Paclitaxel

Source: Wikipedia, the free encyclopedia.

Paclitaxel
Clinical data
Trade namesTaxol, Abraxane, others
Other namesPTX
AHFS/Drugs.comMonograph
MedlinePlusa607070
License data
Pregnancy
category
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability6.5% (by mouth)[3]
Protein binding89 to 98%
MetabolismLiver (CYP2C8 and CYP3A4)
Elimination half-life5.8 hours
ExcretionFecal and urinary
Identifiers
  • (2α,4α,5β,7β,10β,13α)-4,10-Bis(acetyloxy)-13-{[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate
JSmol)
  • CC1=C2[C@@]([C@]([C@H]([C@@H]3[C@]4([C@H](OC4)C[C@@H]([C@]3(C(=O)[C@@H]2OC(=O)C)C)O)OC(=O)C)OC(=O)c5ccccc5)(C[C@@H]1OC(=O)[C@H](O)[C@@H](NC(=O)c6ccccc6)c7ccccc7)O)(C)C
  • InChI=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 checkY
  • Key:RCINICONZNJXQF-MZXODVADSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Paclitaxel, sold under the brand name Taxol among others, is a

intravenous injection.[4] There is also an albumin-bound formulation.[4]

Common side effects include

birth defects.[5][4] Paclitaxel is in the taxane family of medications.[6] It works by interference with the normal function of microtubules during cell division.[4]

Paclitaxel was isolated in 1971 from the

Pacific yew and approved for medical use in 1993.[7][8] It is on the World Health Organization's List of Essential Medicines.[9] It has been made from precursors, and more recently through cell culture.[8]

Medical use

Paclitaxel is approved in the UK for ovarian, breast, lung, bladder, prostate, melanoma, esophageal, and other types of solid tumor cancers as well as Kaposi's sarcoma.[10]

It is recommended in

adjuvant treatment of early node-positive breast cancer.[11]

As of 2018[update], it is approved in the United States for the treatment of breast, pancreatic, ovarian, Kaposi's sarcoma and non-small-cell lung cancers.[12][13]

Similar compounds

Further information: Protein-bound paclitaxel and Docetaxel

Albumin-bound paclitaxel (brand name

Cremophor EL in which it is dissolved for delivery.[14]

adenocarcinoma of the pancreas as well.[16]

Synthetic approaches to paclitaxel production led to the development of docetaxel. Docetaxel has a similar set of clinical uses to paclitaxel, and it is marketed under the brand name Taxotere.

10-deacetylbaccatin III, baccatin III, paclitaxel C, and 7-epipaclitaxel, have been found in the leaves and shells of hazel.[17] 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.[18]

Restenosis

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.[19] Paclitaxel drug-eluting stents for coronary artery placement are sold under the trade name Taxus by Boston Scientific in the United States. Paclitaxel drug-eluting stents for femoropopliteal artery placement are also available.

Side effects

Common side effects include nausea and vomiting,

Neuropathy may also occur.[4]

Dexamethasone is given prior to paclitaxel infusion to mitigate some of the side effects.[21]

A number of these side effects are associated with the excipient used, Cremophor EL, a polyoxyethylated castor oil. Allergies to cyclosporine, teniposide, and other drugs delivered in polyoxyethylated castor oil may increase the risk of adverse reactions to paclitaxel.[22]

Mechanism of action

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

Paclitaxel is one of several

mitotic checkpoint triggers apoptosis or reversion to the G0-phase of the cell cycle without cell division.[23][24]

The ability of paclitaxel to inhibit spindle function is generally attributed to its suppression of microtubule dynamics,[25] 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 centrosomes, a process normally activated during mitosis.[26] Paclitaxel binds to the beta-tubulin subunits of microtubules.[27]

Chemistry

The

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

Production

Undisturbed Pacific yew bark contains paclitaxel and related chemicals.

Bark processing

The bark is peeled and processed to provide paclitaxel.

From 1967 to 1993, almost all paclitaxel produced was derived from bark of the Pacific yew, Taxus brevifolia, the harvesting of which kills the tree in the process.[28] The processes used were descendants of the original isolation method of Monroe Wall and Mansukh Wani; by 1987, the U.S. National Cancer Institute (NCI) had contracted Hauser Chemical Research of Boulder, Colorado, to handle bark on the scale needed for phase II and III trials.[citation needed] While both the size of the wild population of the Pacific yew and the magnitude of the eventual demand for paclitaxel were uncertain, it was clear that an alternative, sustainable source of the natural product would be needed. Initial attempts to broaden its sourcing used needles from the tree, or material from other related Taxus species, including cultivated ones,[citation needed] 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.[29]

Semisynthesis

Concurrently, synthetic chemists in the U.S. and France had been interested in paclitaxel, beginning in the late 1970s.[

10-deacetylbaccatin from the European yew, Taxus baccata, which grew on the CNRS campus and whose needles were available in large quantity.[citation needed] By virtue of its structure, 10-deacetylbaccatin was seen as a viable starting material for a short semisynthesis to produce paclitaxel. By 1988, Poitier and collaborators had published a semisynthetic route from needles of the European yew to paclitaxel.[30]

The view of the NCI, however, was that even this route was not practical.[

Bristol-Myers Squibb (BMS) 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 isolated from the needles of the European yew.[citation needed] 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] This announcement also made good their commitment to develop an alternative supply route, made to the NCI in their cooperative research and development agreement
(CRADA) application of 1989.

