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Paclitaxel
Paclitaxel
(PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer.[2] This includes ovarian cancer, breast cancer, lung cancer, Kaposi sarcoma, cervical cancer, and pancreatic cancer.[2] It is given by injection into a vein.[2] There is also an albumin bound formulation.[2] Common side effects include hair loss, bone marrow suppression, numbness, allergic reactions, muscle pains, and diarrhea.[2] Other serious side effects include heart problems, increased risk of infection, and lung inflammation.[2] There are concerns that use during pregnancy may cause birth defects.[3][2] Paclitaxel
Paclitaxel
is in the taxane family of medications.[4] It works by interference with the normal function of microtubules during cell division.[2] Paclitaxel
Paclitaxel
was first isolated in 1971 from the Pacific yew
Pacific yew
and approved for medical use in 1993.[5][6] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] The wholesale cost in the developing world is about 7.06 to 13.48 USD per 100 mg vial.[8] This amount in the United Kingdom costs the NHS
NHS
about 66.85 pounds.[9] It is now manufactured by cell culture.[6]

Contents

1 Medical use

1.1 Similar compounds 1.2 Restenosis

2 Side effects 3 Mechanism of action 4 Production

4.1 Biosynthesis 4.2 Synthesis

5 History

5.1 Plant screening program 5.2 Early clinical trials, supply and the transfer to BMS

6 Society and culture

6.1 Names 6.2 Cost

7 Research 8 Additional images 9 References 10 Sources 11 External links

Medical use[edit] Paclitaxel
Paclitaxel
is approved in the UK for ovarian, breast and lung, bladder, prostate, melanoma, esophageal, and other types of solid tumor cancers as well as Kaposi's sarcoma.[10] It is recommended in NICE
NICE
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
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
NICE
recommended paclitaxel should not be used in the adjuvant treatment of early node-positive breast cancer.[11] In 2005, its use in the United States for the treatment of breast, pancreatic, and non-small cell lung cancers was approved by the FDA.[12] Similar compounds[edit] Albumin-bound paclitaxel (trade name Abraxane, also called nab-paclitaxel) is an alternative formulation where paclitaxel is bound to albumin nano-particles. Much of the clinical toxicity of paclitaxel is associated with the solvent Cremophor EL in which it is dissolved for delivery.[13] Abraxis BioScience developed Abraxane, in which paclitaxel is bonded to albumin as an alternative delivery agent to the often toxic solvent delivery method. This was approved by the U.S. Food and Drug Administration
Food and Drug Administration
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.[14] Synthetic approaches to paclitaxel production led to the development of docetaxel. Docetaxel
Docetaxel
has a similar set of clinical uses to paclitaxel and is marketed under the name of Taxotere. Recently the presence of taxanes including paclitaxel, 10-deacetylbaccatin
10-deacetylbaccatin
III, baccatin III, paclitaxel C, and 7-epipaclitaxel in the shells and leaves of hazel plants has been reported.[15] 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. Restenosis[edit] Paclitaxel
Paclitaxel
is used as an antiproliferative agent for the prevention of restenosis (recurrent narrowing) of coronary and peripheral stents; locally delivered to the wall of the artery, a paclitaxel coating limits the growth of neointima (scar tissue) within stents.[16] Paclitaxel
Paclitaxel
drug eluting coated stents for coronary artery placement are sold under the trade name Taxus by Boston Scientific
Boston Scientific
in the United States. Paclitaxel
Paclitaxel
drug eluting coated stents for femoropopliteal artery placement are sold under the trade name Zilver PTX by Cook Medical, Inc. Side effects[edit] 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.[citation needed] More serious side effects such as unusual bruising or bleeding, pain/redness/swelling at the injection site, hand-foot syndrome, 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, female infertility by ovarian damage, and chest pain can also occur.[citation needed] Neuropathy
Neuropathy
may also occur.[2] Dexamethasone
Dexamethasone
is given prior to beginning paclitaxel treatment to mitigate some of the side effects.[citation needed] A number of these side effects are associated with the excipient used, Cremophor EL, a polyoxyethylated castor oil, and allergies to cyclosporine, teniposide, and other drugs containing polyoxyethylated castor oil may indicate increased risk of adverse reactions to paclitaxel.[17] Mechanism of action[edit]

Complex of α, β tubulin subunits and paclitaxel. Paclitaxel
Paclitaxel
is shown as yellow stick.

Paclitaxel
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 G-phase of the cell cycle without cell division.[18][19] The ability of paclitaxel to inhibit spindle function is generally attributed to its suppression of microtubule dynamics,[20] 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.[21] Paclitaxel
Paclitaxel
binds to beta-tubulin subunits of microtubules.[22] Production[edit]

Undisturbed Pacific yew
Pacific yew
bark contains paclitaxel and related chemicals.

