Taxus brevifolia, commonly known as the Pacific yew, is a member of the yew family (Taxaceae). It is a small, slow growing evergreen tree native to the northwestern United States (Wheeler et al., 1992). In 1971, a natural product called taxol that was isolated from T. brevifolia. Taxol has been found to be useful in the treatment of various cancers.
Taxol is derived from the bark of the Pacific yew which is a potentially limited source (Wheeler et al., 1992). This limitation has been overcome by combined efforts of pharmaceutical, agricultural, and governmental agencies (Foa et al., l994). Using analytical methods, the needles and stems of the Taxus species are examined for 10-deacetylbaccatin III, a related compound that could be converted to taxol through a semi-synthetic route (Witherup et al., 1990). The concentration of taxol is less in the tips of the branches than at the base of the trunk because branch tips have more taxol in the phloem tissue, and the inner bark is thinner. Concentrations were generally lower in the needles than in the bark. Concentrations of taxol in the bark increased from May through August while the concentration in the needles changed little during that time (Vance et al., 1994)
Taxol, a diterpene alkaloid, has poor aqueous solubility and is formulated as a solution in 50% Cremophor EL and 50% dehydrated alcohol, USP (Adams et al., 1993). For medical use, it is administered intravenously by a 3 to 24 hour infusion three times per week (Guchelaar et al., 1994).
Taxol's mechanism of antitumor activity is unique because it promotes microtubule assembly and stabilizes the microtubules, thus preventing mitosis (Huizing et al., 1995). Taxol does this by reversibly and specifically binding to the B subunit of tubulin, forming microtubule polymers leading to growth arrest in the G2/M phase of the cell cycle (Gotaskie and Andreassi, 1994). This makes taxol unique in comparison to vincristine and vinblastine which cause microtubule disassembly (Gatzemeier et al., 1995). Additionally, recent evidence indicates that the microtubule system is essential to the release of various cytokines and modulation of cytokine release may play a major role in the drug's antitumor activity (Smith et al., 1995).
Due to taxol's antimitotic activity, it is a useful cytotoxic drug in treating several classic refractory tumors including head and neck cancer, small cell and non-small cell lung cancer and most notably breast and ovarian carcinomas. It may also slow the course of melanoma. Response rates to taxol treatment varies among cancers. Advanced drug refractory ovarian cancer responds at a 19-36% rate, previously treated metastatic breast cancer at 27-62%, and various lung cancers at 21-37%. Taxol has also been shown to produce complete tumor remission in some cases (Guchelaar et al., 1994).
In addition, taxol plus radiation treatment has an additive but not synergistic effect as shown in an experiment using a cervical carcinoma line (Minarik and Hall, 1994). Elderly patients aged more than 60 years did not differ with respect to administered dose intensity, number of cycles of therapy administered, or the occurrence of serious or mild toxicities (Bichner et al., 1993). Thus, elderly patients receiving taxol can be treated as aggressively as younger patients. Clinically, taxol treatment is a possible adjunct to radiation.
Taxol has a variety of harmful side effects particularly producing alterations in liver function. During taxol clearance, the liver may accumulate a 25-fold higher concentration than that found in the plasma, which may induce alterations in liver function. When isolated rat hepatocytes were exposed to taxol, aerobic metabolism was reduced, leading to an insufficient increase of the ATP via anaerobic glycolysis. The respiratory chain is also directly affected by this drug (Manzano et al., l996) Several other toxic side effects have been attributed to taxol, including hypersensitivity reactions, cardiotoxicity, neutropenia, peripheral neuropathy, mucositis, gastrointestinal toxicities, alopecia, arthralgias, and myalgias (Gotaskie and Andreassi, 1994). Myelosuppression, especially neutropenia, appears to be the dose-limiting toxicity in solid tumors at 200-250 mg/m2. Sensory neurotoxicity with typical numbness, tingling and painful paraesthesial in the extremities, diarrhea, and alopecia appear frequently. Mucositis appears to be the non-haemotological dose-limiting side effect at 390 mg/m2 that has been determined in patients with leukemia. Mypersensitivity reactions which have been fatal might be schedule dependent. Anti-allergic prophylaxis must be given, although this precaution may not be considered to fully protective (Guchelaar et al., 1994). Taxol also can suppress the immune systems of patients, deaden sensory nerves or cause nausea and hair loss (Nicoloau et al., 1996).
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Bichner, A., G. Sarosy, E. Kohn, D.O. Adams, P. Davis, J. Jacob, B.A. Chabner, and E. Reed. 1993. Age does not influence taxol dose intensity in recurrent carcinoma of the ovary. Cancer 71: 594-600.
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Foa, R., L. Norton, and A.D. Seidman. 1994. Taxol (paclitaxel): a novel anti-microtubule agent with remarkable anti-neoplastic activity. International Journal of Clinical Laboratory Research 24: 6-14.
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Guchelaar, H.J., C.H. ten-Napel, E.G. de-Vries, and N.M. Mulder. 1994. Clinical, toxicological and pharmaceutical aspects of the antineoplastic drug taxol: a review. Clinical Oncology -R- Coll Radiology. 6: 40-48.
Huizing, M.T., V.H. Misser, R.C. Pieters, W.W. ten-Bokkel-Huinink, and C.H. Veenhof. 1995. Taxanes: a new class of antitumor agents. Cancer Invest. 13: 381-404.
Manzano, A., T. Roig, J. Bermudez, and R. Bartrons. 1996. Effects of taxol on isolated rat hepatocyte metabolism. 1996. American Journal of Physiology. 271:C1957-C1962.
Minarik, L. and E.J. Hall. 1994. Taxol in combination with acute and low dose rate irradiation. Radiotherapy-Oncology. 32: 124-128.
Nicolaou, K.C., R.K. Guy, and P. Potier. 1996. Taxoids: New weapons against cancer. Scientific American 94-98.
Smith, R.E., D.E. Thornton, and J. Allen. 1995. A phase II trial of paclitaxel in squamous cell carcinoma of the head and neck with correlative laboratory studies. Semin Oncology 22:41-46.
Vance, N.C., R.G. Kelsey, T.E. Sabin. 1994. Seasonal and tissue variation in taxane concentrations of Taxus brevifolia. Phytochemistry. 36: 1241-1244.
Wall, M.E., and Wani, M. C. 1995. Camptothecin and taxol: discovery to the clinic. Cancer Res. 55: 753-760.
Wheeler, N.C., K. Jech, S. Masters, S.W. Brobst, A.B. Alvarado, A.J. Hoover, and K.M. Snader. 1992. Effects of genetic, epigenetic, and environmental factors on taxol content in Taxus brevifolia and related species. Journal of Natural Products. 55: 430-440.
Witherup, K.M., S.A. Look, M.W., Stasko, T.J. Ghiorzi, G.M.
Muschik, and G.M. Cragg. 1990. Taxus spp. needles contain
amounts of taxol comparable to the bark of Taxus brevifolia:
analysis and isolation. Journal of Natural Products. 53:
1249-1255.
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