| Revision as of 14:02, 1 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEMBL').← Previous edit |
Latest revision as of 16:30, 9 December 2024 edit undoCitation bot (talk | contribs)Bots5,420,401 edits Added bibcode. | Use this bot. Report bugs. | Suggested by Dominic3203 | Linked from User:Marbletan/sandbox | #UCB_webform_linked 295/2664 |
| (565 intermediate revisions by more than 100 users not shown) |
| Line 1: |
Line 1: |
|
|
{{Short description|Medication used for cancer}} |
|
{{drugbox |
|
|
|
{{Use dmy dates|date=August 2024}} |
|
|
{{cs1 config |name-list-style=vanc |display-authors=6}} |
|
|
{{Infobox drug |
|
| Verifiedfields = changed |
|
| Verifiedfields = changed |
|
| verifiedrevid = 402171120 |
|
| verifiedrevid = 458461737 |
|
| IUPAC_name = (2α,4α,5β,7β,10β,13α)-4,10-bis(acetyloxy)-13-{oxy}- 1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate |
|
|
| image = Taxol.svg |
|
| image = Taxol.svg |
|
| width = 350 |
|
| width = 250 |
|
|
| alt = |
|
| image2 = Taxol(Paclitaxel)3D.png |
|
|
|
| caption = |
|
|
| image2 = Paclitaxel-from-hydrate-xtal-Mercury-3D-sk.png |
|
|
| alt2 = |
|
|
|
|
|
<!--Clinical data--> |
|
<!-- Clinical data --> |
|
|
| pronounce = |
|
| tradename = Abraxane, Taxol |
|
|
|
| tradename = Taxol, Abraxane, others |
|
| Drugs.com = {{drugs.com|monograph|paclitaxel}} |
|
| Drugs.com = {{drugs.com|monograph|paclitaxel}} |
|
| pregnancy_AU = |
|
| MedlinePlus = a607070 |
|
|
| DailyMedID = Paclitaxel |
|
| pregnancy_US = D |
|
|
| pregnancy_category = |
|
| pregnancy_AU = D |
|
|
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{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 }}</ref> |
|
| legal_status = Rx-=only |
|
|
|
| pregnancy_category = |
|
| routes_of_administration = ] |
|
|
|
| routes_of_administration = ] |
|
|
| class = |
|
|
| ATC_prefix = L01 |
|
|
| ATC_suffix = CD01 |
|
|
| ATC_supplemental = |
|
|
|
|
|
<!-- Legal status --> |
|
|
| legal_AU = S4 |
|
|
| legal_AU_comment = |
|
|
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
|
|
| legal_BR_comment = |
|
|
| legal_CA = Rx-only |
|
|
| legal_CA_comment = |
|
|
| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
|
|
| legal_DE_comment = |
|
|
| legal_NZ = <!-- Class A, B, C --> |
|
|
| legal_NZ_comment = |
|
|
| legal_UK = POM |
|
|
| legal_UK_comment = |
|
|
| legal_US = Rx-only |
|
|
| legal_US_comment = <ref name="Taxol FDA label">{{cite web | title=Taxol (paclitaxel) injection | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=54508 | access-date=28 July 2024}}</ref><ref name="Abraxane FDA label">{{cite web | title=Abraxane- paclitaxel injection, powder, lyophilized, for suspension | website=DailyMed | date=31 October 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d10449-2936-4cd3-b7db-a7683db721e4 | access-date=28 July 2024}}</ref> |
|
|
| legal_EU = Rx-only |
|
|
| legal_EU_comment = <ref>{{cite web | title=Abraxane EPAR | website=European Medicines Agency (EMA) | date=11 January 2008 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/abraxane | access-date=30 August 2024}}</ref><ref name="Naveruclif EPAR" /><ref name="Apexelsin EPAR" /><ref name="Naveruclif PI">{{cite web | title=Naveruclif PI | website=Union Register of medicinal products | date=8 January 2024 | url=https://ec.europa.eu/health/documents/community-register/html/h1778.htm | access-date=28 July 2024}}</ref><ref name="Apexelsin PI">{{cite web | title=Apexelsin PI | website=Union Register of medicinal products | date=26 July 2024 | url=https://ec.europa.eu/health/documents/community-register/html/h1835.htm | access-date=28 July 2024}}</ref> |
|
|
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
|
|
| legal_UN_comment = |
|
|
| legal_status = <!-- For countries not listed above --> |
|
|
|
|
|
<!--Pharmacokinetic data--> |
|
<!-- Pharmacokinetic data --> |
|
| bioavailability = 6.5% (oral)<ref name="bioavail">{{cite journal |journal=Pharmaceutical Research |volume=23 |issue=6 |month=June |year=2006 |doi=10.1007/s11095-006-0022-2 |pages=1243–50 |title=Enhanced Oral Paclitaxel Bioavailability After Administration of Paclitaxel-Loaded Lipid Nanocapsules |author=Sandra Peltier, S.; Oger, J.-M., Lagarce, F.; Couet, W.; Benoît, J.-P. |pmid=16715372 }}</ref> |
|
| bioavailability = 6.5% (by mouth)<ref name="bioavail">{{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 }}</ref> |
|
| protein_bound = 89 to 98% |
|
| protein_bound = 89 to 98% |
|
| metabolism = ] (] and ]) |
|
| metabolism = ] (] and ]) |
|
|
| metabolites = |
|
|
| onset = |
|
| elimination_half-life = 5.8 hours |
|
| elimination_half-life = 5.8 hours |
|
|
| duration_of_action = |
|
| excretion = Fecal and urinary |
|
| excretion = Fecal and urinary |
|
|
|
|
|
<!--Identifiers--> |
|
<!-- Identifiers --> |
|
| CAS_number_Ref = {{cascite|correct|??}} |
|
| CAS_number_Ref = {{cascite| correct| ??}} |
|
| CAS_number = 33069-62-4 |
|
| CAS_number = 33069-62-4 |
|
|
| CAS_supplemental = |
|
| ATC_prefix = L01 |
|
|
| ATC_suffix = CD01 |
|
|
| ATC_supplemental = <br>{{ATC|L01|CD03}} (paclitaxel poliglumex) |
|
|
| ChEBI_Ref = {{ebicite|changed|EBI}} |
|
|
| ChEBI = 45863 |
|
|
| PubChem = 36314 |
|
| PubChem = 36314 |
|
|
| IUPHAR_ligand = 2770 |
|
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
|
|
|
| DrugBank_Ref = {{drugbankcite| correct| drugbank}} |
|
| DrugBank = DB01229 |
|
| DrugBank = DB01229 |
|
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
|
| ChemSpiderID_Ref = {{chemspidercite| correct| chemspider}} |
|
| ChemSpiderID = 10368587 |
|
| ChemSpiderID = 10368587 |
|
| UNII_Ref = {{fdacite|changed|FDA}} |
|
| UNII_Ref = {{fdacite| correct| FDA}} |
|
| UNII = P88XT4IS4D |
|
| UNII = P88XT4IS4D |
|
| KEGG_Ref = {{keggcite|changed|kegg}} |
|
| KEGG_Ref = {{keggcite| correct| kegg}} |
|
| KEGG = D00491 |
|
| KEGG = D00491 |
|
| ChEMBL_Ref = {{ebicite|changed|EBI}} |
|
| ChEBI_Ref = {{ebicite| correct| EBI}} |
|
|
| ChEBI = 45863 |
|
| ChEMBL = <!-- blanked - oldvalue: 48 --> |
|
|
|
| ChEMBL_Ref = {{ebicite| changed| EBI}} |
|
| C=47 | H=51 | N=1 | O=14 |
|
|
|
| ChEMBL = 428647 |
|
| molecular_weight = 853.906 ]/] |
|
|
|
| NIAID_ChemDB = |
|
| smiles = CC1=C2(((34((OC4)C(3(C(=O)2OC(=O)C)C)O)OC(=O)C)OC(=O)c5ccccc5)(C1OC(=O)(O)(NC(=O)c6ccccc6)c7ccccc7)O)(C)C |
|
|
|
| PDB_ligand = TA1 |
|
| InChI = 1/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 |
|
|
|
| synonyms = PTX |
|
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
|
|
|
|
|
|
<!-- Chemical and physical data --> |
|
|
| IUPAC_name = (2α,4α,5β,7β,10β,13α)-4,10-Bis(acetyloxy)-13-{oxy}-1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate |
|
|
| C = 47| H = 51| N = 1| O = 14 |
|
|
| SMILES = CC1=C2(((34((OC4)C(3(C(=O)2OC(=O)C)C)O)OC(=O)C)OC(=O)c5ccccc5)(C1OC(=O)(O)(NC(=O)c6ccccc6)c7ccccc7)O)(C)C |
|
|
| StdInChI_Ref = {{stdinchicite| correct| chemspider}} |
|
| 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 |
|
| 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 |
|
|
| StdInChI_comment = |
|
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
|
|
|
| StdInChIKey_Ref = {{stdinchicite| correct| chemspider}} |
|
| StdInChIKey = RCINICONZNJXQF-MZXODVADSA-N |
|
| StdInChIKey = RCINICONZNJXQF-MZXODVADSA-N |
|
|
| density = |
|
|
| density_notes = |
|
|
| melting_point = |