The bark is peeled and processed to provide paclitaxel.

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.[23] The processes used were descendants of the original isolation method of Monroe Wall and Mansukh Wani; by 1987, the NCI had contracted Hauser Chemical Research of Boulder, Colorado, to handle bark on the scale needed for Phase II and III trials.[citation needed] While both the size of the wild population of Taxus brevifola and the magnitude of the eventual demand for taxol were uncertain, it was clear for many years[vague] that an alternative, sustainable source of supply 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] 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.[24] Concurrently, synthetic chemists in the US and France had been interested in taxol, beginning in the late 1970s.[citation needed] 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
10-deacetylbaccatin
from the European yew, Taxus baccata, which grew on the CNRS
CNRS
campus and whose needles were available in large quantity.[citation needed] By virtue of its structure, 10-deacetylbaccatin
10-deacetylbaccatin
was seen as a viable starting material for a short semisynthesis to produce taxol. By 1988 Poitier and collaborators had published a semisynthetic route from needles of T. baccata to taxol.[25] The view of the NCI, however, was even this route was not practical.[citation needed] 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.[citation needed] Florida State University, where Holton worked, signed a deal with Bristol-Myers Squibb to license their semisynthesis and future patents.[citation needed] 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
10-deacetylbaccatin
isolated from the needles of the European yew.[citation needed] In early 1993, BMS announced that it would cease reliance on Pacific yew
Pacific yew
bark by the end of 1995, effectively terminating ecological controversy over its use.[citation needed] This announcement also made good their commitment to develop an alternative supply route, made to the NCI in their CRADA application of 1989. As of 2013, paclitaxel production for BMS is sourced using a semisynthetic method from Taxus baccata
Taxus baccata
(European yew).[26] Another company which worked with BMS until 2012,[27] Phyton Biotech, Inc., uses plant cell fermentation (PCF) technology.[28] By cultivating a specific Taxus cell line in fermentation tanks, they no longer need ongoing sourcing of material from actual yew tree plantations.[29] Paclitaxel
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 chromatographic step followed by crystallization[30]. Compared to the semisynthesis® , PCF eliminates the need for many hazardous chemicals and saves a considerable amount of energy.[31] In 1993, taxol was discovered as a natural product in a newly described endophytic fungus living in the yew tree.[32] It has since been reported in a number of other endophytic fungi, including Nodulisporium sylviforme,[33] Alternaria taxi, Cladosporium cladosporioides MD2, Metarhizium anisopliae, Aspergillus candidus MD3, Mucor rouxianus, Chaetomella raphigera, Phyllosticta tabernaemontanae, Phomopsis, Pestalotiopsis pauciseta, Phyllosticta citricarpa, Podocarpus
Podocarpus
sp., Fusarium solani, Pestalotiopsis terminaliae, Pestalotiopsis breviseta, Botryodiplodia theobromae, Gliocladium sp., Alternaria alternata var. monosporus, Cladosporium cladosporioides, Nigrospora sp., Pestalotiopsis versicolor, and Taxomyces andreanae. However, there has been contradictory evidence for its production by endophytes, with other studies finding independent production is unlikely.[34][35] Biosynthesis[edit] The core synthetic route is via a terpenoid pathway, parts of which having been successfully transplanted into production strains of E.coli[36] and yeast.[37] Synthesis[edit] Main article: Paclitaxel
Paclitaxel
total synthesis

Paclitaxel, with rings labeled and accepted numbering scheme shown.

