Paclitaxel ( PTX ), sold under the trademark Taxol , among others, is a chemotherapy drug used to treat certain types of cancer. These include ovarian cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. This is given by injection into a blood vessel. There is also an albumin-bound formulation.
Common side effects include hair loss, bone marrow suppression, numbness, allergic reactions, muscle aches, and diarrhea. Other serious side effects include heart problems, increased risk of infection, and inflammation of the lungs. There are concerns that use during pregnancy can cause birth defects. Paclitaxel belongs to the taxane group of drugs. It works by disrupting 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. It is on the List of Essential Medicines of the World Health Organization, the most effective and safe medicines needed in the health system. Wholesale costs in developing countries are around 7.06 to 13.48 USD per 100mg bottle. This amount in the United Kingdom costs NHS about  £ 66.85. Now produced by cell culture.
Video Paclitaxel
Medical use
Paclitaxel is approved in the UK for ovarian, breast and lung, bladder, prostate, melanoma, esophagus, and other types of solid tumor cancers as well as Kaposi's sarcoma. It is recommended in the June 2001 NICE guidelines that should be used for non-small cell lung cancer in patients not suited for curative treatment, and in first-line and second-line care of ovarian cancer. In September 2001, NICE recommended paclitaxel should be available for advanced breast cancer treatment after anthracyclic chemotherapy failure, but first-line use should be limited to clinical trials. In September 2006, NICE recommends paclitaxel should be not used in the adjuvant treatment of early positive node breast cancer. In 2005, its use in the United States for breast cancer, pancreatic, and non-small breast cancer treatment was approved by the FDA.
Similar compounds
Albumin-bound Paclitaxel (the Abraxane trade name, also called nab-paclitaxel) is an alternative formulation in which paclitaxel is bound to albumin nano-particles. Most of the clinical toxicities of paclitaxel are associated with diluted Cremophor EL solvents for delivery. Abraxis BioScience developed Abraxane, in which paclitaxel is bound to albumin as an alternative delivery agent for the toxic solvent delivery method. It was approved by the US Food and Drug Administration in January 2005 for the treatment of breast cancer after failure of a combination of chemotherapy for metastatic or recurrent disease within six months after adjuvant chemotherapy.
A synthetic approach to paclitaxel production led to the development of docetaxel. Docetaxel has a set of clinical uses similar to paclitaxel and is marketed under the name Taxotere.
Recent presence of taxanes including paclitaxel, 10-deacetylbaccatin III, baccatin III, paclitaxel C, and 7-epipaclitaxel in the shells and leaves of hazel plants have been reported. The discovery of this compound in the shell, which is considered a material that is discarded and mass-produced by many food industries, is attractive for the availability of paclitaxel in the future.
Restenosis
Paclitaxel is used as an antiproliferative agent for the prevention of restenosis (reconstituted narrowing) of coronary and peripheral stents; locally sent to the arterial wall, the paclitaxel layer limits the growth of neointima (scar tissue) within the stent. Paclitaxel drug eluting coated stent for the placement of coronary arteries is sold under the trade name Taxus by Boston Scientific in the United States. Paclitaxel drug eluting coated stents for femoropopliteal artery placement are sold under the trade name Zilver PTX by Cook Medical, Inc.
Maps Paclitaxel
Side effects
Common side effects include nausea and vomiting, loss of appetite, taste changes, thinning or brittle hair, pain in the joints of the arms or legs lasting two to three days, discoloration 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, hand-foot syndrome, changes in bowel habits for more than two days, fever, chills, cough, sore throat, difficulty swallowing, dizziness , shortness of breath, severe fatigue, skin rashes, facial flushing, female infertility by ovarian damage, and chest pain can also occur. Neuropathy can also occur.
Dexamethasone is given before starting paclitaxel treatment to reduce some of the side effects.