|
|
| melting_high = |
|
|
| melting_notes = |
|
|
| boiling_point = |
|
|
| boiling_notes = |
|
|
| solubility = |
|
|
| sol_units = |
|
|
| specific_rotation = |
|
}} |
|
}} |
|
'''Paclitaxel''' is a ] used in ] ]. It was discovered in a U.S. ] program at the ] in 1967 when ] and ] isolated it from the bark of the ] tree, '']'' and named it '''taxol'''. When it was developed commercially by ] (BMS) the generic name was changed to '''paclitaxel''' and the BMS compound is sold under the ] '''TAXOL'''. In this formulation, paclitaxel is dissolved in ] and ], as a delivery agent. A newer formulation, in which paclitaxel is bound to ], is sold under the trademark ''']'''. |
|
|
|
|
|
|
|
'''Paclitaxel''', sold under the brand name '''Taxol''' among others, is a ] used to treat ], ], ], ], ], ], and ].<ref name=AHFS2015/> It is administered by ] injection.<ref name=AHFS2015/> There is also an ].<ref name=AHFS2015>{{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}}</ref> |
|
Paclitaxel is now used to treat patients with ], ], ], head and neck cancer, and advanced forms of ]. Paclitaxel is also used for the prevention of ]. |
|
|
|
|
|
|
|
<!-- Side effects and mechanism --> |
|
Paclitaxel stabilizes microtubules and as a result, interferes with the normal breakdown of ] during cell division. Together with ], it forms the drug category of the ]s. It was the subject of a notable ] by ]. |
|
|
|
Common side effects include ], ], ], ], ], and ].<ref name=AHFS2015/> Other side effects include heart problems, increased risk of infection, and ].<ref name=AHFS2015/> There are concerns that use during pregnancy may cause ].<ref>{{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 }}</ref><ref name=AHFS2015/> Paclitaxel is in the ] family of medications.<ref>{{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}}</ref> It works by interference with the normal function of ]s during ].<ref name=AHFS2015/> |
|
|
|
|
|
|
<!-- History and culture --> |
|
While offering substantial improvement in patient care, paclitaxel has been a relatively controversial drug. There was originally concern because of the environmental impact of its original sourcing, no longer used, from the Pacific yew. In addition, the assignment of rights, and even the name itself, to Bristol-Myers Squibb were the subject of public debate and Congressional hearings. |
|
|
|
Paclitaxel was isolated in 1971 from the ] and approved for medical use in 1993.<ref name=Fis2006>{{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}}</ref><ref name=NCI2016>{{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 }} </ref> It is on the ].<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> It has been made from precursors, and through ].<ref name=NCI2016/> |
|
|
|
|
|
|
==Medical use== |
|
== Nomenclature == |
|
|
|
Paclitaxel is approved in the UK for ovarian, breast, lung, ], ], ], esophageal, and other types of solid tumor cancers as well as ].<ref name=Saville>{{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 }}</ref> |
|
|
|
|
|
|
It is recommended in ] (NICE) guidance of June 2001 for ] 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 ], but that its first-line use should be limited to clinical trials. In September 2006, NICE recommended paclitaxel should ''not'' be used in the ] of early node-positive breast cancer.<ref>{{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}}</ref> |
|
The ] for paclitaxel is structured on a ] 17-carbon (]) skeleton. There are a total of 11 stereocenters. The active ] is (-)-paclitaxel (shown here). |
|
|
|
|
|
|
|
It is approved in the United States for the treatment of breast, pancreatic, ovarian, Kaposi's sarcoma and non-small-cell lung cancers.<ref name="Taxol FDA label" /> |
|
{|align="center" class="wikitable" |
|
|
|- |
|
|
|| |
|
|
] |
|
|
|- |
|
|
|| |
|
|
] |
|
|
|- |
|
|
|| |
|
|
<small>(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-Diacetoxy-15-{oxy}-1,9- dihydroxy-10,14,17,17-tetramethyl -11-oxo-6-oxatetracyclo heptadec-13-en-2-yl rel-benzoate</small> |
|
|
|- |
|
|
|} |
|
|
|
|
|
|
|
===Similar compounds=== |
|
==History== |
|
|
|
{{Further|Protein-bound paclitaxel|Docetaxel}} |
|
===The plant screening program, isolation, and preclinical trials=== |
|
|
|
Albumin-bound paclitaxel (brand name ], also called nab-paclitaxel) is an alternative formulation where paclitaxel is bound to ] nanoparticles. Much of the clinical toxicity of paclitaxel is associated with the solvent ] in which it is dissolved for delivery.<ref>{{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 }}</ref> |
|
In 1955, the ] (NCI) set up the ] (CCNSC) to act as a public screening center for anticancer activity in compounds submitted by external institutions and companies.<ref>{{cite book |
|
|
| last1 = Goodman |
|
|
| first1 = Jordan |
|
|
| last2 = Walsh |first2=Vivien |
|
|
| title = The Story of Taxol: Nature and Politics in the Pursuit of an Anti-Cancer Drug |
|
|
| publisher = Cambridge University Press |
|
|
| year = 2001 |
|
|
| isbn = 052156123X |page=17 |ref=harv}}</ref> Although the majority of compounds screened were of synthetic origin, one chemist, Jonathan Hartwell, who was employed there from 1958 onwards, had had experience with ] derived compounds, and began a plant screening operation.<ref>{{harvnb|Goodman|Walsh|2001|p=22}}</ref> After some years of informal arrangements, in July 1960, the NCI commissioned ] botanists to collect samples from about 1000 plant species per year.<ref>{{harvnb|Goodman|Walsh|2001|pp=25,28}}</ref> On 21 August 1962, one of those botanists, ], collected bark from a single Pacific yew tree, '']'', in a forest north of the town of ] as part of a four month trip to collect material from over 200 different species.<ref name="Goodman and Walsh, p51">{{harvnb|Goodman|Walsh|2001|p=51}}</ref> The material was then processed by a number of specialist CCNSC subcontractors, and one of the ''Taxus'' samples was found to be cytotoxic in a cellular assay on 22 May 1964.<ref name="Goodman and Walsh, p51"/> |
|
|
|
|
|
|
|
] developed Abraxane, in which paclitaxel is bonded to ] 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.<ref>{{cite web | title=Drug Approval Package: Abraxane (Pcalitaxel Protein-Bound Particles) NDA #021660 | website=U.S. ] (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21660_AbraxaneTOC.cfm | access-date=30 August 2024}}</ref> It has since been approved for locally advanced or metastatic non-small cell lung cancer and metastatic ] as well.<ref name="Abraxane FDA label" /> |
|
Accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by ] in ], ], began work on fresh ''Taxus'' samples, isolating the active ingredient in September 1966 and announcing their findings at an April 1967 ] meeting in Miami Beach.<ref>{{cite journal |author=Wall ME, Wani MC |title=Camptothecin and taxol: discovery to clinic—thirteenth Bruce F. Cain Memorial Award Lecture |journal=Cancer Res. |volume=55 |issue=4 |pages=753–60 |year=1995 |pmid=7850785 |doi=}}</ref> They named the pure compound taxol in June 1967.<ref name="Goodman and Walsh, p51"/> |
|
|