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.[38] 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 first article to be accepted for publication, and of K. C. Nicolaou who had the 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),[39] 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"[40] or a "photo finish",[38] though each group has argued that their synthetic strategy and tactics were superior.[40] As of 2006, five additional research groups had reported successful total syntheses of paclitaxel: Wender et al. in 1997, and Kuwajima et al. and Mukaiyama et al. in 1998 with further linear syntheses, and Danishefsky et al. in 1996 and Takahashi et al. in 2006 with further convergent syntheses.[needs update] 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-hydroxyl group.[38] While the "political climate surrounding taxol and Taxus brevifolia
Taxus brevifolia
in the early 1990s… helped bolster [a] link between total synthesis and the [taxol] supply problem", and though total synthesis activities were a requisite to explore the structure-activity relationships of taxol 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.[41] History[edit] The discovery of paclitaxel began in 1962 as a result of a U.S. National Cancer
Cancer
Institute-funded screening program.[6] A number of years later it was isolated from the bark of the Pacific yew, Taxus brevifolia, hence its name "taxol".[6] The discovery was made by Monroe E. Wall
Monroe E. Wall
and Mansukh C. Wani
Mansukh C. Wani
at the Research Triangle Institute, Research Triangle Park, North Carolina, in 1971.[42] These scientists isolated the natural product from the bark of the Pacific yew
Pacific yew
tree, Taxus brevifolia, determined its structure and named it "taxol", and arranged for its first biological testing.[citation needed] The compound was then developed commercially by Bristol-Myers Squibb
Bristol-Myers Squibb
(BMS), who had the generic name assigned as "paclitaxel".[citation needed] Plant screening program[edit] In 1955, the National Cancer
Cancer
Institute (NCI) in the United States set up the Cancer
Cancer
Chemotherapy
Chemotherapy
National Service Center (CCNSC) to act as a public screening center for anticancer activity in compounds submitted by external institutions and companies.[43] 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.[44] After some years of informal arrangements, in July 1960, the NCI commissioned USDA
USDA
botanists to collect samples from about 1,000 plant species per year.[45] On 21 August 1962, one of those botanists, Arthur S. Barclay, collected bark from a single Pacific yew
Pacific yew
tree, Taxus brevifolia, in a forest north of the town of Packwood, Washington
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 Taxus samples was found to be cytotoxic in a cellular assay on 22 May 1964.[46] Accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by Monroe E. Wall
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
American Chemical Society
meeting in Miami Beach.[47] They named the pure compound taxol in June 1967.[46] Wall and his colleague Wani published their results, including the chemical structure, in 1971.[48] 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 10 g of pure material,[49] 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.[50] This required increasing quantities of purified taxol, up to 600 g, and in 1977 a further request for 7,000 lbs of bark was made. In 1978, two NCI researchers published a report showing taxol was mildly effective in leukaemic mice.[51] In November 1978, taxol was shown to be effective in xenograft studies.[52] 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 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 20,000 lbs of bark.[53] Animal toxicology studies were complete by June 1982, and in November NCI applied for the IND necessary to begin clinical trials in humans.[53] Early clinical trials, supply and the transfer to BMS[edit] Phase I clinical trials began in April 1984, and the decision to start Phase II trials was made a year later.[54] 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.[55] 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.[56] 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.[55] 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)".[55] Although the offer was widely advertised, only four companies responded to the CRADA, including the American firm Bristol-Myers Squibb (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 General Accounting Office
General Accounting Office
in 2003, which concluded the NIH had failed to ensure value for money.[57] In related CRADAs with the USDA
USDA
and Department of the Interior, Bristol-Myers Squibb
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 monopoly".[58] Eighteen months after the CRADA, BMS filed a new drug application (NDA), which was given FDA approval at the very end of 1992. [55] Although there was no patent on the compound, the provisions of the Waxman-Hatch Act 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 (INN) name of the compound. Critics, including the 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.[59] 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.[60] 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".[61] 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. In October 2007 it was approved by Drug controller General of India for the treatment of breast cancer and launched by collaboration with Biocon.[62] Society and culture[edit] Names[edit] The nomenclature for paclitaxel is structured on a tetracyclic 17-carbon (heptadecane) skeleton. There are a total of 11 stereocenters. The active stereoisomer is (−)-paclitaxel (shown here).

Position numbering

Absolute stereochemistry

(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-Diacetoxy-15- [(2R,3S)-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

Cost[edit] As of 2006[update], the cost to the NHS
NHS
per patient in early breast cancer, assuming four cycles of treatment, was about £4000 (approx. $6000).[63] Research[edit] A recent study suggested that caffeine may inhibit paclitaxel-induced apoptosis in colorectal cancer cells.[64] 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
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.[65] 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 .[66] Paclitaxel
Paclitaxel
is sometimes used for in vivo studies as well; it can be fed to test organisms, such as 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[67] and inhibits hPAD2 in vitro though its methyl ester side chain.[68] Angiotech Pharmaceuticals Inc. began phase II clinical trials in 1999[69] as a multiple sclerosis treatment but in 2002, reported that the results showed no statistical significance.[70] In 2016 in vitro multi-drug resistant mouse tumor cells were treated with paclitaxel encased in 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.[71][72] Additional images[edit]

Space-filling model
Space-filling model
of paclitaxel

Rotating paclitaxel molecule model

Crystal structure of paclitaxel

Total charge surface of taxol. Minimum energy conformation.

