General Description

The Pacific yew is now well known as the original source of the chemotherapy agent paclitaxel. Because of the low yield, cost of extraction, and environmental concerns, alternative sources were developed. Nonetheless, the success of paclitaxel provides strong support that mining nature for new medicines is an extremely viable approach to drug development.

Yews are evergreen trees or shrubs that were difficult to class taxonomically because they look like conifers but, because of the absence of cones and resin ducts, they were placed in a separate order. Although the yew appears to be tenacious, it is slow to reproduce. The species is dioecious, with female trees producing relatively scarce fruits. Seedlings are rare. Most often, new yew trees come from offshoots of a “mother tree,” which is why they are usually found in clusters. They grow best on deep, moist, rich rocky or gravelly soils. The largest known living Pacific yew is in Lewis County, in Washington State, near Mount Rainier. It stands 21.3 m tall, has a girth of 4.5 m, and is estimated to be 1000 years old.

Paclitaxel (Taxol) and complex diterpenoid taxanes are compounds found in Taxus brevifolia. Docetaxel (Taxotere) is a semisynthetic agent similar in action to paclitaxel derived from 10-deacetyl baccatin III, a taxane isolated from the needles of Taxus baccata, the English yew. Prior to their formal drug development, these compounds were cited as among the most promising plant compounds tested for anticancer properties in 1990.¹ The Pacific yew was first collected in 1962 by a U.S. Department of Agriculture team in Washington State as part of the large natural products screening program of the U.S. National Cancer Institute. Confirmed activity by a bark extract against the KB cell line in tissue culture was reported in 1964. Isolation studies began in 1965, and by 1971, Wall et al² at the Research Triangle Institute (Durham, N.C.) had identified paclitaxel as the active constituent.² Paclitaxel became big news in 1989, when investigators at the Johns Hopkins Oncology Center in Baltimore reported a 30% response rate in cases of refractory ovarian cancer, a remarkable rate for this type of cancer.³ The development of docetaxel began in 1981 in France. Taxanes used in conjunction with chemotherapy and irradiation have demonstrated improved results as compared with either of these therapies alone as well as better tolerance of these therapies.^3a

From 1967 to 1993, almost all paclitaxel produced was derived from the bark of the Pacific yew, the harvesting of which kills the tree. Currently, all paclitaxel production uses plant cell fermentation technology. This starts from a specific Taxus cell line propagated in aqueous medium in large fermentation tanks. Paclitaxel is then extracted directly, purified by chromatography, and isolated by crystallization.

Chemical Composition

The Pacific yew is poisonous because it contains at least 11 alkaloids, known collectively as taxines. The structure of only two of the alkaloid constituents is known: taxine A, which accounts for 30%, and taxine B, which accounts for 2%. Paclitaxel (Figure 128-1) is a pseudoalkaloid but not a constituent of taxine because its nitrogen is acylated with benzoic acid and has no basic principle. The concentration of paclitaxel in yew bark is low, only 0.01%.

FIGURE 128-1 Paclitaxel.

History and Folk Use

Historically, the yew has been highly valued for its dense, resilient, decay-resistant, tight-grained wood and its medicinal properties. The Greeks named the yew toxus in reference to its use for making a strong bow (toxon), and its poisonous nature (toxikon).² It was used as an animal and fish poison by primitive cultures as well as for murder and suicide. In the first century AD, Claudius suggested its use as an antidote for viper bites. Europeans used it as an abortifacient as well as to treat heart ailments and hydrophobia.² Native Americans used the yew for many ailments, as follows:

Women ate yew berries to prevent conception. Youths rubbed smooth sticks of yew on their developing bodies to gain its strength. Both the bark and the leaves have been brewed for tea, and powders have been made from the bark alone. The fleshy red aril (berry) that surrounds the seed is not poisonous, although the seed itself is.⁴

There is a lot of folklore about the yew’s supernatural powers. Because it is a slow-growing, long-lived tree, it was associated with immortality and used in spells to raise the dead.⁵ Because it was regarded as among the most potent of trees for protection against evil, it was considered unlucky to cut down or damage a yew tree. Many were planted in churchyards/graveyards and alongside homes for protection. Specimens survive today in spite of main trunks being hollowed out from decay following hundreds of years of existence.

Pharmacology

Paclitaxel’s anticancer action is unique in that it inhibits cell division by promoting the formation of microtubules, the rodlike structures that function as a cell skeleton, making cells more stable and resistant to depolymerization. In contrast, other anticancer phytoagents (e.g., colchicine and vinca alkaloids) induce the polymerization of microtubules. In addition, under the influence of paclitaxel, the microtubules polymerize independently of the microtubule-organizing center, which is in a perinuclear area, and instead localize predominantly in the cell’s periphery.⁶ This interferes with the mitotic spindle and selectively blocks cells in the G₂ and M phases of the cell cycle, the most radiosensitive phases. Additionally, paclitaxel induces the formation of abnormal spindle asters that do not require centrioles for enucleation and are reversible after treatment.^7–10 Furthermore, in vivo, paclitaxel has demonstrated an ability to activate the local release of an apoptosis-inducing cytokine.¹¹ Studies on cancer cell lines induced with gml, a novel gene, have demonstrated a marked increase in sensitivity to paclitaxel via apoptosis. An assay for gml expression could serve as a clinically useful predictor of chemotherapeutic sensitivity.¹²