A number of these side effects associated with the excipient used, Cremophor EL, polyoxyethylene castor oil, and allergic to cyclosporine, teniposide, and other drugs containing polyoxyethylene cotton oil may show an increased risk of adverse reactions to paclitaxel.
Action mechanism
Paclitaxel is one of several cytoskeletal drugs that target tubulin. Cells treated with paclitaxel have defects in the assembly of mitotic spindles, chromosomal segregation, and cell division. Unlike other tubulin targeting drugs such as colchicine that inhibit the assembly of microtubules, paclitaxel stabilizes the microtubule polymer and protects it from discharge. The chromosome can not reach the metaphase spindle configuration. This inhibits the proliferation of mitosis and the prolonged activation of the mitotic checkpoint triggers apoptosis or regression to the G-phase of the cell cycle without cell division.
The ability of paclitaxel to inhibit spindle function is generally associated with its emphasis on the dynamics of microtubules, but recent research has shown that emphasis on dynamics occurs at lower concentrations than is needed to block mitosis. At higher therapeutic concentrations, paclitaxel appears to suppress microtubule detachment from centrosomes, a process usually activated during mitosis. Paclitaxel binds to the microtubule beta-tubulin subunit.
Production
From 1967 to 1993, almost all paclitaxel produced came from the bark of the Pacific yew, the harvest that killed the trees in the process. The process used is derived from the original isolation methods of Monroe Wall and Mansukh Wani; in 1987, NCI has contracted Hauser Chemical Research from Boulder, Colorado, to deal with bark on the scale required for Phase II and III trials. While the size of the wild population of Taxus brevifola and the substantial demand for taxol is uncertain, it has been clear for years that an alternative, sustainable source of natural supply will be needed. Early attempts to expand the source use needles from trees, or materials from other related species, including those cultivated, but these efforts are challenged by relatively low yields and often vary widely. In the early 1990s, along with increased sensitivity to forest ecology in the Northwest Pacific, paclitaxel was successfully extracted on clinically useful scales from these sources.
Simultaneously, synthetic chemists in the US and France were attracted to taxol, beginning in the late 1970s. As noted, in 1992 extensive efforts were underway to achieve total paclitaxel synthesis, efforts were motivated by a desire to generate a new chemical understanding rather than to achieve practical commercial production. In contrast, the French group Pierre Potier at the National Center de la recherche scientifique (CNRS) addressed the problem of the overall outcome of the process, suggesting that it was feasible to isolate the 10-deacetylbaccatin compound in relatively large quantities from the European yew, Taxus baccata , who grew up on the CNRS campus and whose needles are available in large quantities. Based on its structure, 10-deacetylbaccatin is seen as a viable starting material for brief semisintesis to produce taxol. In 1988 Poitier and collaborators have published a semisynthetic route of the needle from T. baccata
The NCI view, however, even this route is not practical. The Robert A. Holton group also pursues a practical semisynthetic production route; by the end of 1989, the Holton group had developed a semisynthetic route to paclitaxel with twice the yield of the Potier process. Florida State University, where Holton works, signed an agreement with Bristol-Myers Squibb to license their semisintesis and future patents. In 1992 Holton patented an 80% enhanced process, and BMS took the in-house process and began producing paclitaxel in Ireland from 10-deacetylbaccatin isolated from European yew needles. In early 1993, BMS announced that it would stop relying on the bark of the Pacific in late 1995, effectively halting the ecological controversy over its use. The announcement also made their good commitment to develop an alternative supply route, made for NCI in their CRADA application in 1989.
In 2013, the production of paclitaxel for BMS came from a semisynthetic method of Taxus baccata (European yew). Other companies working with BMS until 2012, Phyton Biotech, Inc., use cell plant fermentation technology (PC cell). By cultivating the special cell lines of Taxus in the fermentation tank, they no longer need the ongoing material resources of the actual yew tree plantations. Paclitaxel is then captured directly from the suspension broth by resin which allows concentration for highly enriched powders containing about 40% paclitaxel. The compound is then purified by a single step of chromatography followed by crystallization. Compared to semisynthesis®, PCF eliminates the need for many harmful chemicals and saves a lot of energy.