References[edit]

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Nodulisporium sylviforme". Nature and Science. 2 (2): 52–59. doi:10.7537/marsnsj020204.09.  ^ Staniek, A; Woerdenbag, H; Kayser, O (2009). "Taxomyces andreanae: A Presumed Paclitaxel
Paclitaxel
Producer Demystified?". Planta Med. 75 (15): 1561–6. doi:10.1055/s-0029-1186181.  ^ Heinig, U; Scholz, S; Jennewein, S (2013). "Getting to the bottom of taxol biosynthesis by fungi". Fungal Diversity. 60: 161–170. doi:10.1007/s13225-013-0228-7.  ^ Boghigian, Brett A.; Myint, Melissa; Wu, Jiequn; Pfeifer, Blaine A. (2011). "Simultaneous production and partitioning of heterologous polyketide and isoprenoid natural products in an Escherichia coli two-phase bioprocess". Journal of Industrial Microbiology & Biotechnology. 38 (11): 1809–1820. doi:10.1007/s10295-011-0969-9.  ^ Engels, Benedikt; Dahm, Pia; Jennewein, Stefan (2008). "Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (Paclitaxel) production". Metabolic Engineering. 10 (3–4): 201–6. doi:10.1016/j.ymben.2008.03.001. PMID 18485776.  ^ a b c Nina Hall, 2003, Creating complexity: The beauty and logic of synthesis, Chem. Commun., 661 – 664, doi:10.1039/b212248k ^ See N. Hall, ibid. See also the American Chemical Society publication Chemical and Engineering News
Chemical and Engineering News
(C&EN), Feb. 21, 1994, page 32, and primary citations appearing at Holton and Nicolaou taxol total synthesis articles. ^ a b Flam, Faye (1994). "Race to synthesize Taxol ends in a tie". Science. 263 (5149): 911. doi:10.1126/science.7906053. PMID 7906053.  ^ Goodman & Walsh 2001, pp. 179–182. ^ ME, WALL; MC, Wani (February 15, 1995). "amptothecin and taxol: discovery to clinic—thirteenth Bruce F. Cain Memorial Award Lecture". Cancer
Cancer
Res. 55 (4): 753–60. PMID 7850785. Archived from the original on November 24, 2016.  ^ Goodman & Walsh 2001, p. 17. ^ Goodman & Walsh 2001, p. 22. ^ Goodman & Walsh 2001, pp. 25,28. ^ a b Goodman & Walsh 2001, p. 51. ^ Wall, ME; Wani, MC (1995). " Camptothecin
Camptothecin
and taxol: Discovery to clinic—thirteenth Bruce F. Cain Memorial Award Lecture". Cancer Research. 55 (4): 753–60. PMID 7850785.  ^ Wani M, Taylor H, Wall M, Coggon P, McPhail A (1971). "Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia". J Am Chem Soc. 93 (9): 2325–7. doi:10.1021/ja00738a045. PMID 5553076.  ^ Goodman & Walsh 2001, p. 81. ^ Goodman & Walsh 2001, pp. 79,81. ^ Fuchs, David A; Johnson, Randall K (1978). "Cytologic evidence that taxol, an antineoplastic agent from Taxus brevifolia, acts as a mitotic spindle poison". Cancer
Cancer
Treatment Reports. 62 (8): 1219–22. PMID 688258.  ^ Goodman & Walsh 2001, p. 95. ^ a b Goodman & Walsh 2001, p. 97 ^ Goodman & Walsh 2001, p. 115. ^ a b c d Goodman & Walsh 2001, p. 120 ^ Rowinsky, EK; et al. (1988). "Phase II study of taxol in advanced epithelial malignancies". Proceedings of the Association of Clinical Oncology. 7: 136.  ^ "Technology Transfer: NIH-Private Sector Partnership in the Development of Taxol" (PDF). Archived (PDF) from the original on 2007-07-26.  ^ Nader, Ralph; Love, James. "Looting the medicine chest: how Bristol-Myers Squibb
Bristol-Myers Squibb
made off with the public's cancer research." The Progressive. February 1993. Retrieved on March 9, 2007. ^ "Names for hi-jacking". Nature. 373 (6513): 370. 1995. doi:10.1038/373370a0. PMID 7830775.  ^ Goodman & Walsh 2001, p. 170. ^ Bristol-Myers Squibb, The development of TAXOL (paclitaxel), March 1997, as cited in Goodman & Walsh 2001, p. 2 ^ Template:Cite citation needed ^ " NICE
NICE
Guidance TA108". Archived from the original on 2007-06-30.  ^ Mhaidat, NM (January 2014). " Caffeine
Caffeine
inhibits paclitaxel‑induced apoptosis in colorectal cancer cells through the upregulation of Mcl-1 levels". J Mol Med Rep. 9 (1): 243–8. doi:10.3892/mmr.2013.1763. PMID 24173825. Archived from the original on 2015-06-22.  ^ Kachooei, E; Moosavi-Movahedi, AA; Khodagholi, F; Mozaffarian, F; Sadeghi, P; Hadi-Alijanvand, H; Ghasemi, A; Saboury, AA; Farhadi, M; Sheibani, N (2014). "Inhibition study on insulin fibrillation and cytotoxicity by paclitaxel". The Journal of Biochemistry. 155 (6): 361–373. doi:10.1093/jb/mvu012. PMID 24535601.  ^ Kachooei, E; Mozaffarian, F; Khodagholi, F; Sadeghi, P; Karami, L; Ghasemi, A; Vahdat, E; Saboury, AA; Sheibani, N; Moosavi-Movahedi, AA (2018). " Paclitaxel
Paclitaxel
inhibited lysozyme fibrillation by increasing colloidal stability through formation of "off-pathway" oligomers". Int J Biol Macromol. 111: 870–879. doi:10.1016/j.ijbiomac.2018.01.072. PMID 29352977.  ^ Moscarello, MA; Mak, B; Nguyen, TA; Wood, DD; Mastronardi, F; Ludwin, SK (2002). " Paclitaxel
Paclitaxel
(Taxol) attenuates clinical disease in a spontaneously demyelinating transgenic mouse and induces remyelination". Multiple sclerosis (Houndmills, Basingstoke, England). 8 (2): 130–8. doi:10.1191/1352458502ms776oa. PMID 11990870.  ^ Musse, AA; Polverini, E; Raijmakers, R; Harauz, G (2008). "Kinetics of human peptidylarginine deiminase 2 (hPAD2)--reduction of Ca2+ dependence by phospholipids and assessment of proposed inhibition by paclitaxel side chains". Biochemistry and cell biology = Biochimie et biologie cellulaire. 86 (5): 437–47. doi:10.1139/o08-124. PMID 18923545.  ^ MS Society of Canada Phase II Clinical trial
Clinical trial
of Micellar Paclitaxel for secondary-progressive MS underway in Canada Archived 2012-03-15 at the Wayback Machine. ^ MS Society of Canada Angiotech Halts Study of Micellar Paclitaxel stating no benefit of statistical significance seen Archived 2012-03-15 at the Wayback Machine. ^ Lavars, Nick (2016-01-14). "Cloaking chemo drugs in cellular bubbles destroys cancer with one fiftieth of a regular dose". www.gizmag.com. Archived from the original on 2016-02-24. Retrieved 2016-02-14.  ^ Kim, Myung Soo; Haney, Matthew J.; Zhao, Yuling; Mahajan, Vivek; Deygen, Irina; Klyachko, Natalia L.; Inskoe, Eli; Piroyan, Aleksandr; Sokolsky, Marina (2016). "Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells". Nanomedicine: Nanotechnology, Biology and Medicine. 12: 655–664. doi:10.1016/j.nano.2015.10.012. PMC 4809755 . PMID 26586551. 

