T. brevifolia 2
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Taxus brevifolia
Ben Merritt
-Biology, Chemistry, and Pharmacology
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Taxus (Taxaceae)- Evergreen trees or shrubs; not resinous
or aromatic
Roots – fibrous, woody
Leaves – needles, persist for several years (evergreen), spirally arranged
(alternate), resin canals may be present or absent
Bark – scaly or fissured
-6-10 species --- mostly unique
because of geographical
location
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Taxus Growth Forms
T. chinensis
T. bacata“Repandens”
T. bacata“Little Gem”
T. brevifolia var. reptaneta
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Taxus
Seeds – one per “cone,” surrounded by fleshy aril Pollen Cones – produced annually,
axillary, globose/ovoid
- Reproductive Structures
Seed Cones – 1-2 ovules, axillary
T. cuspidata
- Aril is edible but seeds are toxic
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T. brevifolia Anatomy-shrub/small
tree 15-25m tall (200y to mature)
-dioecious
-bark scaly; outer scales
purplish/brown
-branches horizontal/droo
ping
-vegetative reproduction
common
-inner scales reddish/purple
-leaves 1-2cm x 1-4mm
-epidermal cells mostly taller
than wide
-seeds mature late
summer/fall
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Habitat
-Western NA – Alaska south to Montana, Idaho and
California- Lives in moist
areas around river banks, ravines
-Sea-level to 2200m
-May grow in sun or shade
(needs acclimation
period)
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Common Names
The only common names seem to be “Pacific Yew” and
“Western Yew.” - “yōl’-kō” in
Concow language (CA)
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Latin Name
Taxus brevifolia (Nutt.)
brevi - = short, abbreviated
-folia = foliage; leaves
↵1. Loanword of Scythian (Iranian) origin; means simply “yew” in Latin
2. From the Greek, meaning “bow”; origin of word “toxic”
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Traditional Uses
-Was sometimes used in Native American
(Algonquin) smoking mixtures called
kinnikinnick
-Needles of Taxus with uva-ursi plant said to
produce “too strong of an effect”
-Wood was used by Native
American tribes to make bows
-Used similarly by the ancient
Greeks/Romans –
considered toxic
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Modern Uses
-Originally found to have cytotoxic effects on cancer cells (antineoplastic) -Less toxic than other species, most taxol Used on a variety of
cancers (breast, ovarian, lung, colon, leukemia)
-Often 24-h infusion every few weeks
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Parts used
Primarily the bark and leaves (active
constituents in phloem)
-Was initially tested against KB cells (HeLa
derivatives); have carcinoma and
papilloma cancersOrder of potency (extract)
stem > bark > root > needles > wood >twigs
-Needles first require non-polar wash to
remove fats (then CO2, or other)
T. cuspidata
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Constituents
- Taxol – Isolated first in 1966 by Wall and Wani (0.02%, dried bark)
Contains variety of Taxanes –
taxol most active
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Mechanism of Action
Microtubule (MT) stabilization
-Beta-tubulin binding only
-Promotes assembly, discourages depolymerization
-Prevents mitosis, eventual cell death
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Undesirable Effects of Taxol Administration
(Long-term)
Causes build-up of MT’s
Effects rapidly-dividing cells – gut, bone marrow, lymphocytes
-Hypersensitivity (allergic reaction)
-Mostly due to vehicle (cremophor) – some use albumin -Peripheral Neuropathy (doses greater than 170mg/m2) – also may result from cremophor
-Neutropaenia
-Problems with heart (arrythmia, bradycardia)
-Vomiting-Mucositis (dig., painful)-Dysphagia
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Isolation/SynthesisFrom the bark (0.01-0.02%):
MeOH, then methylene chloride/H20 (or chloroform)
From the needles (0.025-0.044%):
Hexane pre-wash (waxes, lipids)
- [ ] in bark rises over summer- Concentration increases in plant material after letting sit for a week or two
Hauser Chemical used 15,000lb of bark for 1kg of taxol (0.015%)
Semi-synthetic route (80%)
10-deacetlybaccatin IIITotal synthesis
possible
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Other Methods of Isolation
Plant Cell Fermentation: Grow Taxus calluses in aqueous media, extract taxol (chromatography, crystallization)-Bristol-Myers Squibb
Endophytic Fungi?-Taxomyces andreanae
Original study – (1993)-15-20% of taxanes is taxol-24-50ng/liter-May require precursors
Later study – (2013)-Not found to have homologous genes/evidence of trans-kingdom gene transfer
- Thought to remain in membrane after isolation from tree!!!
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The Future
Taxol and related taxanes are useful in the treatment of cancer, but they have many terrible side effects.
Further research should be centered around:
1. Molecules with less toxic effects2. Specific cell targeting (work is being done with IG)3. Better vehicles for administration (albumin, pro-drug)
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• ATCC. “KB (ATCC® CCL-17TM).” <http://www.atcc.org/products/all/CCL-17.aspx> May 1 2014. • EPA. “Greener Synthetic Pathways Award: Bristol-Myers Squibb Company.”
<http://www2.epa.gov/green-chemistry/2004-greener-synthetic-pathways-award> Last updated 16 March 2014. • Hagiwara, H. and Y. Sunada. “Mechanism of Taxane Neurotoxicity.” Breast Cancer. Vol. 11(1): pp. 82-5. 2004. • Heinig, U., S. Scholz, and S. Jennewein. “Getting to the Bottom of Taxol Biosynthesis by Fungi.” Fungal Diversity. Vol. 60:
pp. 161-170. 9 April 2013. • Itokawa, H. and Kuo-Hsiung Lee. Taxus: The Genus Taxus. New York: Taylor and Francis, 2003. eBook. • Lowe, J., H. Li, K.H. Downing, and E. Nogales. “Refined Structure of αβ-Tubulin at 3.5 Å Resolution.” Journal of Molecular
Biology. Vol. 313(5): pp. 1045-57. 9 November 2001. • Markman, M. “Taxol: An Important New Drug in the Management of Epithelial Ovarian Cancer.” The Yale Journal of
Biology and Medicine. Vol. 64: pp. 583-90. 26 March 1991. • Mitchell, A.K. “Acclimation of the Pacific Yew (Taxus brevifolia) Foliage to Sun and Shade.” Tree Physiology. Vol. 18: pp.
749-57. 1998. • Morin, N. R. Flora of North America: Volume 2: Pteridophytes and Gymnosperms. Edited by Flora of North America
Editorial Committee. Toronto: Oxford University Press, 1993. eBook. • Sarosy, G., and E. Reed. “Taxol Dose Intensification and Its Clinical Implications.” Journal of the National Medical
Association. Vol. 85(6): pp. 427-31. 1993. • Stierle, A, G. Stobel, and D. Stierle. “Taxol and Taxane Production by Taxomyces andreanae, an Endophytic Fungus of
Pacific Yew.” Science. Vol. 260: pp. 214-216. 9 April 1993. • Suffness, M. Taxol Science and Applications. Boca Raton: CRC Press LLC, 1995. eBook.