Paclitaxel
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| Clinical data | |
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| Routes of administration | iv |
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| Legal status | |
| Pharmacokinetic data | |
| Protein binding | 89 to 98% |
| Metabolism | Hepatic (CYP2C8 and CYP3A4) |
| Elimination half-life | 5.8 hours |
| Excretion | Fecal and urinary |
| Identifiers | |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.127.725 |
| Chemical and physical data | |
| Formula | C47H51NO14 |
| Molar mass | 853.906 g/mol g·mol−1 |
Paclitaxel (Taxol®) is a drug used in the treatment of cancer. It was discovered at Research Triangle Institute (RTI) in 1967 when Monroe E. Wall and Mansukh C. Wani isolated the compound from the bark of the Pacific yew tree, Taxus brevifolia, and noted its antitumor activity in a broad range of rodent tumors. By 1970, the two scientists had determined the structure of paclitaxel, which is extremely complex. Paclitaxel has since become an effective tool of doctors who treat patients with lung, ovarian, breast cancer, and advanced forms of Kaposi's sarcoma (Saville et al 1995). It is sold under the tradename Taxol®. Together with docetaxel, it forms the drug category of the taxanes. Paclitaxel is also used for the prevention of restenosis (recurrent narrowing) of coronary stents; locally delivered to the wall of the coronary artery, a paclitaxel coating limits the growth of neointima (scar tissue) within stents (Heldman et al 2001).
History
The history of paclitaxel begins with a 1958 National Cancer Institute study that commissioned Department of Agriculture botanists to collect samples of over 30,000 plants to test for anticancer properties. Arthur S. Barclay, one of those botanists, collected 15 lbs of twigs, needles, and bark from Pacific yew trees in a forest near Mount St. Helens. Months later, in 1963, Monroe E. Wall discovered that bark extract from the Pacific yew possessed antitumor qualities, beginning to reveal the tree's hidden treasure. Soon after, Wall and his colleague Mansukh C. Wani were busy isolating and purifying plant compounds for anticancer tests in Research Triangle Park, North Carolina. In 1967 the team had isolated the active ingredient, announcing their findings at an American Chemical Society meeting in Miami Beach. Wall and Wani published their results, including the chemical structure, in a 1971 issue of the Journal of the American Chemical Society.
The paper was noticed immediately by Robert A. Holton who was starting postdoctoral research at Stanford University in natural products synthesis. But, it would be several years before he dedicated his attention to synthesizing pacilitaxel at Florida State University, quelling an emerging environmental controversy; a 40-foot Pacific yew tree, which may have taken 200 years to reach that height, yields only a half gram of paclitaxel, but Holton's group perfected a four-step procedure to convert 10-deacetylbaccatin (a related compound in Pacific yew needles) into paclitaxel.
In the late 1970s, Susan B. Horwitz, a molecular pharmacologist at Albert Einstein College of Medicine in New York City, unravelled the key mystery of how paclitaxel works. Largely in part of an enormous research and development effort, starting in government facilities and later in commercial labs, paclitaxel quickly became an all-time best-selling pharmaceutical. Paclitaxel was brought to the market by Bristol-Myers Squibb in 1993 as Taxol®. Annual sales peaked in 2000, reaching US$1.6 billion.
Production
Unfortunately, the Pacific yew is one of the slowest growing trees in the world. Furthermore, the treatment of just one patient requires the cutting down and processing of six 100-year old trees. This supply problem combined with the threat to the endangered spotted owl (Strix occidentalis) has prompted researchers to develop actinobacteria from which paclitaxel-like compounds can be obtained by fermentation. Cultures of the fungus Nodulisporium sylviforme can be used to produce paclitaxel itself. [1]
Although other paclitaxel-like compounds may be extracted from various parts of yew trees, these are not as potent as paclitaxel itself. Total synthesis provides one means of accessing paclitaxel from petrochemical-derived starting materials, the results of which are summarised in the Taxol total synthesis.
However, total synthesis is not an economically feasible way of manufacturing paclitaxel, so it is commercially produced by semisynthesis. 10-Deacetylbaccatin can be extracted in relatively large amounts from various yew-related species and is easily converted by several steps of organic synthesis into paclitaxel. Cell-cultures can also be used to provide the starting 10-deactylbaccatin material.
Method of action
Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, paclitaxel binds to the β subunit of tubulin. Tubulin is the "building block" of microtubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a mechanism to transport other cellular components. For example, during mitosis, microtubules position the chromosomes during their replication and subsequent separation into the two daughter-cell nuclei.
Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function.
One common characteristic of most cancer cells is their rapid rate of cell division. In order to accommodate this, the cytoskeleton of a cell undergoes extensive restructuring. Paclitaxel is an effective treatment for aggressive cancers because it adversely affects the process of cell division by preventing this restructuring. Cancer cells are also destroyed by the aforementioned anti-Bcl-2 mechanism. Other cells are also affected adversely, but since cancer cells divide much faster than non-cancerous cells, they are far more susceptible to paclitaxel treatment.
Marketing
The license to commercialize and market Paclitaxel (as Taxol®) was held by the Bristol-Myers Squibb Co., which was selected for this role by the U.S. National Cancer Institute. Bristol-Myers held an exclusive contract in the harvesting of yew trees from US government lands; it was criticized for having a "cancer monopoly" (Palast p.188).
ABI-007
In January 2005 the Food and Drug Administration (FDA) approved Abraxane® (ABI-007) after clinical trials. Abraxane® was approved 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 this preparation, paclitaxel is bonded to albumin as the delivery agent as an alternative to solvent (often toxic) delivery. [2]. The manufacturer heralds the drug as a breakthrough in nanotechnology [3].
References
- Mitch Jacoby. Chemical & Engineering News. Volume 83, Number 25. 20 June 2005.
- Greg Palast. The Best Democracy Money Can Buy. 2002 ISBN 0452283914
- 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. PMID 5553076.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Heldman A, Cheng L, Jenkins G, Heller P, Kim D, Ware M, Nater C, Hruban R, Rezai B, Abella B, Bunge K, Kinsella J, Sollott S, Lakatta E, Brinker J, Hunter W, Froehlich J (2001). "Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis". Circulation. 103 (18): 2289–95. PMID 11342479.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Saville M, Lietzau J, Pluda J, Feuerstein I, Odom J, Wilson W, Humphrey R, Feigal E, Steinberg S, Broder S (1995). "Treatment of HIV-associated Kaposi's sarcoma with paclitaxel". Lancet. 346 (8966): 26–8. PMID 7603142.
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External links
- Molecule of the Month: TAXOL by Neil Edwards, University of Bristol.
- A Tale of Taxol from Florida State University.
- Paclitaxel from Fermentek, a vendor's product page
- Abraxane Information from Chemo Care, a nonprofit program of the Scott Hamilton CARES Initiative
- Paclitaxel coated stents from Sahajanand Medical Technologies, a Paclitaxel Coated Coronary Stent Manufacturer
- ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.