As of 2013, BMS was using the semisynthetic method utilizing needles from the European yew to produce paclitaxel.

cell line in fermentation tanks, they no longer need ongoing sourcing of material from actual yew tree plantations.[36] 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.[37] Compared to the semisynthesis method, PCF eliminates the need for many hazardous chemicals and saves a considerable amount of energy.[38]

In 1993, paclitaxel was discovered as a natural product in Taxomyces andreanae, a newly described

Phyllosticta citricarpa, Podocarpus sp., Fusarium solani, Pestalotiopsis terminaliae, Pestalotiopsis breviseta, Botryodiplodia theobromae, Gliocladium sp., Alternaria alternata var. monosporus, Cladosporium cladosporioides, Nigrospora sp. and Pestalotiopsis versicolor. However, there has been contradictory evidence for its production by endophytes, with other studies finding independent production is unlikely.[40][41]

Biosynthesis

Biosynthesis of Taxol

Taxol is a tetracyclic

NADPH, forming the intermediate taxadiene-5α-acetoxy-10β-ol (multiple steps later in the figure). A series of hydroxylations and esterficiations occur, forming the intermediate 10-deacetyl-baccatin III, which undergoes a further series of esterifications and a side-chain hydroxylation.[42]
This finally yields the product taxol.

Total synthesis

Main article: 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

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),[46] 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"[47] or a "photo finish",[45] though each group has argued that their synthetic strategy and tactics were superior.[47]

As of 2006, five additional research groups had reported successful total syntheses of paclitaxel:

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.[45]

While the "political climate surrounding [paclitaxel] and [the Pacific yew] in the early 1990s ... helped bolster [a] link between total synthesis and the [paclitaxel] supply problem," and though total synthesis activities were a requisite to explore the

structure-activity relationships 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.[48]

History

The discovery of paclitaxel began in 1962 as a result of a NCI-funded screening program.[8] A number of years later it was isolated from the bark of the Pacific yew, Taxus brevifolia, hence its name "taxol".[8]

The discovery was made by

Research Triangle Institute, Research Triangle Park, North Carolina, in 1971.[49] 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.[50] The compound was then developed commercially by BMS, who had the generic name assigned as "paclitaxel".[citation needed
]

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.[51] 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.[52] After some years of informal arrangements, in July 1960, the NCI commissioned the United States Department of Agriculture (USDA) botanists to collect samples from about 1,000 plant species per year.[53] On 21 August 1962, one of those botanists, Arthur S. Barclay, collected bark from a single Pacific yew tree in a forest north of the town of Packwood, Washington, as part of a four-month trip to collect material from over 200 different species. The material was then processed by a number of specialist CCNSC subcontractors, and one of the tree's samples was found to be cytotoxic in a cellular assay on 22 May 1964.[54]

Accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by Monroe E. Wall in Research Triangle Park, North Carolina, began work on fresh Taxus samples, isolating the active ingredient in September 1966 and announcing their findings at an April 1967 American Chemical Society meeting in Miami Beach.[55] They named the pure compound taxol in June 1967.[54] Wall and his colleague Wani published their results, including the chemical structure, in 1971.[56]

The NCI continued to commission work to collect more Taxus bark and to isolate increasing quantities of taxol. By 1969, 28 kg (62 lb) of crude extract had been isolated from almost 1,200 kg (2,600 lb) of bark, although this ultimately yielded only 10 g (0.35 oz) of pure material,[57] 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.[58] This required increasing quantities of purified taxol, up to 600 g (21 oz), and in 1977 a further request for 7,000 lb (3,200 kg) of bark was made.

In 1978, two NCI researchers published a report showing taxol was mildly effective in leukaemic mice.

xenograft studies.[60] 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 lb (9,100 kg) of bark.[61] Animal toxicology studies were complete by June 1982, and in November NCI applied for the IND necessary to begin clinical trials in humans.[61]

Early clinical trials, supply and the transfer to BMS

Phase I clinical trials began in April 1984, and the decision to start Phase II trials was made a year later.[62] 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.[63]

The first public report from a phase II trial in May 1988 showed promising effects in melanoma and refractory ovarian cancer.[64] 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.[63] 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)".[63]

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
Department of the Interior
, 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".[66] Eighteen months after the CRADA, BMS filed a
new drug application
(NDA), which was given FDA approval at the very end of 1992. [63] 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.[67] 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.[68]
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".
US$
1.6 billion; paclitaxel is now available in generic form.

Society and culture

Legal status

Paclitaxel was approved for medical use in the European Union in 2008.[70]

In November 2023, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Naveruclif, intended for the treatment of metastatic breast cancer, metastatic adenocarcinoma of the pancreas and non-small cell lung cancer.[70] The applicant for this medicinal product is Accord Healthcare S.L.U.[70]

Economics

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).[71]

Research

Caffeine has been speculated to inhibit paclitaxel-induced apoptosis in colorectal cancer cells.[72]

Aside from its direct clinical use, paclitaxel is used extensively in biological and biomedical research as a

motor proteins, or for studies of mutant motor proteins. Moreover, Paclitaxel has been used in vitro to inhibit insulin fibrillation; in a molar ratio of 10:1 (insulin:paclitaxel), it hindered insulin fibrillation near 70%. Iso-thermal titration calorimetry (ITC) findings indicated a spontaneous tendency of paclitaxel to interact with insulin through hydrogen bonds and van der Waal's forces.[73] 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.[74] 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[75] and inhibits hPAD2 in vitro though its methyl ester side chain.[76] Angiotech Pharmaceuticals Inc. began phase II clinical trials in 1999[77] as a multiple sclerosis treatment but in 2002, reported that the results showed no statistical significance.[78]

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.[79][80]

Additional images

  • Space-filling model of paclitaxel
    Space-filling model of paclitaxel
  • Rotating paclitaxel molecule model
    Rotating paclitaxel molecule model
  • Crystal structure of paclitaxel
    Crystal structure of paclitaxel
  • Total charge surface of taxol. Minimum energy conformation.
    Total charge surface of taxol. Minimum energy conformation.

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Further reading

External links
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