Wall and his colleague Wani published their results, including the chemical structure, in 1971.<ref>{{cite journal | author = Wani M, Taylor H, Wall M, Coggon P, McPhail A | title = Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from ''Taxus brevifolia'' | journal = J Am Chem Soc | volume = 93 | issue = 9 | pages = 2325–7 | year = 1971 | pmid = 5553076 | doi = 10.1021/ja00738a045}}</ref> |
|
|
|
|
|
|
|
]s, including paclitaxel, ], ], paclitaxel C, and 7-epipaclitaxel, have been found in the leaves and shells of ].<ref>{{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 }}</ref> 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.<ref name="pmid36227807">{{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 }}</ref> |
|
The NCI continued to commission work to collect more ''Taxus'' bark and to isolate increasing quantities of taxol. By 1969, 28 kg of crude extract had been isolated from almost 1,200 kg of bark, although this ultimately yielded only 10g of pure material,<ref>{{harvnb|Goodman|Walsh|2001|p=81}}</ref> 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.<ref>{{harvnb|Goodman|Walsh|2001|pp=79,81}}</ref> This required increasing quantities of purified taxol, up to 600g, and in 1977 a further request for 7,000 lbs of bark was made. |
|
|
|
|
|
|
|
===Restenosis=== |
|
In 1978, two NCI researchers published a report showing taxol was mildly effective in leukaemic mice.<ref> |
|
|
|
Paclitaxel is used as an antiproliferative agent for the prevention of ] (recurrent narrowing) of coronary and peripheral ]s; locally delivered to the wall of the ], a paclitaxel coating limits the growth of ] (scar tissue) within stents.<ref name=Heldman>{{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 }}</ref> Paclitaxel ]s for coronary artery placement are sold under the trade name Taxus by ] in the United States. Paclitaxel drug-eluting stents for femoropopliteal artery placement are also available.{{cn|date=September 2024}} |
|
{{cite journal | author = Fuchs, David A and Johnson, Randall K | title = Cytologic evidence that taxol, an antineoplastic agent from ''Taxus brevifolia'', acts as a mitotic spindle poison | journal = Cancer Treatment Reports | volume = 62 | pages = 1219–22 | year = 1978 | pmid = 688258 | issue = 8 }}</ref> |
|
|
In November 1978, taxol was shown to be effective in ] studies.<ref>{{harvnb|Goodman|Walsh|2001|p=95}}</ref> |
|
|
Meanwhile, taxol began to be well known in the cell biology, as well as the cancer community, with a publication in early 1979 by ], a molecular pharmacologist at ], showing taxol had a previously unknown mechanism of action involving the stabilization of ]. Together with formulation problems, this increased interest from researchers meant that by 1980, the NCI envisaged needing to collect 20,000 lbs of bark.<ref name="Goodman and Walsh p97">{{harvnb|Goodman|Walsh|2001|p=97}}</ref> |
|
|
Animal toxicology studies were complete by June 1982, and in November NCI applied for the ] necessary to begin clinical trials in humans.<ref name="Goodman and Walsh p97"/> |
|
|
|
|
|
|
|
==Side effects== |
|
===Early clinical trials, supply and the transfer to BMS=== |
|
|
|
Common side effects include nausea and vomiting, ], ], thinned or brittle hair, ] of the arms or legs lasting two to three days, changes in the color of the nails, and ] in the hands or toes.<ref name="mammaltoxic">{{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}}</ref> More serious side effects such as unusual bruising or bleeding, pain, redness or swelling at the injection site, ], change in normal bowel habits for more than two days, fever, chills, cough, ], ], dizziness, ], severe exhaustion, ], ], ] by ovarian damage, and ] can also occur.<ref name="mammaltoxic" /> <!-- MOVED PRIMARY SOURCE APPEARING WITH ONE A.E., SEE END OF SECTION. --> ] may also occur.<ref name=AHFS2015/> |
|
] clinical trials began in April 1984, and the decision to start ] trials was made a year later.<ref>{{harvnb|Goodman|Walsh|2001|p=115}}</ref> 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.<ref name="Goodman and Walsh p120"/> |
|
|
|
|
|
|
|
] is given prior to paclitaxel infusion to mitigate some of the side effects.<ref>{{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}}</ref><!-- THE ABOVE, OR ONLY THE EXCIPIENT-ASSOCIATED A.E.'S? NO SOURCE, NO REAL VALUE. --> |
|
The first public report from a phase II trial in May 1988 showed an effect in melanoma patients and a remarkable response rate of 30% in patients with refractory ovarian cancer.<ref> |
|
|
{{cite journal | author = Rowinsky, EK and others | title = Phase II study of taxol in advanced epithelial malignancies | journal = Proceedings of the Association of Clinical Oncology | volume = 7 | pages = 136 | year = 1988 }}</ref> |
|
|
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.<ref name="Goodman and Walsh p120"/> |
|
|
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 ] (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, <blockquote> |
|
|
was thinking, not of collaboration, ... but of a hand-over of taxol (and its problems) |
|
|
<ref name="Goodman and Walsh p120">{{harvnb|Goodman|Walsh|2001|p=120}}</ref> |
|
|
</blockquote> |
|
|
Although widely advertised, only four companies responded to the CRADA, including ] (BMS), |
|
|
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 ] in 2003, which concluded the NIH had failed to ensure value for money.<ref>{{cite web|url=http://wyden.senate.gov/leg_issues/reports/taxol.pdf|format=PDF|title=Technology Transfer: NIH-Private Sector Partnership in the Development of Taxol}}</ref> In related CRADAs with the ] and ], Bristol-Myers Squibb was given exclusive first refusal on all Federal supplies of ''Taxus brevifolia''. |
|
|
This exclusive contract lead to some criticism for giving BMS a "cancer ]".<ref name="monopoly">Nader, Ralph; Love, James. "." ''].'' February, 1993. Retrieved on March 9, 2007.</ref> |
|
|
Eighteen months after the CRADA, BMS filed a ] (NDA), which was given FDA approval at the very end of 1992. |
|
|
<ref name="Goodman and Walsh p120"/> |
|
|
Although there was no patent on the compound, the provisions of the ] gave Bristol-Myers Squibb five years exclusive marketing rights. |
|
|
|
|
|
|
|
A number of these side effects are associated with the ] used, Cremophor EL, a polyoxyethylated ]. Allergies to ], ], and other drugs delivered in polyoxyethylated castor oil may increase the risk of adverse reactions to paclitaxel.<ref name="medline">"{{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 }}</ref> |
|
In 1990, BMS applied to trademark the name taxol as '''TAXOL'''. This was controversially approved in 1992. At the same time, paclitaxel replaced taxol as the generic name of the compound. Critics, including the journal '']'', 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.<ref>{{cite journal |author= |title=Names for hi-jacking |journal=Nature |volume=373 |issue=6513 |pages=370 |year=1995 |pmid=7830775 |doi=10.1038/373370a0}}</ref> 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.<ref>{{harvnb|Goodman|Walsh|2001|p=170}}</ref> |
|
|
BMS has also been criticized for misrepresentation by Goodman and Walsh, who quote from a company report saying |
|
|
<blockquote> |
|
|
It was not until 1971 that ... testing ... enabled the isolation of paclitaxel, initially described as 'compound 17'<ref>Bristol-Myers Squibb, The development of TAXOL (paclitaxel), March 1997, as cited in {{harvnb|Goodman|Walsh|2001|p=2}}</ref> |
