Attention:

Certain features of Sigma-Aldrich.com will be down for maintenance the evening of Friday August 18th starting at 8:00 pm CDT until Saturday August 19th at 12:01 pm CDT.   Please note that you still have telephone and email access to our local offices. We apologize for any inconvenience.

Plant Profiler

Yew (Taxus sp)


Yew (Taxus sp) Image
Synonyms / Common Names / Related Terms
Chinwood, common yew, Coniferae (family), docetaxel, Eibe (German), euar (Manx), European yew, hagina (Basque), Himalayan yew, idegran (Swedish), if (French), Irish yew, iubhar (Scottish Gaelic), iúr (Irish), ivenenn (Breton), marjakuusi (Finnish), Japanese yew, Pacific yew, paclitaxel, phloroglucindimethylether (3,5-dimethoxyphenol), porsukagaci (Turkish), snottle berries, snotty grogs, T. bourcieri Carrière, taks (Danish), tasso (Italian), Taxaceae (family), taxine, taxis (Dutch), Taxol®, Taxomyces andreanae, Taxotere® N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol, Taxus baccata L., Taxus brevifolia, Taxus canadensis, Taxus cuspidata, Taxus wallichiana, Taxuspine C., tejo (Spanish), tisa (Romanian), tis (Czech), western yew, ywen (Welsh), ywenn (Cornish).


Mechanism of Action

Pharmacology:

  • Constituents: An alkaloid taxine has been obtained from the seeds; this is a poisonous, white, crystalline powder, only slightly soluble in water; another principle, Milossin, has also been found.
  • Yew bark is reported to have antispasmodic, nerve toxicant, and cardiac metabolism effects. It contains many alkaloids of which taxine A and B are considered to be cardiotoxic.1,2 Taxine B affects myocardial cells of the heart by inhibiting both calcium and sodium transport across cell membranes.2 Yew also contains flavonoids. Based on herbal textbooks, old growth Pacific yew bark contains 0.01% paclitaxel. English yew needles can be used to isolate 10 desacetylbaccatin III, which can be converted to paclitaxel.
  • As a result of electrophysiological investigations, significant progress has been made with regard to the pharmacological and toxicological mechanisms of action. Current investigations suggest that the chief action is on cardiac myocytes resulting in heart failure and death in instances of animal and human poisoning.6
  • Anticarcinogenic/chemotherapeutic enhancement: Japanese yew, Taxus cuspidata, has been shown to increase the cellular accumulation of vincristine (VCR) in multidrug-resistant tumor cells. Data suggests that some taxoids in the yew may be useful for overcoming multidrug resistance in tumor cells.4 Taxol is a cytostatic drug from the yew tree.5 The prescription drug Taxol has been shown to have anticarcinogenic activity.
  • Needles from a series of wild yews (Taxus baccata L.) from Sardinia were investigated for their contents of 10-deacetyl baccatin III (DAB-III), paclitaxel (Taxol) and taxine.7 Despite a common geographical origin, ample variation of the taxoid profile was discovered, and several samples were surprisingly devoid of all terpenoid markers above. This finding is unprecedented within the European yew, while the general lack of taxine might rationalize the observation that most plants investigated are actively browsed by goats.
  • Toxic gas elimination has been reported to occur from yew trees.8
  • Taxomyces andreanae, a fungal endophyte, was isolated from the phloem (inner bark) of the Pacific yew, Taxus brevifolia.9 The fungus is hyphomyceteous and, when grown in a semi-synthetic liquid medium, produces Taxol and related compounds. Taxol was identified by mass spectrometry, chromatography, and reactivity with monoclonal antibodies specific for taxol. Both [1-14C]acetic acid and L-[U-14C]phenylalanine served as precursors of [14C]taxol in fungal cultures. No Taxol was detected in zero-time cultures or in the small agar plugs used to inoculate the culture flasks.
  • Taxotere (docetexel) [N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol] is a new chemical entity obtained by semisynthesis from 10-deacetylbaccatin III, a non cytotoxic precursor extracted from the needles of the European yew Taxus baccata.10 Taxotere retains the unique mechanism of action of Taxol and inhibits the depolymerisation of microtubules into tubulin. In vitro, Taxotere is cytotoxic against murine and human tumor cells with IC50 values ranging from 4 to 35ng/mL. Taxotere inhibits the clonogenic properties of fresh human tumor cells at clinically relevant concentrations. Taxotere is highly active in vivo against several experimental models: it is 2.7-fold more active than Taxol on a log cell kill basis against B16 melanoma; ten out of the twelve models of grafted murine tumors tested respond to Taxotere; it is active with 80% complete regressions against advanced C38 colon adenocarcinoma and PO3 pancreatic ductal adenocarcinoma. Finally, Taxotere is active against several human xenografts implanted in nude mice. Safety studies were performed in dogs and mice according to NCI guidelines. Toxicological effects are observed mostly is tissues with high cell turnover (bone marrow in mice and dogs, gastrointestinal tract in dogs only) or in those where microtubules play an important role (peripheral nerves in mice only). Because of its availability, due to an efficient process using a renewable source of natural precursor, its preclinical profile (higher antitumor activity than Taxol with a comparable toxicological profile) and its unique mechanism of action, Taxotere entered clinical trials and is now an FDA approved drug. Evidence of clinical activity has been noted (breast, ovarian, lung). The dose limiting toxicity is a neutropenia.
  • Docetaxel (Taxotere; Rhone-Poulenc Rorer, Antony, France) is a hemisynthetic derivative from European yew that inhibits tubulin depolymerization and enhances the formation of microtubule bundle aggregates, causing cell death.11 Activity against a variety of tumor types has been reported. Single-agent chemotherapy is rarely curative; hence, combination regimens are the logical next step in the attempt to improve tumor reduction and prolong survival. In preclinical studies, docetaxel has shown synergism with vinorelbine (Navelbine®; Burroughs Wellcome Company, Research Triangle Park, NC), etoposide, cyclophosphamide, 5-fluorouracil, and methotrexate against a variety of murine tumors; in each case, at least 60% of the maximum tolerated dose could be administered without additional toxicity. Similar studies indicated an overlap in dose-limiting toxicity for docetaxel with cisplatin or doxorubicin, whereas with vincristine at least 80% of the maximum tolerated dose could be administered without additional toxicity. A number of docetaxel combinations are currently undergoing clinical evaluation and preliminary results appear to be encouraging. In a phase I trial, the docetaxel/5-fluorouracil combination exhibited activity against refractory solid tumors; grade IV neutropenia was observed, but there was no increase in gastrointestinal toxicity. The docetaxel/doxorubicin combination demonstrated impressive antitumor activity as front-line therapy for metastatic breast cancer (response rate, 70%), with little evidence of mucositis and dose-limiting toxicity experienced by only a minority of patients. Among 12 heavily pretreated phase I patients, the docetaxel/cyclophosphamide combination produced two partial responses in patients with breast cancer; three patients had febrile neutropenia and two had grade II mucositis. The docetaxel/vinorelbine combination produced responses at all dose levels as front-line therapy for metastatic breast cancer; dose-limiting toxicity was experienced by two patients, but only when the vinorelbine dose was raised to 22.5 mg/m2. In phase II studies in non-small cell lung cancer, preliminary results have shown the docetaxel/cisplatin combination to have a promising level of activity and an acceptable toxicity profile. Future trials will continue to evaluate the role of docetaxel in combination and in sequential regimens, most particularly in metastatic breast cancer and non-small cell lung cancer.
  • Immunomodulatory effects: The needles of Taxus wallichiana (also known as Himalayan yew) gave a taxoid 1-hydroxy-2-deacetoxy-5-decinnamoyl-taxinine j, whose structure was established by spectroscopic data and confirmed by X-ray crystallography.12 This taxoid was found to possess cytotoxic and immunomodulatory activity.
  • Multidrug resistance reversal activity: The taxoid, 5alpha,13alpha-diacetoxy-10beta- cinnamoyloxy-4(20),11-taxadien-9alpha-ol (1) along with its 9,10-isomer, taxinine NN-11 (2) were isolated from Taxus cuspidata.3 Based on in vitro study, Taxus cuspidata showed low cytotoxicity against three cell lines and potent multidrug resistance reversal activity toward tumor cells.