Sources[edit]

Goodman, Jordan; Walsh, Vivien (5 March 2001). The Story of Taxol: Nature and Politics in the Pursuit of an Anti- Cancer
Cancer
Drug. Cambridge University Press. ISBN 978-0-521-56123-5. 

External links[edit]

NCI Drug Information Summary for Patients. NCI Drug Dictionary Definition Molecule of the Month: TAXOL by Neil Edwards, University of Bristol. A Tale of Taxol from Florida State University. Berenson, Alex (October 1, 2006). "Hope, at $4,200 a Dose". The New York Times. Retrieved 2007-03-31.  U.S. National Library of Medicine: Drug Information Portal
Portal
– Paclitaxel

v t e

Intracellular chemotherapeutic agents / antineoplastic agents (L01)

SPs/MIs (M phase)

Block microtubule assembly

Vinca alkaloids (Vinblastine# Vincristine# Vinflunine§ Vindesine Vinorelbine#)

Block microtubule disassembly

Taxanes (Cabazitaxel Docetaxel# Larotaxel Ortataxel† Paclitaxel# Tesetaxel) Epothilones (Ixabepilone)

DNA replication inhibitor

DNA precursors/ antimetabolites (S phase)

Folic acid

Dihydrofolate reductase inhibitor
Dihydrofolate reductase inhibitor
(Aminopterin Methotrexate# Pemetrexed Pralatrexate) Thymidylate synthase inhibitor (Raltitrexed Pemetrexed)

Purine

Adenosine deaminase inhibitor
Adenosine deaminase inhibitor
(Pentostatin)

Halogenated/ribonucleotide reductase inhibitors (Cladribine Clofarabine Fludarabine) Nelarabine

Thiopurine
Thiopurine
(Tioguanine# Mercaptopurine#)