|
|
</blockquote> |
|
|
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. |
|
|
|
|
|
|
|
==Mechanism of action== |
|
Annual sales peaked in 2000, reaching ]1.6 billion; paclitaxel is now available in generic form. |
|
|
|
] |
|
|
Paclitaxel is one of several ] that target ]. Paclitaxel-treated cells have defects in ] assembly, ], and ]. Unlike other tubulin-targeting drugs, such as ], that inhibit ] assembly, paclitaxel stabilizes the microtubule polymer and protects it from disassembly. Chromosomes are thus unable to achieve a ] spindle configuration. This blocks the progression of ] and prolonged activation of the ] triggers ] or reversion to the ] of the cell cycle without cell division.<ref>{{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 = }}</ref><ref>{{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 }}</ref> |
|
|
|
|
|
|
The ability of paclitaxel to inhibit spindle function is generally attributed to its suppression of microtubule dynamics,<ref>{{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 }}</ref> 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 ]s, a process normally activated during mitosis.<ref>{{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 }}</ref> Paclitaxel binds to the beta-tubulin subunits of microtubules.<ref>{{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 }}</ref> |
|
|
|
|
|
== Chemistry == |
|
|
|
|
|
The ] for paclitaxel is structured on a ] 17-atom skeleton. There are a total of 11 stereocenters. The active ] is (−)-paclitaxel (shown here). |
|
|
<div class="skin-invert-image"> |
|
|
{{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-{{(}}oxy}-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracycloheptadec-13-en-2-yl rel-benzoate |
|
|
}} |
|
|
</div> |
|
==Production== |
|
==Production== |
|
|
] |
|
{{see also|Paclitaxel total synthesis}} |
|
|
] |
|
|
] |
|
|
|
|
|
|
|
=== Bark processing === |
|
From 1967 to 1993, almost all paclitaxel produced was derived from bark from the Pacific yew, the harvesting of which kills the tree in the process. The processes used were descendants of the original isolation method of Wall and Wani; by 1987, the NCI had contracted ] of Boulder, Colorado, to handle bark on the scale needed for Phase II and III trials. While there was considerable uncertainty about how large the wild population of ''Taxus brevifola'' was and what the eventual demand for taxol would be, it had been clear for many years that an alternative, sustainable source of supply would be needed. Initial attempts used needles from the tree, or material from other related ''Taxus'' species, including cultivated ones, but these attempts were bedevilled by the relatively low and often highly variable yields obtained. It was not until the early 1990s, at a time of increased sensitivity to the ecology of the forests of the ], that taxol was successfully extracted on a clinically useful scale from these sources.<ref>{{harvnb|Goodman|Walsh|2001|p=172–5}}</ref> |
|
|
|
] |
|
|
|
|
|
|
From 1967 to 1993, almost all paclitaxel produced was derived from bark of the Pacific yew, '']'', the harvesting of which kills the tree in the process.<ref name="Gersmann 2011">{{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}}</ref> The processes used were descendants of the original isolation method of ] and ]; by 1987, the U.S. ] (NCI) had contracted Hauser Chemical Research of ], to handle bark on the scale needed for ] 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 ] would be needed. Initial attempts to broaden its sourcing used needles from the tree, or material from other related '']'' 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 ], paclitaxel was extracted on a clinically useful scale from these sources.{{sfn|Goodman|Walsh|2001|pp=172–5}} |
|
From the late 1970s, chemists in the US and France had been interested in taxol. A number of US groups, including one led by ], attempted a ], starting from ]-derived starting materials. This work was primarily motivated as a way of generating chemical knowledge, rather than with any expectation of developing a practical production technique. By contrast, the French group of ] at the ] quickly recognized the problem of yield. His laboratory was on a campus populated by the related yew ''Taxus baccata'', so needles were available locally in large quantity. By 1981, he had shown that it was feasible to isolate relatively large quantities of the compound ], a plausible first step for a semisynthetic production route to taxol. By 1988 he copublished such a semisynthetic route from needles of ''T. baccata''.<ref>{{harvnb|Goodman|Walsh|2001|pp=100–1}}</ref> |
|
|
The view of the NCI, however, was even this route was not practical.<ref name="Stephenson_2003">{{cite journal|title=A tale of taxol|author=Stephenson, Frank|journal=Florida State University Research in Review|volume=12|issue=3|date=Fall|year=2003|url=http://www.rinr.fsu.edu/fall2002/taxol.html}}</ref> |
|
|
|
|
|
|
|
=== Semisynthesis === |
|
By 1988, and particularly with Potier's publication, it was clear to Holton as well a practical semisynthetic production route would be important. By late 1989, Holton's group had developed a semisynthetic route to paclitaxel with twice the yield of the Potier process. ], where Holton worked, signed a deal with ] to license this and future patents. In 1992, Holton patented an improved process with an 80% yield. BMS took the process in-house and started to manufacture paclitaxel in Ireland from 10-deacetylbaccatin isolated from the needles of the European yew.<ref name="Stephenson_2003"/> In early 1993, BMS was able to announce that it would cease reliance on Pacific yew bark by the end of 1995, effectively terminating the ecological controversy over its use. This announcement also made good their commitment to develop an alternative supply route, made to the NCI in their CRADA application of 1989. |
|
|
|
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 ] 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 ] at the ] (CNRS) addressed the matter of overall process yield, showing that it was feasible to isolate relatively large quantities of the compound ] from the European yew, '']'', 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 ] 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}} |
|
|
|
|
|
|
The view of the NCI, however, was that even this route was not practical.{{citation needed|date=June 2014}} The group of ] 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.<ref>{{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 }}</ref> The main innovation was "Ojima−Holton coupling", a ring-opening method independently discovered by Holton and Ojima.<ref name=Ojima2018>{{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 }}</ref> ], where Holton worked, signed a deal with ] (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 ] (CRADA) application of 1989.{{cn|date=September 2024}} |
|
