in a spontaneously demyelinating transgenic mouse and induces remyelination | journal = Multiple Sclerosis | volume = 8 | issue = 2 | pages = 130–138 | date = April 2002 | pmid = 11990870 | doi = 10.1191/1352458502ms776oa | s2cid = 45994154 }} and inhibits hPAD2 in vitro though its methyl ester side chain.{{cite journal | vauthors = Musse AA, Polverini E, Raijmakers R, Harauz G | title = Kinetics of human peptidylarginine deiminase 2 (hPAD2)--reduction of Ca2+ dependence by phospholipids and assessment of proposed inhibition by paclitaxel side chains | journal = Biochemistry and Cell Biology | volume = 86 | issue = 5 | pages = 437–447 | date = October 2008 | pmid = 18923545 | doi = 10.1139/o08-124 }} Angiotech Pharmaceuticals Inc. began phase II clinical trials in 1999MS Society of Canada [http://mssociety.ca/en/research/PT991213.htm Phase II Clinical trial of Micellar Paclitaxel for secondary-progressive MS underway in Canada] {{webarchive|url=https://web.archive.org/web/20120315095242/http://mssociety.ca/en/research/PT991213.htm|date=15 March 2012 }} as a multiple sclerosis treatment but in 2002, reported that the results showed no statistical significance.MS Society of Canada [http://mssociety.ca/en/research/PT020227.htm Angiotech Halts Study of Micellar Paclitaxel stating no benefit of statistical significance seen] {{webarchive|url=https://web.archive.org/web/20120315095318/http://mssociety.ca/en/research/PT020227.htm|date=15 March 2012 }} [230] => [231] => In 2016 ''in vitro'' multi-drug resistant mouse tumor cells were treated with paclitaxel encased in [[Exosome (vesicle)|exosomes]]. Doses 98% less than common dosing had the same effect. Also, dye-marked exosomes were able to mark tumor cells, potentially aiding in diagnosis.{{cite web|title = Cloaking chemo drugs in cellular bubbles destroys cancer with one fiftieth of a regular dose|url = http://www.gizmag.com/drug-delivery-method-cancer-dose/41349|website = www.gizmag.com|access-date = 14 February 2016|date = 14 January 2016| vauthors = Lavars N |url-status = live|archive-url = https://web.archive.org/web/20160224221957/http://www.gizmag.com/drug-delivery-method-cancer-dose/41349/|archive-date = 24 February 2016}}{{cite journal | vauthors = Kim MS, Haney MJ, Zhao Y, Mahajan V, Deygen I, Klyachko NL, Inskoe E, Piroyan A, Sokolsky M, Okolie O, Hingtgen SD, Kabanov AV, Batrakova EV | title = Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells | journal = Nanomedicine | volume = 12 | issue = 3 | pages = 655–664 | date = April 2016 | pmid = 26586551 | pmc = 4809755 | doi = 10.1016/j.nano.2015.10.012 }} [232] => [233] => ==Additional images== [234] => [235] => Image:Taxol.jpg|[[Space-filling model]] of paclitaxel [236] => Image:Taxol.gif|Rotating paclitaxel molecule model [237] => Image:Paclitaxel JMolBiol 2001 1045.jpg|Crystal structure of paclitaxel [238] => Image:Taxol total charge surface.gif|Total charge surface of taxol. Minimum energy conformation. [239] => [240] => [241] => == References == [242] => {{Reflist}} [243] => [244] => == Further reading == [245] => {{refbegin}} [246] => * {{cite book|vauthors=Jordan G, Vivien W|title=The Story of Taxol: Nature and Politics in the Pursuit of an Anti-Cancer Drug|url=https://books.google.com/books?id=vHOOcw4buKoC|date=5 March 2001|publisher=Cambridge University Press|isbn=978-0-521-56123-5|access-date=2 June 2021|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114002052/https://books.google.com/books?id=vHOOcw4buKoC|url-status=live}} [247] => {{refend}} [248] => [249] => == External links == [250] => * {{cite web|title=Paclitaxel|website=National Cancer Institute|date=5 October 2006|url=https://www.cancer.gov/about-cancer/treatment/drugs/paclitaxel }} [251] => * {{cite web|title=Paclitaxel|website=NCI Drug Dictionary|date=2 February 2011|url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/paclitaxel }} [252] => * [http://www.bris.ac.uk/Depts/Chemistry/MOTM/taxol/taxol2.htm ''Molecule of the Month: TAXOL''] by Neil Edwards, [[University of Bristol]]. [253] => * [https://web.archive.org/web/20050606012941/http://www.research.fsu.edu/researchr/fall2002/taxol.html ''A Tale of Taxol''] from [[Florida State University]]. [254] => * {{cite news|url = https://www.nytimes.com/2006/10/01/business/yourmoney/01drug.html|title = Hope, at $4,200 a Dose| vauthors = Berenson A |date = 1 October 2006|access-date = 31 March 2007|newspaper = [[The New York Times]] }} [255] => [256] => {{Chemotherapeutic agents}} [257] => {{Transient receptor potential channel modulators}} [258] => {{Xenobiotic-sensing receptor modulators}} [259] => {{Portal bar | Medicine}} [260] => {{Authority control}} [261] => [262] => [[Category:Drugs developed by Bristol Myers Squibb]] [263] => [[Category:Microtubule inhibitors]] [264] => [[Category:Mitotic inhibitors]] [265] => [[Category:Benzoate esters]] [266] => [[Category:Carboxylate esters]] [267] => [[Category:Benzamides]] [268] => [[Category:Secondary alcohols]] [269] => [[Category:Tertiary alcohols]] [270] => [[Category:Ketones]] [271] => [[Category:Acetate esters]] [272] => [[Category:Taxanes]] [273] => [[Category:Pregnane X receptor agonists]] [274] => [[Category:World Health Organization essential medicines]] [275] => [[Category:Wikipedia medicine articles ready to translate]] [276] => [[Category:Plant toxins]] [] => )
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Paclitaxel

Paclitaxel is a chemotherapy medication that is used to treat various types of cancer. It is derived from the Pacific yew tree and belongs to a class of drugs called taxanes.

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It is derived from the Pacific yew tree and belongs to a class of drugs called taxanes. This medication works by interfering with the growth and division of cancer cells, ultimately leading to their death. Paclitaxel is primarily used to treat ovarian, breast, lung, and pancreatic cancers. It is administered intravenously and is often combined with other chemotherapy drugs to enhance its effectiveness. The dosage and frequency of paclitaxel treatment vary depending on the specific cancer being treated and the patient's overall health. Although paclitaxel has proven to be a valuable treatment option for many cancer patients, it does come with potential side effects. Common side effects include hair loss, nausea, vomiting, and fatigue. However, these side effects are generally temporary and manageable. The discovery and development of paclitaxel have been significant milestones in the field of cancer treatment. It has revolutionized the way certain cancers are managed, providing hope and improved outcomes for patients. Paclitaxel continues to be an important and widely used chemotherapy drug in the fight against cancer.

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