Pyrimidine

Thymidylate synthase inhibitor (Fluorouracil# Capecitabine# Doxifluridine Tegafur
Tegafur
(+gimeracil/oteracil) Carmofur Floxuridine)

DNA polymerase inhibitor (Cytarabine#)

Ribonucleotide reductase inhibitor (Gemcitabine#)

Hypomethylating agent (Azacitidine Decitabine)

Deoxyribonucleotide

Ribonucleotide reductase inhibitor (Hydroxycarbamide#)

Topoisomerase inhibitors (S phase)

I

Camptotheca
Camptotheca
(Camptothecin Cositecan† Belotecan Gimatecan Exatecan Irinotecan Lurtotecan‡ Silatecan§ Topotecan Rubitecan‡)

II

Podophyllum (Etoposide# Teniposide)

II+Intercalation

Anthracyclines (Aclarubicin Daunorubicin# Doxorubicin# Epirubicin Idarubicin Amrubicin† Pirarubicin Valrubicin Zorubicin) Anthracenediones (Mitoxantrone Pixantrone)

Crosslinking of DNA (CCNS)

Alkylating

Nitrogen mustards: Mechlorethamine Cyclophosphamide# (Ifosfamide# Trofosfamide) Chlorambucil# (Melphalan Prednimustine) Bendamustine# Estramustine phosphate Uramustine

Nitrosoureas: Carmustine Lomustine
Lomustine
(Semustine) Fotemustine Nimustine Ranimustine Streptozocin

Alkyl sulfonates: Busulfan
Busulfan
(Mannosulfan Treosulfan)

Aziridines: Carboquone Thiotepa Triaziquone Triethylenemelamine

Platinum-based

Carboplatin# Cisplatin# Dicycloplatin Nedaplatin Oxaliplatin# Satraplatin

Nonclassical

Hydrazines (Procarbazine#) Triazenes (Dacarbazine# Temozolomide) Altretamine Mitobronitol Pipobroman

Intercalation

Streptomyces
Streptomyces
(Actinomycin# Bleomycin# Mitomycins Plicamycin)

Photosensitizers/PDT

Aminolevulinic acid / Methyl aminolevulinate Efaproxiral Porphyrin
Porphyrin
derivatives (Porfimer sodium Talaporfin Temoporfin Verteporfin)

Other

Enzyme inhibitors

FI (Tipifarnib§) CDK inhibitors (Abemaciclib Alvocidib† Palbociclib Ribociclib Seliciclib†) PrI

Bortezomib Carfilzomib Ixazomib

PhI (Anagrelide) IMPDI (Tiazofurin§) LI (Masoprocol) PARP inhibitor
PARP inhibitor
(Niraparib Olaparib Rucaparib) HDAC (Belinostat Panobinostat Romidepsin Vorinostat) PIKI (Idelalisib)

Receptor antagonists

ERA (Atrasentan) Retinoid X receptor (Bexarotene) Sex steroid
Sex steroid
(Testolactone)

Other/ungrouped

Amsacrine Trabectedin Retinoids (Alitretinoin Tretinoin#) Arsenic trioxide Asparagine
Asparagine
depleters (Asparaginase#/Pegaspargase) Celecoxib Demecolcine Elesclomol§ Elsamitrucin Etoglucid Lonidamine Lucanthone Mitoguazone Mitotane Oblimersen† Omacetaxine mepesuccinate Eribulin

#WHO-EM ‡Withdrawn from market Clinical trials:

†Phase III §Never to phase III

v t e

TRP channel modulators

TRPA

Activators

4-Hydroxynonenal 4-Oxo-2-nonenal 4,5-EET 12S-HpETE 15-Deoxy-Δ12,14-prostaglandin J2 α- Sanshool
Sanshool
(ginger, Sichuan and melegueta peppers) Acrolein Allicin
Allicin
(garlic) Allyl isothiocyanate
Allyl isothiocyanate
(mustard, radish, horseradish, wasabi) AM404 Bradykinin Cannabichromene
Cannabichromene
(cannabis) Cannabidiol
Cannabidiol
(cannabis) Cannabigerol
Cannabigerol
(cannabis) Cinnamaldehyde
Cinnamaldehyde
(cinnamon) CR gas
CR gas
(dibenzoxazepine; DBO) CS gas
CS gas
(2-chlorobenzal malononitrile) Curcumin
Curcumin
(turmeric) Dehydroligustilide (celery) Diallyl disulfide Dicentrine
Dicentrine
( Lindera
Lindera
spp.) Farnesyl thiosalicylic acid Formalin Gingerols (ginger) Hepoxilin A3 Hepoxilin B3 Hydrogen peroxide Icilin Isothiocyanate Ligustilide (celery, Angelica acutiloba) Linalool
Linalool
(Sichuan pepper, thyme) Methylglyoxal Methyl salicylate
Methyl salicylate
(wintergreen) N-Methylmaleimide Nicotine
Nicotine
(tobacco) Oleocanthal
Oleocanthal
(olive oil) Paclitaxel
Paclitaxel
(Pacific yew) Paracetamol
Paracetamol
(acetaminophen) PF-4840154 Phenacyl chloride Polygodial
Polygodial
(Dorrigo pepper) Shogaols (ginger, Sichuan and melegueta peppers) Tear gases Tetrahydrocannabinol
Tetrahydrocannabinol
(cannabis) Thiopropanal S-oxide
Thiopropanal S-oxide
(onion) Umbellulone
Umbellulone
(Umbellularia californica) WIN 55,212-2