Currently, all paclitaxel production for BMS uses plant cell fermentation (PCF) technology developed by the biotechnology company ] and carried out at their plant in Germany.<ref>{{cite web|title=Phyton news release|url=http://www.phytonbiotech.com/news_031215.htm}}</ref> This starts from a specific ''Taxus'' cell line propagated in aqueous medium in large fermentation tanks. Paclitaxel is then extracted directly, purified by chromatography and isolated by crystallization. Compared to the semisynthesis, PCF eliminates the need for many hazardous chemicals and saves a considerable amount of energy.<ref name="2004_EPA_award">{{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}}</ref> |
|
|
|
|
|
|
|
As of 2013, BMS was using the semisynthetic method utilizing needles from the European yew to produce paclitaxel.<ref>{{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}}</ref> Another company which worked with BMS until 2012,<ref>{{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}}</ref> Phyton Biotech, Inc., uses plant cell fermentation (PCF) technology.<ref>{{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}}</ref> By cultivating a specific ''Taxus'' ] in fermentation tanks, they no longer need ongoing sourcing of material from actual yew tree plantations.<ref>{{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 }}</ref> 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 ] step followed by ].<ref>Gilbert Gorr and Roland Franke. Commercial Pharmaceutical Production of Complex APIs via Plant Cell Fermentation (PCF) Technology. Presentation at CPhI 2015, 13 Oct..</ref> Compared to the semisynthesis method, PCF eliminates the need for many hazardous chemicals and saves a considerable amount of energy.<ref name="2004_EPA_award">{{cite web|url=https://www.epa.gov/greenchemistry/presidential-green-chemistry-challenge-2004-greener-synthetic-pathways-award|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}}</ref> |
|
In 1993, taxol was coincidentally discovered to be produced in a newly described ] living in the yew tree.<ref>{{cite journal | author = Stierle A. | authorlink2 = Gary Strobel, Strobel Gary ''et al.'' | year = 1993 | title = Taxol and Taxane Production by ''Taxomyces-Andreanae'', an Endophytic Fungus of Pacific Yew | url = | journal = Science | volume = 260 | issue = 5105| pages = 214–6 | doi = 10.1126/science.8097061 | pmid = 8097061 | last2 = Strobel | first2 = G | last3 = Stierle | first3 = D }}</ref> It has since been found in a number of other ] fungi, including ''Nodulisporium sylviforme'',<ref name="ZhaoK">{{cite journal | author = Zhao K. ''et al.'' | year = 2004 | title = Study on the Preparation and Regeneration of Protoplast from Taxol-producing Fungus ''Nodulisporium sylviforme' | url = http://www.sciencepub.org/nature/0202/09zhao.pdf | format = PDF | journal = Nature and Science | volume = 2 | issue = 2| pages = 52–9 }}</ref> ''Alternaria taxi'', ''Cladosporium cladosporioides MD2'', ''Metarhizium anisopliae'', ''Aspergillus candidus MD3'', ''Mucor rouxianus sp.'', ''Chaetomella raphigera'', ''Phyllosticta tabernaemontanae'', ''Phomopsis'', ''Pestalotiopsis pauciseta'', ''Phyllosticta citricarpa'', ''Podocarpus'',''Fusarium solani'', ''Pestalotiopsis terminaliae'', ''Pestalotiopsis breviseta'', ''Botryodiplodia theobromae Pat.'', ''Gliocladium sp.'', ''Alternaria alternata var. monosporus'', ''Cladosporium cladosporioides'', ''Nigrospora sp.'', ''Pestalotiopsis versicolor'', and ''Taxomyces andreanae'', opening the possibility of taxol production by culturing one of these fungal species. |
|
|
|
|
|
|
|
In 1993, paclitaxel was discovered as a natural product in ''Taxomyces andreanae'', a newly described ] ] living in the yew tree.<ref>{{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 }}</ref> 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, '']'', ''Aspergillus candidus'' MD3, ''Mucor rouxianus'', ''Chaetomella raphigera'', ''Phyllosticta tabernaemontanae'', '']'', ''Pestalotiopsis pauciseta'', '']'', '']'' sp., '']'', ''Pestalotiopsis terminaliae'', ''Pestalotiopsis breviseta'', ''Botryodiplodia theobromae'', ''Gliocladium'' sp., ''Alternaria alternata'' var. ''monosporus'', '']'', ''Nigrospora'' sp. and '']''. However, there has been contradictory evidence for its production by endophytes, with other studies finding independent production is unlikely.<ref>{{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 }}</ref><ref>{{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 }}</ref> |
|
The initial motivation for synthetic approaches to paclitaxel included the opportunity to create closely related compounds. Indeed, this approach led to the development of ]. |
|
|
|
|
|
|
|
===Biosynthesis=== |
|
==Prevalence in Hazelnuts== |
|
|
|
] |
|
|
Taxol is a tetracyclic ], 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 (]).<ref name=":2">{{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 }}</ref> The biosynthesis of Taxol contains nineteen steps.<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref> The biosynthesis of Taxol is illustrated in more detail in the figure, with steps 1-7 all occurring in the enzyme ] (TS on the figure). Taxol's biosynthesis begins with E,E,E-GGPP losing pyrophosphate via an ] 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 ], 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.<ref name=":2" /> This finally yields the product taxol. |
|
|
|
|
|
|
===Total synthesis=== |
|
Recently a group of Italian researchers in the Department of Translational Oncology, National Institute for Cancer Research, IST, Genova with the collaboration of the ], Italy, has confirmed the presence of ]s in the shells and leaves of hazel plants, including ], 10-deacetylbaccatin III, baccatin III, paclitaxel C, and 7-epipaclitaxel. 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 (]).<ref>{{cite journal |doi=10.1021/np0704046 |year=2008 |month=Jan |author=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 |volume=71 |issue=1 |pages=58–60 |issn=0163-3864 |pmid=18163585 |journal=Journal of natural products}}</ref> |
|
|
|
{{Main|Paclitaxel total synthesis}} |
|
|
|
|
|
|
] |
|
==Mechanism of action== |
|
|
|
By 1992, at least thirty academic research teams globally were working to achieve a ] of this ], with the synthesis proceeding from simple natural products and other readily available starting materials.<ref name=Hall2003>{{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 }}</ref> 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 ], who had the ], and of ] who had the ] (by a week, on 7 February 1994). Though the Holton submission preceded the Nicolaou by a month (21 December 1993 versus 24 January 1994),<ref>See N. Hall, ibid. See also the ] publication ] (C&EN), 21 February 1994, page 32, and primary citations appearing at Holton and Nicolaou taxol total synthesis articles.</ref> 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"<ref name=Flam1994>{{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 }}</ref> or a "photo finish",<ref name=Hall2003/> though each group has argued that their synthetic strategy and tactics were superior.<ref name=Flam1994/> |
|