Clinical Applications

Paclitaxel has demonstrated a broad spectrum of antitumor activity. Phase I trials, begun in 1983, demonstrated paclitaxel`s antineoplastic activity against several tumor types, such as the following^13–20:

In early studies, impressive results were seen using paclitaxel in combination with other antineoplastic agents, such as cisplatin.²¹ Having treated patients who were previously resistant to cisplatin with the combination of cisplatin and paclitaxel, the Gynecology Oncology Group reported a 33% response rate.²² Trials were quickly conducted on a number of solid tumor types, including small cell and non–small cell lung, renal, gastric, breast, advanced ovarian, colon, and cervical carcinomas; head and neck cancers; small cell lung and prostate carcinomas; and low-grade non-Hodgkin’s lymphoma.²³ Paclitaxel also has activity in other malignancies that are refractory to conventional chemotherapy, including previously treated lymphoma, small cell lung cancers, and esophageal, gastric, endometrial, bladder, and germ cell tumors. Paclitaxel is also active against AIDS-associated Kaposi’s sarcoma. Although paclitaxel is a well-accepted treatment option for these cancers and others, significant toxicities, such as myelosuppression and peripheral neuropathy, limit the effectiveness of paclitaxel-based treatment regimens.^24,25 These toxicities will be discussed further.

Toxicity

Human poisoning from the deliberate consumption of yew leaves or seeds is now rare. Published cases involving psychiatric patients and prisoners describe the first symptoms of intoxication as appearing 1 hour after ingestion. The manifestations include mydriasis, nausea, vomiting, abdominal cramping, and arrhythmia. Death occurs from cardiac arrest 3 to 24 hours after ingestion.²⁶ The lethal dose in humans is approximately four or five handfuls of leaves, corresponding to 150 needles. No specific antidote is known.

Paclitaxel binds 95% to 98% with plasma proteins yet is readily eliminated through hepatic metabolism, biliary excretion, and/or extensive tissue binding. Total urinary excretion has been insignificant, indicating that renal clearance contributes minimally to systemic clearance.^20,27–29 Hepatic metabolism via cytochrome P450 (CYP) is involved for both paclitaxel and docetaxel. However, the former is hydroxylated by CYP2C8, whereas the latter is hydroxylated by CYP3A4.³⁰

Toxicity manifests as follows:

Junctional tachycardia via conduction block rather than direct primary toxicity on myocytes has been suggested.³¹ Hypersensitivity, skin reactions, and accumulated fluid retention syndrome are minimized with a 3- to 5-day regimen of corticosteroids prior to paclitaxel infusion.³²

Patients with leukemia who are treated with high doses of paclitaxel exhibited mucositis, which has also appeared in response to lower, cumulative dosing. An accumulation of epidermal cells with abnormal paclitaxel-induced spindle asters has been evident in ulcerated mucosa, indicating that the cell cycle was arrested in mitosis.³³

Paclitaxel has been known to inhibit neurite growth and induce prominent morphologic effects, such as microtubule bundles in neurons, satellite cells, and Schwann cells in organotypic dorsal root ganglion cultures.^34–39 Clinically, the most common symptoms have been glove-and-stocking paresthesias and perioral numbness. Distal sensory loss to large-fiber (proprioception, vibration) and small-fiber (pinprick, temperature) modalities and loss or decrease of distal deep tendon reflexes have been noted, although motor nerves seem to be spared. In general, the clinical incidence and severity of peripheral neurotoxicity have been dose-related. Patients with a history of substantial alcohol use have appeared to be more predisposed to the development of the neurosensory toxic effects of cisplatin and paclitaxel.^{13–16,40–42}

The development of a suitable clinical formulation has been hampered by paclitaxel`s poor aqueous solubility. Cremophor is being used as the vehicle for administration and has been implicated in side effects, such as type 1 hypersensitivity reactions.⁴³

Neutropenia, the principal dose-limiting toxic effect of paclitaxel, resolves rapidly (in 15 to 21 days) after treatment is stopped.⁴⁰ The major clinical risk factor for neutropenia seems to be the extent of prior myelotoxic chemotherapy and/or irradiation.

Bradyarrhythmias, which have been noted as transient and asymptomatic, have been reported during paclitaxel infusion in at least 29% of patients with ovarian cancer.⁴⁰ This development appears to be related more to paclitaxel, because other agents formulated with Cremophor have not been associated with similar arrhythmias. Atypical chest pains during paclitaxel infusion have been observed, but they are believed to be a manifestation of a hypersensitivity reaction.^26,41

Other paclitaxel- or Cremophor-related side effects are sudden and complete alopecia, often occurring in a single day; local venous toxic effects such as erythema, tenderness, and cellulitis in areas of dermal extravasation; as well as fatigue, headaches, taste perversions, significant elevations in serum triglycerides, and minor rises in hepatic and renal function values.²⁰

Additional precautions may be necessary with the concurrent use of the medications listed in Box 128-1.

Medical problems that may affect the use of paclitaxel are listed in Box 128-2. Studies in rats and rabbits have shown that paclitaxel causes miscarriages and fetal deaths. Breastfeeding is contraindicated during paclitaxel therapy. Paclitaxel bound to albumin rather than using a solvent results in fewer and less severe side effects, with much reduced allergic reactions.⁴⁴