Blockers

Dehydroligustilide (celery) Nicotine
Nicotine
(tobacco) Ruthenium red

TRPC

Activators

Adhyperforin
Adhyperforin
(St John's wort) Diacyl glycerol GSK1702934A Hyperforin
Hyperforin
(St John's wort) Substance P

Blockers

DCDPC DHEA-S Flufenamic acid GSK417651A GSK2293017A Meclofenamic acid N-(p-amylcinnamoyl)anthranilic acid Niflumic acid Pregnenolone
Pregnenolone
sulfate Progesterone Pyr3 Tolfenamic acid

TRPM

Activators

ADP-ribose BCTC Calcium
Calcium
(intracellular) Cold Coolact P Cooling Agent 10 CPS-369 Eucalyptol
Eucalyptol
(eucalyptus) Frescolat MGA Frescolat ML Geraniol Hydroxycitronellal Icilin Linalool Menthol
Menthol
(mint) PMD 38 Pregnenolone
Pregnenolone
sulfate Rutamarin (Ruta graveolens) Steviol glycosides (e.g., stevioside) (Stevia rebaudiana) Sweet tastants (e.g., glucose, fructose, sucrose; indirectly) Thio-BCTC WS-3 WS-12 WS-23

Blockers

Capsazepine Clotrimazole DCDPC Flufenamic acid Meclofenamic acid Mefenamic acid N-(p-amylcinnamoyl)anthranilic acid Nicotine
Nicotine
(tobacco) Niflumic acid Ruthenium red Rutamarin (Ruta graveolens) Tolfenamic acid TPPO

TRPML

Activators

MK6-83 PI(3,5)P2 SF-22

TRPP

Activators

Triptolide
Triptolide
(Tripterygium wilfordii)

Blockers

Ruthenium red

TRPV

Activators

2-APB 5',6'-EET 9-HODE 9-oxoODE 12S-HETE 12S-HpETE 13-HODE 13-oxoODE 20-HETE α- Sanshool
Sanshool
(ginger, Sichuan and melegueta peppers) Allicin
Allicin
(garlic) AM404 Anandamide Bisandrographolide (Andrographis paniculata) Camphor
Camphor
(camphor laurel, rosemary, camphorweed, African blue basil, camphor basil) Cannabidiol
Cannabidiol
(cannabis) Cannabidivarin
Cannabidivarin
(cannabis) Capsaicin
Capsaicin
(chili pepper) Carvacrol
Carvacrol
(oregano, thyme, pepperwort, wild bergamot, others) DHEA Diacyl glycerol Dihydrocapsaicin
Dihydrocapsaicin
(chili pepper) Estradiol Eugenol
Eugenol
(basil, clove) Evodiamine
Evodiamine
(Euodia ruticarpa) Gingerols (ginger) GSK1016790A Heat Hepoxilin A3 Hepoxilin B3 Homocapsaicin
Homocapsaicin
(chili pepper) Homodihydrocapsaicin
Homodihydrocapsaicin
(chili pepper) Incensole
Incensole
(incense) Lysophosphatidic acid Low pH (acidic conditions) Menthol
Menthol
(mint) N-Arachidonoyl dopamine N-Oleoyldopamine N-Oleoylethanolamide Nonivamide
Nonivamide
(PAVA) (PAVA spray) Nordihydrocapsaicin
Nordihydrocapsaicin
(chili pepper) Paclitaxel
Paclitaxel
(Pacific yew) Paracetamol
Paracetamol
(acetaminophen) Phorbol esters
Phorbol esters
(e.g., 4α-PDD) Piperine
Piperine
(black pepper, long pepper) Polygodial
Polygodial
(Dorrigo pepper) Probenecid Protons RhTx Rutamarin (Ruta graveolens) Resiniferatoxin
Resiniferatoxin
(RTX) (Euphorbia resinifera/pooissonii) Shogaols (ginger, Sichuan and melegueta peppers) Tetrahydrocannabivarin
Tetrahydrocannabivarin
(cannabis) Thymol
Thymol
(thyme, oregano) Tinyatoxin
Tinyatoxin
(Euphorbia resinifera/pooissonii) Tramadol Vanillin
Vanillin
(vanilla) Zucapsaicin