In 1993, taxol was discovered as a natural product in a newly described endophytic mushroom on yew trees. Since then it has been reported in a number of other endophytic fungi, including Nodulisporium sylviforme, Alternaria , Cladosporium cladosporioides MD2, Metarhizium anisopliae < , Aspergillus candidus MD3, Mucor rouxianus , Chaetomella raphigera Phyllosticta tabernaemontanae < , Pestalotiopsis pauciseta , Phyllosticta citricarpa , 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 is contradictory evidence for its production by endophytes, with other studies finding independent production impossible. Biosynthesis
The synthetic route of the nucleus is through terpenoid pathways, parts that have been successfully transplanted into E.coli and yeast production lines.
Synthesis
In 1992, at least thirty academic research teams globally worked to achieve the total synthesis of these natural products, with continued synthesis of simple natural products and other available starting materials. This total synthesis effort is motivated primarily by a desire to generate a new chemical understanding, rather than in the hope of the commercial production of practically paclitaxel. The first laboratory to complete the total synthesis of a much less complex starting material was the research group Robert A. Holton, who had the first article accepted for publication, and KC Nicolaou whose first article appeared in print (by a week, on February 7, 1994 ). Although Holton's submission preceded Nicolaou by one month (December 21, 1993 versus January 24, 1994), a close coincidence of the publications arising from each, a massive multiyear effort - 11-18 authors appeared in each of the 1994 publications- the end of the race to be called a "tie" or "finished photo", although each group argues that their synthetic strategy and tactics are superior.
In 2006, five additional research groups have reported the total success of paclitaxel synthesis: Wender et al. in 1997, and Kuwajima et al. and Mukaiyama et al. in 1998 with further linear synthesis, and Danishefsky et al. in 1996 and Takahashi et al. in 2006 with further convergent synthesis. On that date, all strategies aimed at preparing a 10-Deacetylbaccatin type core containing the ABCD ring system, followed generally by the addition of the last stage of the "tail" to the 13-hydroxyl group.
While "the political climate surrounding Taxol and Taxus brevifolia in the early 1990s... helped to strengthen [a] the relationship between total synthesis and inventory [taxol]", and although total synthesis activities are a requirement to explore the relationship of the taxol-activity structure through analogue generation to the test, the total synthesis effort was never seen "as a serious commercial route" to provide a large number of natural products for medical testing or therapeutic use.
History
The discovery of paclitaxel began in 1962 as a result of a US National Cancer Screening screening program. A few years later it was isolated from the bark of Pacific yew, Taxus brevifolia, the name "taxol".
The discovery was made by Monroe E. Wall and Mansukh C. Wani at the Research Triangle Institute, Research Triangle Park, North Carolina, in 1971. These scientists isolated the natural product from the bark of the Pacific yew, Taxus brevifolia , define its structure and name it "taxol", and arrange for its first biological test. The compound was then developed commercially by Bristol-Myers Squibb (BMS), which has a generic name defined as "paclitaxel".
Crop filtering program
In 1955, the National Cancer Institute (NCI) in the United States established the National Cancer Chemotherapy Service Center (CCNSC) to act as a public screening center for anticancer activity in compounds put forward by external agencies and companies. Although most of the filtered compounds come from synthetics, a chemist Jonathan Hartwell, employed there from 1958 onwards, had experience with natural product derivatives, and started a plant screening operation. After several years of informal arrangement, in July 1960, NCI commissioned USDA botanists to collect samples from about 1,000 plant species per year. On August 21, 1962, one of the botanists, Arthur S. Barclay, collected bark from a Pacific yew tree, Taxus brevifolia, in the northern woods of Packwood, Washington as part of a four-day journey to collect materials from more than 200 different species. The material was then processed by a number of CCNSC-specific subcontractors, and one of the samples of Taxus was found to be cytotoxic in the cellular test on May 22, 1964.
