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Paclitaxel is a drug used in the treatment of cancer. It was discovered at
Research Triangle Institute (RTI) in 1967 when Dr. Monroe E. Wall and Dr.
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 ovarian and breast cancer and Kaposi's sarcoma.
It is sold under the trade name Taxol®. Together with docetaxel, it forms the
drug category of the taxanes. Production
Unfortunately, the Pacific Yew is one of the slowest growing trees in the world.
Further, 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 a bacterium (Streptomyces coelicolor) that fermentatively
produces a paclitaxel-like compound, as well as to examine the possibility of
extracting paclitaxel-like compounds from the tree's needles instead of its
bark. 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 tubulin
protein of microtubules and locks them 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 transportation highway for the
cell. Chromosomes, for example, rely upon this property of microtubules during
mitosis. 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. ABI-007
ABI-007 is a special form of paclitaxel that may have fewer side effects and may
be able to be given in higher doses.
See [1] (http://professional.cancerconsultants.com/jc_issue1_breast.aspx?id=29858)
Marketing
The license to commercialize and market Taxol is held by the Bristol-Myers
Squibb Co., which was selected for this role by the U.S. National Cancer
Institute. Bristol-Myers holds an exclusive contract in the harvesting of yew
trees from US government lands; it has been criticized for having a "cancer
monopoly" (Palast p.64).
In January 2005 the FDA approved AbraxaneTM for clinical trials. In this
potential breast cancer drug Taxol is bonded to albumin as the delivery agent as
an alternative to solvent (often toxic) delivery.
[2] (http://www.fda.gov/cder/foi/label/2005/021660lbl.pdf).
The manufacturer heralds the drug as a breakthrough in nanotechnology
[3] (http://www.appdrugs.com)
References
Greg Palast. The Best Democracy Money Can Buy. 2002.
Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI.
The isolation and structure of taxol, a novel antileukemic and antitumor agent
from Taxus brevifolia. J Am Chem Soc 1971;93:2325-7. PMID 5553076.
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