Blockers

α- Spinasterol
Spinasterol
( Vernonia
Vernonia
tweediana) AMG-517 Asivatrep BCTC Cannabigerol
Cannabigerol
(cannabis) Cannabigerolic acid (cannabis) Cannabigerovarin (cannabis) Cannabinol
Cannabinol
(cannabis) Capsazepine DCDPC DHEA DHEA-S Flufenamic acid GRC-6211 HC-067047 Lanthanum Meclofenamic acid N-(p-amylcinnamoyl)anthranilic acid NGD-8243 Niflumic acid Pregnenolone
Pregnenolone
sulfate RN-1734 RN-9893 Ruthenium red SB-705498 Tivanisiran Tolfenamic acid

See also: Receptor/signaling modulators • Ion channel modulators

v t e

Xenobiotic-sensing receptor modulators

CAR

Agonists: 6,7-Dimethylesculetin Amiodarone Artemisinin Benfuracarb Carbamazepine Carvedilol Chlorpromazine Chrysin CITCO Clotrimazole Cyclophosphamide Cypermethrin DHEA (prasterone) Efavirenz Ellagic acid Griseofulvin Methoxychlor Mifepristone Nefazodone Nevirapine Nicardipine Octicizer Permethrin Phenobarbital Phenytoin Pregnanedione (5β-dihydroprogesterone) Reserpine TCPOBOP Telmisartan Tolnaftate Troglitazone Valproic acid

Antagonists: 3,17β-Estradiol 3α-Androstanol 3α-Androstenol 3β-Androstanol 17-Androstanol AITC Ethinylestradiol Meclizine Nigramide J Okadaic acid PK-11195 S-07662 T-0901317

PXR

Agonists: 17α-Hydroxypregnenolone 17α-Hydroxyprogesterone Δ4-Androstenedione Δ5-Androstenediol Δ5-Androstenedione AA-861 Allopregnanediol Allopregnanedione (5α-dihydroprogesterone) Allopregnanolone
Allopregnanolone
(brexanolone) Alpha-Lipoic acid Ambrisentan AMI-193 Amlodipine besylate Antimycotics Artemisinin Aurothioglucose Bile acids Bithionol Bosentan Bumecaine Cafestol Cephaloridine Cephradine Chlorpromazine Ciglitazone Clindamycin Clofenvinfos Chloroxine Clotrimazole Colforsin Corticosterone Cyclophosphamide Cyproterone acetate Demecolcine Dexamethasone DHEA (prasterone) DHEA-S (prasterone sulfate) Dibunate sodium Diclazuril Dicloxacillin Dimercaprol Dinaline Docetaxel Docusate calcium Dodecylbenzenesulfonic acid Dronabinol Droxidopa Eburnamonine Ecopipam Enzacamene Epothilone
Epothilone
B Erythromycin Famprofazone Febantel Felodipine Fenbendazole Fentanyl Flucloxacillin Fluorometholone Griseofulvin Guggulsterone Haloprogin Hetacillin potassium Hyperforin Hypericum perforatum
Hypericum perforatum
(St John's wort) Indinavir sulfate Lasalocid sodium Levothyroxine Linolenic acid LOE-908 Loratadine Lovastatin Meclizine Metacycline Methylprednisolone Metyrapone Mevastatin Mifepristone Nafcillin Nicardipine Nicotine Nifedipine Nilvadipine Nisoldipine Norelgestromin Omeprazole Orlistat Oxatomide Paclitaxel Phenobarbital Piperine Plicamycin Prednisolone Pregnanediol Pregnanedione (5β-dihydroprogesterone) Pregnanolone Pregnenolone Pregnenolone
Pregnenolone
16α-carbonitrile Proadifen Progesterone Quingestrone Reserpine Reverse triiodothyronine Rifampicin Rifaximin Rimexolone Riodipine Ritonavir Simvastatin Sirolimus Spironolactone Spiroxatrine SR-12813 Suberoylanilide Sulfisoxazole Suramin Tacrolimus Tenylidone Terconazole Testosterone isocaproate Tetracycline Thiamylal sodium Thiothixene Thonzonium bromide Tianeptine Troglitazone Troleandomycin Tropanyl 3,5-dimethulbenzoate Zafirlukast Zeranol

Antagonists: Ketoconazole Sesamin

See also Receptor/signaling modulators Nuclear receptor modulators

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