Paclitaxel-treated cells have defects in mitotic spindle assembly, chromosome segregation, and cell division. Unlike other tubulin-targeting drugs such as ] that inhibit microtubule assembly, paclitaxel stabilizes the ] polymer and protects it from disassembly. Chromosomes are thus unable to achieve a metaphase spindle configuration. This blocks progression of mitosis, and prolonged activation of the mitotic checkpoint triggers apoptosis or reversion to the G-phase of the cell cycle without cell division,.<ref>{{cite journal | author = Bharadwaj R., Yu H. | year = 2004 | title = The spindle checkpoint, aneuploidy, and cancer | url = | journal = Oncogene | volume = 23 | issue = 11| pages = 2016–27 | doi = 10.1038/sj.onc.1207374 | pmid = 15021889 }}</ref><ref>{{cite journal | author = Brito D. A., Yang Z., Rieder C. L. | year = 2008 | title = Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied | url = | journal = J. Cell Biol. | volume = 182 | issue = 4| pages = 623–9 | doi = 10.1083/jcb.200805072 | pmid = 18710927 | pmc = 2518701 }}</ref> |
|
|
|
|
|
|
|
As of 2006, five additional research groups had reported total syntheses of paclitaxel: ] in 1997, and ] and ] in 1998 with further ], and ] in 1996 and ] in 2006 with further ].{{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-].<ref name=Hall2003/> |
|
The ability of paclitaxel to inhibit spindle function is generally attributed to its suppression of microtubule dynamics,<ref>Jordan MA, Leslie W, Microtubules as a target for anticancer drugs'' Apr 4, 2004”, ""</ref> but recent 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 centrosomes, a process normally activated during mitosis.<ref>Ganguly A, Yang H, Cabral F, Paclitaxel-dependent cell lines reveal a novel drug activity.Mol Cancer Ther. 2010 Nov;9(11):2914-23. Epub 2010 Oct 26., "",</ref> The binding site for paclitaxel has been identified on the beta-tubulin subunit.<ref>{{cite journal | author = Lowe J, Li H, Downing KH, Nogales E | year = 2001 | title = Refined structure of αβ-tubulin at 3.5 Å resolution | url = | journal = Journal of Molecular Biology | volume = 313 | issue = 5| pages = 1045–57 | doi = 10.1006/jmbi.2001.5077 | pmid = 11700061 }}</ref> |
|
|
|
|
|
|
|
While the "political climate surrounding and in the early 1990s ... helped bolster link between total synthesis and the supply problem," and though total synthesis activities were a requisite to explore the ]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}} |
|
==Clinical use== |
|
|
|
|
|
|
|
==History== |
|
Paclitaxel is approved in the UK for ovarian, breast and lung cancers and ].<ref name=Saville>{{cite journal | author = Saville M, Lietzau J, Pluda J, Feuerstein I, Odom J, Wilson W, Humphrey R, Feigal E, Steinberg S, Broder S | title = Treatment of HIV-associated Kaposi's sarcoma with paclitaxel | journal = Lancet | volume = 346 | issue = 8966 | pages = 26–8 | year = 1995 | month=July 1 | pmid=7603142 | doi = 10.1016/S0140-6736(95)92654-2}}</ref> |
|
|
|
The discovery of paclitaxel began in 1962 as a result of a NCI-funded screening program.<ref name=NCI2016/> A number of years later it was isolated from the bark of the Pacific yew, ''Taxus brevifolia'', hence its name "taxol".<ref name=NCI2016/> |
|
It is recommended in ] guidance of June 2001 that it should be used for nonsmall 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 should be available for the treatment of advanced breast cancer after the failure of 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.<ref>{{cite web|url=http://www.bnf.org/bnf/bnf/current/21850.htm|title=British National Formulary}}</ref> |
|
|
|
|
|
|
|
The discovery was made by ] and ] at the ], ], North Carolina, in 1971.<ref>{{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 }}</ref> 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.<ref>{{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}}</ref> The compound was then developed commercially by BMS, who had the generic name assigned as "paclitaxel".{{citation needed|date=June 2014}} |
|
The cost to the NHS per patient in early breast cancer, assuming four cycles of treatment, is about £4000 (approx. $6000).<ref>{{cite web|title=NICE Guidance TA108|url=http://guidance.nice.org.uk/TA108/guidance/pdf/English}}</ref> |
|
|
|
|
|
|
===Similar compounds=== |
|
===Plant screening program=== |
|
|
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 ] (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 ], 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 ] in a cellular assay on 22 May 1964.{{sfn|Goodman|Walsh|2001|p=51}} |
|
The closely related taxane ] has a similar set of clinical uses to paclitaxel. It is marketed under the name of Taxotere. |
|
|
|
|
|
|
|
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 ] meeting in ].<ref>{{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 }}</ref> 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.<ref>{{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 | bibcode = 1971JAChS..93.2325W }}</ref> |
|
Much of the clinical toxicity of paclitaxel is associated with the solvent ] in which it is dissolved for delivery.{{Citation needed|date=October 2010}} |
|
|
] developed ], in which paclitaxel is bonded to ] as an alternative delivery agent as an alternative to the often toxic solvent delivery method. This was approved by the ] 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.<ref name="Abraxane">"." ''].'' January 7, 2005. Retrieved on March 9, 2007.</ref> |
|
|
|
|
|
|
|
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 '']'' 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. |
|
===Restenosis=== |
|
|
Paclitaxel is used as an ] for the prevention of ] (recurrent narrowing) of coronary ]s; locally delivered to the wall of the ], a paclitaxel coating limits the growth of ] (scar tissue) within stents.<ref name=Heldman>{{cite journal | author = Heldman A, Cheng L, Jenkins G, Heller P, Kim D, Ware M, Nater C, Hruban R, Rezai B, Abella B, Bunge K, Kinsella J, Sollott S, Lakatta E, Brinker J, Hunter W, Froehlich J | title = Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis | journal = Circulation | volume = 103 | issue = 18 | pages = 2289–95 | year = 2001 | pmid=11342479}}</ref> Paclitaxel ] are sold under the trade name Taxus by ] in the United States. |
|
|
|
|
|
|
|
In 1978, two NCI researchers published a report showing that taxol was mildly effective in leukaemic mice.<ref> |
|
===Side effects=== |
|
|
|
{{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 }}</ref> In November 1978, taxol was shown to be effective in ] studies.{{sfn|Goodman|Walsh|2001|p=95}} Meanwhile, taxol began to be well known in the cell biology, as well as the cancer communities, with a publication in early 1979 by ], a molecular pharmacologist at ], showing that 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.<ref name="Goodman and Walsh p97">{{harvnb|Goodman|Walsh|2001|p=97}}</ref> Animal toxicology studies were completed by June 1982, and in November, the NCI applied for the ] necessary to begin clinical trials in humans.<ref name="Goodman and Walsh p97"/> |
|
|
|
|
|
|
===Early clinical trials, supply and the transfer to BMS=== |
|