Pharmacodynamics/Kinetics:

  • Two biflavonoids, ginkgetin (1) and sciadopitysin (2), were isolated from the MeOH extract of the young branches of Taxus cuspidata, which inhibited phosphatase of regenerating liver-3 with IC50 values of 25.8 and 46.2 microM, respectively.13

References

  1. Sinn, L. E. and Porterfield, J. F. Fatal taxine poisoning from yew leaf ingestion. J Forensic Sci 1991;36(2):599-601. 2066734
  2. Van Ingen, G., Visser, R., Peltenburg, H., Van Der Ark, A. M., and Voortman, M. Sudden unexpected death due to Taxus poisoning. A report of five cases, with review of the literature. Forensic Sci Int 1992;56(1):81-87. 1398381
  3. Dai, J., Bai, J., Hasegawa, T., Nishizawa, S., Sakai, J., Oka, S., Kiuchi, M., Hirose, K., Tomida, A., Tsuruo, T., Li, M., and Ando, M. A new taxoid from a callus culture of Taxus cuspidata as an MDR reversal agent. Chem Pharm Bull (Tokyo) 2006;54(3):306-309. 16508182
  4. Kobayashi, J., Hosoyama, H., Wang, X. X., Shigemori, H., Sudo, Y., and Tsuruo, T. Modulation of multidrug resistance by taxuspine C and other taxoids from Japanese yew. Bioorg Med Chem Lett 6-16-1998;8(12):1555-1558. 9873389
  5. Wasielewski, S. [Taxol--cytostatic drug from the yew tree]. Med Monatsschr Pharm 1993;16(2):36-37. 8095090
  6. Wilson, C. R., Sauer, J., and Hooser, S. B. Taxines: a review of the mechanism and toxicity of yew (Taxus spp.) alkaloids. Toxicon 2001;39(2-3):175-185. 10978734
  7. Valero, V. Primary chemotherapy with docetaxel for the management of breast cancer. Oncology (Williston Park) 2002;16(6 Suppl 6):35-43. 12108896
  8. Koch, W. [Toxic gas elimination from yew trees]. Munch Med Wochenschr 7-24-1970;112(30):1398. 5468385
  9. Stierle, A., Strobel, G., and Stierle, D. Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew. Science 4-9-1993;260(5105):214-216. 8097061
  10. Lavelle, F., Gueritte-Voegelein, F., and Guenard, D. [Taxotere: from yew's needles to clinical practice]. Bull Cancer 1993;80(4):326-338. 7909695
  11. Burris, H. A., III, Fields, S., and Peacock, N. Docetaxel (Taxotere) in combination: a step forward. Semin Oncol 1995;22(6 Suppl 13):35-40. 8604452
  12. Chattopadhyay, S. K., Pal, A., Maulik, P. R., Kaur, T., Garg, A., and Khanuja, S. P. Taxoid from the needles of the Himalayan yew Taxus wallichiana with cytotoxic and immunomodulatory activities. Bioorg Med Chem Lett 5-1-2006;16(9):2446-2449. 16480866
  13. Choi, S. K., Oh, H. M., Lee, S. K., Jeong, D. G., Ryu, S. E., Son, K. H., Han, D. C., Sung, N. D., Baek, N. I., and Kwon, B. M. Biflavonoids inhibited phosphatase of regenerating liver-3 (PRL-3). Nat Prod Res 2006;20(4):341-346. 16644528




Licensed by Natural Standard Copyright © 2010 by Natural Standard Corporation. All Rights Reserved.

back to Plant Profiler
back to top