Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific Yew tree, ''Taxus brevifolia'' and named it 'taxol'.
When it was developed commercially by Bristol-Myers Squibb (BMS) the generic name was changed to 'paclitaxel' and the BMS compound is sold under the trademark 'TAXOL'. In this formulation, paclitaxel is dissolved in Cremophor EL and ethanol, as a delivery agent. A newer formulation, in which paclitaxel is bound to albumin, is sold under the trademark Abraxane.
Paclitaxel is now used to treat patients with lung, ovarian, breast cancer, head and neck cancer, and advanced forms of Kaposi's sarcoma. Paclitaxel is also used for the prevention of restenosis.
Paclitaxel stabilizes microtubules and as a result, interferes with the normal breakdown of microtubules during cell division. Together with docetaxel, it forms the drug category of the taxanes. It was the subject of a notable total synthesis by Robert A. Holton.
As well as offering substantial improvement in patient care, paclitaxel has been a relatively controversial drug. There was originally concern because of the environmental impact of its original sourcing, no longer used, from the Pacific yew. In addition, the assignment of rights, and even the name itself, to Bristol-Myers Squibb were the subject of public debate and Congressional hearings.
Paclitaxel is approved in the UK for ovarian cancer, breast
cancer, lung cancer. It is also used in the treatment of Kaposi's
It is recommended in NICE guidance of June 2001 that it
should be used for non-small cell lung cancer in patients unsuitable
for curative treatment, and in first-line and second-line treatment of
ovarian cancer. In September 2001 NICE recommended that 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. In September 2006 NICE
recommended that paclitaxel should ''not'' be used in the adjuvant
treatment of early node-positive breast cancer.
The cost to the NHS per patient in early breast cancer, assuming four cycles of treatment, is about $6000.
The closely related taxane docetaxel has a similar set of
clinical uses to paclitaxel. It is marketed under the name of Taxotere.
Much of the clinical toxicity of paclitaxel is associated with the solvent Cremophor in which it is dissolved for delivery.
Abraxis Bioscience developed Abraxane, in which paclitaxel
is bonded to albumin as an alternative delivery agent as an alternative
to the often toxic solvent delivery method. This was approved by the
Food and Drug Administration 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.
Cremophor EL is used in paclitaxel possibly as a dose
limiting agent because of its toxicities. (A formulation of paclitaxel
that uses nanoparticle albumin instead of Cremophor EL is marketed as
an alternative under the trade name of Abraxane.
Paclitaxel is used as an anti-proliferative agent 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.
Paclitaxel drug eluting coated stents are sold under the trade name
Taxus by Boston Scientific in the United States.
Aside from its direct clinical use, paclitaxel is used extensively in
biological and biomedical research as a microtubule stabilizer. In
vitro assays involving microtubules, such as motility assays, generally
rely on paclitaxel to maintain microtubule integrity in the absence of
the various nucleating factors and other stabilizing elements found in
the cell. For example, it is used for in vitro tests of drugs that aim
to alter the behavior of microtubule motor proteins, or for studies of
mutant motor proteins.
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.
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