Common side effects include nausea and vomiting, loss of appetite, change in taste, thinned or brittle hair, pain in the joints of the arms or legs lasting two to three days, changes in the color of the nails, and tingling in the hands or toes. More serious side effects such as unusual bruising or bleeding, pain/redness/swelling at the injection site, change in normal bowel habits for more than two days, fever, chills, cough, sore throat, difficulty swallowing, dizziness, shortness of breath, severe exhaustion, skin rash, facial flushing, ] by ovarian damage<ref name=Ozcelik>{{cite journal |author=Ozcelik B, Turkyilmaz C, Ozgun MT, ''et al.'' |title=Prevention of paclitaxel and cisplatin induced ovarian damage in rats by a gonadotropin-releasing hormone agonist |journal=Fertil. Steril. |volume=93 |issue=5 |pages=1609–14 |year=2010 |month=March |pmid=19339002 |doi=10.1016/j.fertnstert.2009.02.054 |url=}}</ref> and chest pain can also occur. A number of these side effects are associated with the ] used, Cremophor EL, a polyoxyethylated ]. Allergies to drugs such as cyclosporine, teniposide and drugs containing polyoxyethylated castor oil may indicate increased risk of adverse reactions to paclitaxel.<ref name="medline">"." ''].'' Last Reviewed 09/01/2008. Accessed 10-2-21.</ref> ] is given prior to beginning paclitaxel treatment to mitigate some of the side effects. ], a ] may prevent ovarian damage, according to mice studies.<ref name=Ozcelik/> |
|
|
|
] clinical trials began in April 1984, and the decision to start ] 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.<ref name="Goodman and Walsh p120"/> |
|
|
|
|
|
|
The first public report from a phase II trial in May 1988 showed promising effects in melanoma and refractory ovarian cancer.<ref>{{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 }}</ref> 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.<ref name="Goodman and Walsh p120"/> |
|
===Derivatives of paclitaxel=== |
|
|
|
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 ] (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)".<ref name="Goodman and Walsh p120">{{harvnb|Goodman|Walsh|2001|p=120}}</ref> |
|
|
|
|
|
|
Although the offer was widely advertised, only four companies responded to the CRADA, including the American firm ] (BMS), |
|
In recent years, extensive research has been done to find a way to mitigate the side effects of paclitaxel, by altering its administration. DHA-paclitaxel, PG-paclitaxel, and tumor-activated Taxol prodrugs are undergoing continued testing, and are actually on the way to being introduced into widespread clinical use. |
|
|
|
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 ] in 2003, which concluded the NIH had failed to ensure value for money.<ref>{{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}}</ref> In related CRADAs with the ] and ], Bristol-Myers Squibb was given exclusive first refusal on all Federal supplies of ''Taxus brevifolia''. |
|
|
This exclusive contract lead to some criticism for giving BMS a "cancer ]".<ref name="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 = ]|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 }}</ref> |
|
|
Eighteen months after the CRADA, BMS filed a ] (NDA), which was given FDA approval at the very end of 1992. |
|
|
<ref name="Goodman and Walsh p120"/> |
|
|
Although there was no patent on the compound, the provisions of the ] gave Bristol-Myers Squibb five years exclusive marketing rights. |
|
|
|
|
|
|
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 (]) name of the compound. Critics, including the journal '']'', 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.<ref>{{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 }}</ref> 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}} |
|
Protarga has linked paclitaxel to ] (DHA), a fatty acid easily taken up by tumor cells; the ] “appears not to be cytotoxic until the bond with DHA is cleaved within the cell.”<ref name="Whelan 2002, Pages 90">Whelan, Jo. ''Drug Discovery Today'', Volume 7, Issue 2, 15 January 2002, Pages 90–92.</ref> The advantage of DHA-paclitaxel over paclitaxel is DHA-paclitaxel’s ability to carry much higher concentrations of paclitaxel to the cells, which are maintained for longer periods in the tumor cells, thus increasing their action. With increased activity, DHA-paclitaxel, also known as Taxoprexin, may have a more successful response in cancer patients than paclitaxel, and it may be able to treat more types of cancer than paclitaxel has been able to treat. |
|
|
|
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".<ref>Bristol-Myers Squibb, The development of TAXOL (paclitaxel), March 1997, as cited in {{harvnb|Goodman|Walsh|2001|p=2}}</ref> 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 ]1.6 billion; paclitaxel is now available in generic form.{{cn|date=September 2024}} |
|
|
|
|
|
|
== Society and culture == |
|
Cell Therapeutics has formulated PG-paclitaxel, which is paclitaxel bonded to a polyglutamate polymer; tumor cells are significantly more porous to polyglutamate polymers than normal cells, due to the leaky endothelial membranes of tumor cells. PG-paclitaxel has been introduced into clinical use, and has proven to initiate very mild side effects and to effectively treat many patients who were not responsive to the action of Taxol. The PG-paclitaxel may be a very promising anticancer drug, as it is much more selective than paclitaxel for which cells it targets.<ref name="Whelan 2002, Pages 90"/> |
|
|
|
|
|
|
|
=== Legal status === |
|
ImmunoGen has been introducing tumor-activated prodrug (TAP) technology in recent years, and is now working to apply this technology to paclitaxel. Tumor-activated Taxol prodrugs are designed for accurate targeting, by the action of a monoclonal antibody which is very specific to certain cells. Tumor-activated Taxol prodrugs research is progressing, and in mice, the “taxane-based TAP completely eradicated human tumour xenografts at non-toxic doses.”<ref name="Whelan 2002, Pages 90"/> |
|
|
|
Paclitaxel was approved for medical use in the European Union in 2008.<ref name="Naveruclif EPAR" /> |
|
|
|
|
|
|
In November 2023, the ] (CHMP) of the ] 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.<ref name="Naveruclif EPAR" /> The applicant for this medicinal product is Accord Healthcare S.L.U.<ref name="Naveruclif EPAR">{{cite web | title=Naveruclif EPAR | website=] (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.</ref> Naveruclif was approved for medical use in the European Union in January 2024.<ref name="Naveruclif EPAR" /><ref name="Naveruclif PI" /> |
|
] is made up of one molecule of a peptide called angiopep-2 joined with three molecules of paclitaxel. It is in phase I clinical trials for some types of cancer. |
|
|
|
|
|
|
|
In May 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Apexelsin, intended for the treatment of metastatic breast cancer, metastatic adenocarcinoma of the pancreas and non-small cell lung cancer.<ref name="Apexelsin EPAR" /> The applicant for this medicinal product is WhiteOak Pharmaceutical B.V.<ref name="Apexelsin EPAR">{{cite web | title=Apexelsin EPAR | website=European Medicines Agency | date=30 May 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/apexelsin | access-date=31 May 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Apexelsin was approved for medical use in the European Union in July 2024.<ref name="Apexelsin EPAR" /><ref name="Apexelsin PI" /> |
|
==Research use== |
|
|
