The compound was then developed commercially by BMS, who had the generic name assigned as "paclitaxel". ===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.
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.
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.
On 21 August 1962, one of those botanists, Arthur S.
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. Accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by Monroe E.
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. 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.
The active stereoisomer is (−)-paclitaxel (shown here). } ==Production== === Bark processing === 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.
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.
They named the pure compound taxol in June 1967.
By 1969, of crude extract had been isolated from almost of bark, although this ultimately yielded only of pure material, but for several years, no use was made of the compound by the NCI.
and France had been interested in paclitaxel, beginning in the late 1970s.
It works by interference with the normal function of microtubules during cell division. Paclitaxel was first isolated in 1971 from the Pacific yew and approved for medical use in 1993.
Wani at the Research Triangle Institute, Research Triangle Park, North Carolina, in 1971.
Wall and his colleague Wani published their results, including the chemical structure, in 1971. The NCI continued to commission work to collect more Taxus bark and to isolate increasing quantities of taxol.
BMS has continued to defend its rights to the name in the courts. BMS has also been criticized for misrepresentation by Goodman and Walsh, who quote from a company report saying "It was not until 1971 that ...
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.
This required increasing quantities of purified taxol, up to , and in 1977 a further request for of bark was made. In 1978, two NCI researchers published a report showing taxol was mildly effective in leukaemic mice.
This required increasing quantities of purified taxol, up to , and in 1977 a further request for of bark was made. In 1978, two NCI researchers published a report showing taxol was mildly effective in leukaemic mice.
In November 1978, taxol was shown to be effective in xenograft studies.
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.
Together with formulation problems, this increased interest from researchers meant that, by 1980, the NCI envisaged needing to collect of bark.
Animal toxicology studies were complete by June 1982, and in November NCI applied for the IND necessary to begin clinical trials in humans. ===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.
Animal toxicology studies were complete by June 1982, and in November NCI applied for the IND necessary to begin clinical trials in humans. ===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.
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.
The processes used were descendants of the original isolation method of Monroe Wall and Mansukh Wani; by 1987, the U.S.
By 1988, Poitier and collaborators had published a semisynthetic route from needles of the European yew to paclitaxel. The view of the NCI, however, was that even this route was not practical.
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. The first public report from a phase II trial in May 1988 showed promising effects in melanoma and refractory ovarian cancer.
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.
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.
but of a hand-over of taxol (and its problems)". 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.
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. === Semisynthesis === Concurrently, synthetic chemists in the U.S.
The choice of BMS later became controversial and was the subject of Congressional hearings in 1991 and 1992.
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 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.
coli and yeasts. ===Total synthesis=== 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.
The choice of BMS later became controversial and was the subject of Congressional hearings in 1991 and 1992.
This was controversially approved in 1992.
It works by interference with the normal function of microtubules during cell division. Paclitaxel was first isolated in 1971 from the Pacific yew and approved for medical use in 1993.
The active stereoisomer is (−)-paclitaxel (shown here). } ==Production== === Bark processing === 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.
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.
Compared to the semisynthesis method, PCF eliminates the need for many hazardous chemicals and saves a considerable amount of energy. In 1993, paclitaxel was discovered as a natural product in a newly described endophytic fungus living in the yew tree.
Nicolaou who had the first article to appear in print (by a week, on 7 February 1994).
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.
in 1996 and Takahashi et al.
in 1997, and Kuwajima et al.
in 1998 with further linear syntheses, and Danishefsky et al.
began phase II clinical trials in 1999 as a multiple sclerosis treatment but in 2002, reported that the results showed no statistical significance. In 2016 in vitro multi-drug resistant mouse tumor cells were treated with paclitaxel encased in exosomes.
Annual sales peaked in 2000, reaching US$1.6 billion; paclitaxel is now available in generic form. == Society and culture == , the cost to the NHS per patient in early breast cancer, assuming four cycles of treatment, was about £4000 (approx.
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.
Also, dye-marked exosomes were able to mark tumor cells, potentially aiding in diagnosis. ==Additional images== Image:Taxol.jpg|Space-filling model of paclitaxel Image:Taxol.gif|Rotating paclitaxel molecule model Image:Paclitaxel JMolBiol 2001 1045.jpg|Crystal structure of paclitaxel Image:Taxol total charge surface.gif|Total charge surface of taxol.
began phase II clinical trials in 1999 as a multiple sclerosis treatment but in 2002, reported that the results showed no statistical significance. In 2016 in vitro multi-drug resistant mouse tumor cells were treated with paclitaxel encased in exosomes.
While it seems clear the NCI had little choice but to seek a commercial partner, there was also controversy about the terms of the deal, eventually leading to a report by the General Accounting Office in 2003, which concluded the NIH had failed to ensure value for money.
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.
In September 2006, NICE recommended paclitaxel should not be used in the adjuvant treatment of early node-positive breast cancer.
in 2006 with further convergent syntheses.
Another company which worked with BMS until 2012, Phyton Biotech, Inc., uses plant cell fermentation (PCF) technology.
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.
began phase II clinical trials in 1999 as a multiple sclerosis treatment but in 2002, reported that the results showed no statistical significance. In 2016 in vitro multi-drug resistant mouse tumor cells were treated with paclitaxel encased in exosomes.
In 2018, it is approved in the United States for the treatment of breast, pancreatic, ovarian, Kaposi's sarcoma and non-small-cell lung cancers. ===Similar compounds=== Albumin-bound paclitaxel (trade name Abraxane, also called nab-paclitaxel) is an alternative formulation where paclitaxel is bound to albumin nanoparticles.
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