Bioactive Agents from Natural Sources: Trends in Discovery and Application - Advances in Biochemical Engineering Biotechnology - page 111

of a plant-derived drug nowadays. Taxol was discovered at the US National
Cancer Institute (NCI) in the late 1960s in the course of an in vitro antitumor
drug discovery program using human tumor cell lines.Screening of more than
110,000 samples derived from more than 35,000 plant genera collected world-
wide resulted in the isolation and structure elucidation of Taxol from the bark
of the Californian yew tree Taxus brevifolia [57].
Taxol performed outstanding activities against various tumor cell lines,but
clinical studies did not take place due to insufficient amounts of plant material
available.Only after identification ofthe unique mode ofaction ofTaxol [58,59],
both the NCI and pharmaceutical industry were attracted to pursue profiling
Taxol as a completely new anticancer drug [60].Taxol was shown to affect mito-
sis by increasing microtubuli assembling and decreasing microtubuli degrada-
tion rates.In order to enable clinical testings,for years,the only way to get access
to Taxol was to shed the bark of more than sixty year old Californian yew trees
which by the harvesting procedure were damaged irreversibly.However,world-
wide objections by environmentalists were rejected by the US authorities.
In the meantime,the problem of Taxol supply seems to be solved.The Euro-
pean yew tree Taxus baccata was identified as a renewable source of Taxol-type
metabolites.By harvesting and extracting the needles baccatin III or 10-deacetyl
baccatin III are obtained in good yields without injuring the trees substantially
and are used as precusors of Taxol synthesis.Starting from these compounds,
not only Taxol but also analogs such as Taxotère (docetaxel) were synthesized in
satisfying yields.Taxotère was recently launched by the French company Rhône-
Poulenc Rorer.The company was free to apply for a product patent to improve
commercial issues. However, Bristol-Myers Squibb only achieved trade name
protection for Taxol at the time of marketing,because the chemical structure of
Taxol had already been published in 1971.Thus,the generic name of Taxol was
designated paclitaxel. Actually, Taxol is approved for treatment of breast and
ovarian cancer.
Efforts to get access to improved manufacturing processes or improved appli-
cation properties of paclitaxel resulted in two different pathways for the total
synthesis of the natural product, as well as analogs. Furthermore, paclitaxel
and/or precursors can be obtained under optimized conditions from cell cultu-
res of Taxus media generated by hybridizing Taxus baccata and Taxus cuspidata
in overall yields ofabout 130mg l -1 within two weeks [61].Paclitaxel can also be
obtained by the culture ofappropriate microbial strains isolated from paclitaxel
producing yew trees [62-64].
A few years after the introduction of Taxol in 1996,further phytogenic anti-
cancer drugs were launched to treat advanced cancers.Topotecan,marketed by
Smith Kline Beecham under the trade name of Hycamtin,was approved by the
FDA to treat ovarian cancers that have resisted other chemotherapy drugs.
Furthermore, irinotecan was introduced by Pharmacia & Upjohn under the
trade name of Camptosar for the treatment of metastatic cancer of the colon or
rectum. Both compounds are derivatives of camptothecin which was isolated
from the Chinese tree Camptotheca acuminata ,well known in Chinese Traditio-
nal Medicine for anticancer treatment [65].Isolation of the bioactive principle
camptothecin and its structure elucidation had already been performed in 1966