Aside from its direct clinical use, paclitaxel is used extensively in biological and biomedical research as a ] stabilizer. ] assays involving microtubules, such as ]s, generally 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 ], or for studies of mutant motor proteins. Paclitaxel is sometimes used for ] studies as well; it can be fed to test organisms, such as ], 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<ref>Moscarello MA, Mak B, Nguyen TA, Wood DD, Mastronardi F, Ludwin SK. </ref> and inhibits hPAD2 in vitro though its methyl ester side chain did not<ref>Musse AA, Polverini E, Raijmakers R, Harauz G.Musse AA, Polverini E, Raijmakers R, Harauz G. </ref>. Angiotech Pharmaceuticals Inc. began phase II clinical trials in 1999<ref>MS Society of Canada </ref> as a multiple sclerosis treatment but in 2002, reported that the results showed no statistical significance.<ref>MS Society of Canada </ref> |
|
|
|
|
|
|
|
=== Economics === |
|
==Biosynthesis and Biocatalysis== |
|
|
|
{{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).<ref>{{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}}</ref> |
|
The core synthetic route is via an ] pathway, parts of which have been successfully transplanted into production strains of E.coli <ref>{{cite journal | journal=J Ind Microbiol Biotechnol. |date=2011 Apr 13 | title=Simultaneous production and partitioning of heterologous polyketide and isoprenoid natural products in an ''Escherichia coli'' two-phase bioprocess | author=Boghigian BA, Myint M, Wu J, Pfeifer BA |pmid=21487833 | doi=10.1007/s10295-011-0969-9}}</ref> and yeast<ref>{{cite journal|author=Engels B, Dahm P, Jennewein S |date=2008| title= Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol(Paclitaxel) production | journal= Metab Eng |volume=10| pages=201–6|doi=10.1016/j.ymben.2008.03.001|pmid=18485776|issue=3–4}}</ref> |
|
|
|
|
|
|
==Research== |
|
|
] has been speculated to inhibit paclitaxel-induced ] in colorectal cancer cells.<ref name="pmid = 24173825">{{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 }}</ref> |
|
|
|
|
|
In 2016, ''in vitro'' multi-drug resistant mouse tumor cells were treated with paclitaxel encased in ]. Doses 98% less than common dosing had the same effect. Also, dye-marked exosomes were able to mark tumor cells, potentially aiding in diagnosis.<ref>{{cite web |date=14 January 2016 |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 |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 |access-date=14 February 2016 |website=www.gizmag.com |vauthors=Lavars N}}</ref><ref>{{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 |date=April 2016 |title=Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells |journal=Nanomedicine |volume=12 |issue=3 |pages=655–664 |doi=10.1016/j.nano.2015.10.012 |pmc=4809755 |pmid=26586551}}</ref> |
|
|
|
|
|
Aside from its direct clinical use, paclitaxel is also used extensively in biological and biomedical research as a ] stabilizer. In general, '']'' ]s 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 ], or for studies of mutant motor proteins. |
|
|
|
|
|
Paclitaxel has also been used ''in vitro'' to inhibit ] fibrillation. In a ] of 10:1 (insulin:paclitaxel), it hindered insulin fibrillation near 70%. ] (ITC) findings indicated a spontaneous tendency of paclitaxel to interact with insulin through ]s and ]s.<ref>{{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 }}</ref> The inhibitory role of paclitaxel is attributed to its impact on the colloidal stability of protein solution, as it was observed that paclitaxel inhibited ] fibrillation by inducing the formation of "off-pathway" ]ic intermediates, subsequently increasing the colloidal stability.<ref>{{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 }}</ref> |
|
|
|
|
|
Paclitaxel is sometimes used for '']'' studies as well. It can be fed to test organisms, such as ], or injected into individual cells, to inhibit microtubule disassembly or to increase the number of microtubules in the cell. Paclitaxel induces ] in a ] mouse ''in vivo''<ref>{{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 }}</ref> and inhibits human ] (hPAD2) ''in vitro'' though its methyl ] side chain.<ref>{{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 }}</ref> In 1999, Angiotech Pharmaceuticals Inc. began ] of micellar paclitaxel as treatment for ],<ref>{{Cite web |date=13 December 1999 |title=Phase II Clinical trial of Micellar Paclitaxel for secondary-progressive MS underway in Canada |url=http://mssociety.ca/en/research/PT991213.htm |url-status=dead |archive-url=https://web.archive.org/web/20120315095242/http://mssociety.ca/en/research/PT991213.htm |archive-date=15 March 2012 |website=]}}</ref> but reported in 2002 that the results showed no statistical significance.<ref>{{Cite web |date=27 February 2002 |title=Angiotech Halts Study of Micellar Paclitaxel stating no benefit of statistical significance seen |url=http://mssociety.ca/en/research/PT020227.htm |url-status=dead |archive-url=https://web.archive.org/web/20120315095318/http://mssociety.ca/en/research/PT020227.htm |archive-date=15 March 2012 |website=]}}</ref> |
|
|
|
|
|
==Additional images== |
|
==Additional images== |
|
<gallery> |
|
<gallery> |
|
Image:Taxol.jpg|Model of the paclitaxel molecule |
|
Image:Taxol.jpg|] of paclitaxel |
|
Image:Taxol.gif|Rotated paclitaxel molecule model (Animated GIF, 1.2Mb size) |
|
Image:Taxol.gif|Rotating paclitaxel molecule model |
|
Image:Paclitaxel JMolBiol 2001 1045.jpg|Crystal structure of paclitaxel. |
|
Image:Paclitaxel JMolBiol 2001 1045.jpg|Crystal structure of paclitaxel |
|
|
Image:Taxol total charge surface.gif|Total charge surface of taxol. Minimum energy conformation. |
|
</gallery> |
|
</gallery> |
|
|
|
|
|
==References== |
|
== References == |
|
{{Reflist|2}} |
|
{{Reflist}} |
|
|
|
|
|
== Further reading == |
|
|
{{refbegin}} |
|
|
* {{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}} |
|
|
{{refend}} |
|
|
|
|
|
==External links== |
|
== External links == |
|
|
* {{cite web|title=Paclitaxel|website=National Cancer Institute|date=5 October 2006|url=https://www.cancer.gov/about-cancer/treatment/drugs/paclitaxel }} |
|
*. |
|
|
|
* {{cite web|title=Paclitaxel|website=NCI Drug Dictionary|date=2 February 2011|url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/paclitaxel }} |
|
* |
|
|
* by Neil Edwards, ]. |
|
* by Neil Edwards, ]. |
|
* from ]. |
|
* from ]. |
|
|
* {{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 = ] }} |
|
* Virtual Cancer Centre |
|
|
|
|
|
*{{cite news | url = http://query.nytimes.com/gst/fullpage.html?sec=health&res=9B0CE1DD1730F932A35753C1A9609C8B63&partner=rssnyt&emc=rss | title = Hope, at $4,200 a Dose | last = Berenson | first = Alex | date = October 1, 2006 | accessdate = 2007-03-31 | publisher = ]}} |
|
|
* |
|
|
|
|
|
|
{{Chemotherapeutic agents}} |
|
{{Chemotherapeutic agents}} |
|
|
{{Transient receptor potential channel modulators}} |
|
|
{{Xenobiotic-sensing receptor modulators}} |
|
|
{{Portal bar | Medicine}} |
|
|
{{Authority control}} |
|
|
|
|
|
] |
|
] |
|
] |
|
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
|
] |
|
] |
|
] |
|
] |
|
|
] |
|
] |
|
] |
|
] |
|
] |
|
|
] |
|
|
|
|
|
] |
|
] |
|
|
|
] |
|
] |
|
|
|
] |
|
] |
|
|
|
] |
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|