Thus, in late 1964 or early 1965, the fractionation and isolation laboratory run by Monroe E. Wall at Research Triangle Park, North Carolina, began working on a new sample of Taxus, isolating the active ingredient in September 1966 and announced their findings at the April 1967 meeting of the American Chemical Society in Miami Beach. They named the taxol of pure compounds in June 1967. Wall and his colleague Wani published their results, including the chemical structure, in 1971.
NCI continues to commission work to collect more bark and isolate an increase in the amount of taxol. In 1969, 28 kg of crude extract had been isolated from nearly 1,200 kg of bark, although this in turn only produced 10 g of pure ingredients, but for several years, no use was made of compounds by NCI. In 1975, it proved to be active in other in vitro systems ; two years later, the new department head reviewed the data and finally the recommended taxol was moved to the next stage in the discovery process. This required an increasing amount of pure taxol, up to 600 g, and in 1977 a further demand for 7,000 pounds of leather was made.
In 1978, two NCI researchers published a report showing that taxol was slightly effective in leukemia mice. In November 1978, taxol proved effective in xenograft studies. Meanwhile, taxol became known in cell biology, as well as the cancer community, with publication in early 1979 by Susan B. Horwitz, a molecular pharmacologist at Albert Einstein College of Medicine, suggesting taxol had a previously unknown mechanism. actions involving microtubule stabilization. Together with formulation problems, the increased interest of these researchers means that, in 1980, the NCI considered the need to collect 20,000 pounds of bark. Animal toxicology research was completed in June 1982, and in November the NCI applied for an IND to initiate clinical trials in humans.
Initial clinical trial, supply and transfer to BMS
Phase I clinical trials began in April 1984, and the decision to begin Phase II trials was conducted a year later. These larger trials required more bark and the collection of more than 12,000 pounds assigned, allowing some phase II trials to begin in late 1986. But by then it was acknowledged that the demand for taxol might be large and that more than 60,000 pounds of leather may be required as a minimum. This unprecedented amount brings ecological concerns about the impact on the yew population to focus for the first time, as local politicians and foresters express anxiety in the program.
The first public report of a phase II trial in May 1988 showed an effect on melanoma patients and a remarkable response rate of 30% in patients with refractory ovarian cancer. At this point, Gordon Cragg of Natural Product Branch NCI calculates the synthesis of taxol sufficient to treat all ovarian cancers and melanoma cases in the US will require the destruction of 360,000 trees each year. For the first time, serious consideration is given to supply problems. Because of the practical and, in particular, the financial scale of the required program, NCI decided to seek association with pharmaceutical companies, and in August 1989, it published a Cooperative Research and Development Agreement (CRADA) that offers its current supply and supply. of current bark stocks, and exclusive access to data so far collected, to companies willing to commit to provide funds to collect further raw materials, isolate taxol, and fund most clinical trials. In the words of Goodman and Welsh, the author of an important scientific book on taxol, "NCI is thinking, not collaboration,... but handing over taxol (and its problems)".
Although the offer was widely advertised, only four companies responded to CRADA, including the American company Bristol-Myers Squibb (BMS), who was elected as a partner in December 1989. BMS's choice then became controversial and was the subject of a Congressional hearing in 1991 and 1992. While it seems clear that NCI has little choice but to seek commercial partners, there is also controversy about terms of agreement, eventually leading to a report by the General Accounting Office in 2003, which concluded NIH failed to ensure the value of money. In CRADAs linked to the USDA and the Department of Internal Affairs, Bristol-Myers Squibb was granted an exclusive first rejection of all Federal Supply Taxus brevifolia . This exclusive contract caused some criticism for giving BMS a "cancer monopoly". Eighteen months after CRADA, BMS filed a new drug application (NDA), which was approved by the FDA at the end of 1992. Although there is no patent on the compound, the provisions of the Waxman-Hatch Act give Bristol-Myers Squibb a five-year exclusive marketing rights.
