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Dimère
alpha-beta
tubuline
Paclitaxel and docetaxel
• Paclitaxel is currently regarded as one of the best new anticancer
agents (1-5). The drug was approved by the U.S. Food and Drug
Administration (FDA) for the treatment of advanced ovarian cancer in
1992 and breast cancer in 1994. Since the isolation of paclitaxel from
the bark of the Pacific yew, Taxus brevifolia, in 1966, enormous
research has been performed on the drug's applications. The attention
of the medical world turned toward this new natural product in 1979
when Susan B. Horwitz and co-workers reported paclitaxel's unique
mechanism in stopping the proliferation of cancer cells (6, 7).
• Paclitaxel is the first anticancer agent that promotes tubulin assembly (a
dynamic process involved in cell proliferation) and stabilizes the
resulting microtubules. Because the cell cannot break down the
microtubules, it is incapable of going through the whole cell cycle, and
so the cell ultimately dies. Paclitaxel is currently undergoing clinical
trials for treatment of lung, head, neck, and gastrointestinal cancers. A
semisynthetic analogue called docetaxel (generic name for Taxotere),
developed by Rhône-Poulenc Rorer, was approved by the FDA in 1996
for the treatment of breast cancer (8).
The epothilones
are a novel class of non-taxane microtubule-stabilizing agents
obtained from the fermentation of the cellulose degrading
myxobacteria, Sorangium cellulosum. Preclinical studies have
shown that the epothilones are more potent than the taxanes
and active in some taxane-resistant models. Similar to
paclitaxel and other taxanes, the epothilones block cells in
mitosis, resulting in cell death. The chief components of the
fermentation process are epothilones A and B, with epothilones
C and D found in smaller amounts. Trace amounts of other
epothilones have also been detected. Pre-clinical studies have
shown that epothilone B is the most active form, exhibiting
significantly higher antitumor activity than paclitaxel and
docetaxel. Several phase I and phase II clinical trials are
ongoing with epothilone B and BMS 247550, an epothilone B
analog. Preliminary reports indicate these agents are active
against human cancers in heavily pre-treated patients. The
epothilones appear to be well tolerated, with a side effect profile
that is similar to that reported with the taxanes.
TOXICITY:
The two commercially available taxanes (paclitaxel
and docetaxel) are widely employed in standard
oncologic practice. Toxicity of the agents includes
bone marrow suppression (principally neutropenia),
complete alopecia, and hypersensitivity reactions.
While both drugs can cause neurotoxicity and
myalgias/arthralgias, this is a greater clinical
concern with paclitaxel. Docetaxel can be associated
with the development of significant fluid retention
(e.g., edema, ascites, pleural effusions), the
incidence and severity of which appear to be limited
by prophylactic treatment with corticosteroids both
before and after each treatment. If patients are
monitored closely (e.g., for hypersensitivity
reactions, bone marrow suppression) the taxanes
have a favorable side effect profile, and it is currently
uncommon for treatment to be discontinued because
of the development of excessive toxicity.