In 1990, BMS applied the trademark under taxol name as Taxol (R) . It was controversially approved in 1992. At the same time, paclitaxel replaced the taxol as a generic name (INN) of the compound. Critics, including the journal Nature, have argued that taxonomic names have been used for more than two decades and in over 600 scientific articles and suggested trademarks should not be given and the BMS must waive its right to me. BMS believes a name change will cause confusion among oncologists and may endanger the health of the patient. BMS continues to defend its rights on behalf of the court. BMS has also been criticized for being misrepresented by Goodman and Walsh, who cite from company reports saying "It was not until 1971 that... the test... permits paclitaxel isolation, was originally described as' compound 17". This quote, explicitly, accurately: it seems that this objection is misleadingly misleading to explain that it is a scientist performing an isolation that calls the taxol compound and it has not been called 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 was approved by the Indian Medicines Supervisor for breast cancer treatment and launched in collaboration with Biocon.
Society and culture
Name
The nomenclature for paclitaxel is structured on the tetracyclic 17-carbon (heptadecane) skeleton. There are a total of 11 stereocenters. The active steroisoisomer is (-) - paclitaxel (shown here).
Cost
In 2006, the cost for NHS per patient in early breast cancer, assuming four treatment cycles, was about Ã, Â £ 4000 (about $ 6000).
Research
A recent study suggests that caffeine may inhibit apoptosis caused by paclitaxel in colorectal cancer cells.
In addition to its immediate clinical use, paclitaxel is widely used in biological and biomedical research as microtubule stabilizers. In general, in vitro tests involving microtubules, such as motility tests, depend on paclitaxel to maintain microtubule integrity in the absence of various nucleating factors and other stabilizing elements found in the cell. For example, it is used for in vitro drug tests aimed at changing the behavior of microtubule motor proteins, or for the study of mutant motor proteins. In addition, Paclitaxel has been used in vitro to inhibit insulin fibrillation; in a 10: 1 molar ratio (insulin: paclitaxel), it inhibits insulin fibrillation by nearly 70%. Iso-thermal titration calorimetry (ITC) shows the spontaneous tendency of paclitaxel to interact with insulin through hydrogen bonding and van der Waal forces. Also, the role of paclitaxel inhibition was associated with its impact on the stability of colloid protein solutions, as it was observed that paclitaxel inhibits lysozyme fibrillation by inducing the formation of an intermediate oligomeric "off-pathway" and improving colloidal stability later. 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 discharge or to increase the number of microtubules inside the cell. Paclitaxel induces remielination in in vivo demyelinating mice and inhibits hPAD2 in vitro despite its methyl ester side chain. Angiotech Pharmaceuticals Inc. started phase II clinical trials in 1999 as a treatment of multiple sclerosis but in 2002, reported that the results did not show statistical significance.
In 2016 in vitro resistant multi-drug mouse tumor cells were treated with paclitaxel wrapped in exosomes. 98% fewer doses than common doses have the same effect. Also, color marked exosomes are able to mark tumor cells, potentially helpful in diagnosis.
Additional images
References
Source
- Goodman, Jordan; Walsh, Vivien (March 5, 2001). Taxol Stories: Nature and Politics in Pursuing Anti-Cancer Drugs . Cambridge University Press. ISBN: 978-0-521-56123-5.
External links
- Summary of NCI Drug Information for Patients.
- Definition of NCI Drug Dictionary
- Molecule of the Month: TAXOL by Neil Edwards, University of Bristol.
- Taxol Story from Florida State University.
- Berenson, Alex (October 1, 2006). "Hope, at $ 4,200 a Dose". The New York Times . Retrieved 2007-03-31 .
- US. National Library of Medicine: Drug Information Portal - Paclitaxel
Source of the article : Wikipedia
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