Taxanes docetaxel

The addition of taxanes, docetaxel and paditaxel, a newer class of agents, to adjuvant regimens comprised of the drugs listed above resulted in consistently and significantly improved disease-free survival and OS in node-positive breast cancer patients. 

The taxanes originally were extracted from the bark of the Pacific Yew tree and have found widespread use as anticancer agents. The structurally related taxanes, docetaxel and pacUtaxel, bind to and stabilize polymerized microtubules. Cells that enter mitosis in the presence of paclitaxel attempt to assemble a spindle apparatus, however the inhibition of depolymerization renders this structure unable to properly position chromosomes at the metaphase plate. Therefore, although kinetochores bind to microtubules, there is insufficient tension to inactivate the SAC. Paclitaxel-treated cells become blocked in mitosis, and eventually die by the mechanisms just described. Currently, there... 

Studies in mice have found that the taxanes docetaxel and paclitaxel, and the vehicle used for paclitaxel Cremophor, may all modify the distribution and metabolism of doxorubicin increasing its levels in the heart, liver and kidneys. This may contribute to the cardiac toxicity seen during use with paclitaxel. Similarly, m vitro studies in human myocardium showed that paclitaxel and docetaxel increased the conversion of doxorubicin to doxorubicinol, the metabolite that is thought to be responsible for cardiotoxicity. An in vitro study on the effect of paclitaxel and Cremophor on epirubicin metabolism in human blood found that paclitaxel slightly decreased production of epirubicinol. A marked inhibition of epirubicinol production occurred in the presence of Cremophor, hut because of the low... 

Evidence is limited, nevertheless the UK manufacturers advise that paclitaxel should be given to patients also receiving protease inhibitors with caution. The manufacturers of docetaxel also advise that it should be used with caution with drugs that inhibit CYP3A4, see Taxanes Docetaxel + Miscellaneous , below, which would include the protease inhibitors. 

It is probable that enzyme-inducing antiepileptics increase the metabolism of paclitaxel, and therefore it is likely that patients taking these antiepileptics will require an increase in paclitaxel dose. Further study is needed. Note that barbiturates are predicted to increase the metabolism of docetaxel, see Taxanes Docetaxel + Miscellaneous , above. 

Taxanes (paclitaxel, docetaxel) are derivatives of yew tree bark (Taxus brevifolia). They stabilize microtubules in the polymerized state leading to nonfunctional microtubular bundles in the cell. Inhibition occurs during G2- and M-phases. Taxanes are also radiosensitizers. Unwanted effects include bone marrow suppression and cumulative neurotoxicity. 

Docetaxel, another taxane, binds to tubulin to promote microtubule assembly. The pharmacokinetics of docetaxel are best described by a three-compartment model, with an a half-life of 0.08 hours, a 3 half-life of 1.6 to 1.8 hours, and a terminal half-life of 65 to 73 hours.14 Docetaxel has activity in the treatment of breast, non-small cell lung, prostate, bladder, esophageal, stomach, ovary, and head and neck cancers. Dexamethasone, 8 mg twice daily for 3 days starting the day before treatment, is used to prevent the fluid retention syndrome associated with docetaxel and possible hypersensitivity reactions. The fluid... 

The taxanes (e.g., paclitaxel and docetaxel) are a newer class of agents that rival the anthracyclines in their activity in metastatic breast cancer, becoming (arguably) the most active class of chemotherapy for this disease. 

Docetaxel -semisynthetic taxane stabilizes tubulin polymers leading to death of mitotic cells -bone marrow suppression -nausea and vomiting -mucocutaneous effects (mucositis, stomatitis, diarrhea) -hypersensitivity reactions -fluid retention syndrome -fatigue -myalgias -alopecia (universal)... 

Trastuzumab is licensed for the treatment of early breast cancer that overexpresses human epidermal growth factor receptor-2 (HER2). It may be administered as monotherapy or in combination with, for example, paclitaxel, docetaxel (taxanes) or anastrozole (aromatase inhibitors). Since trastuzumab can cause cardiotoxicity, concomitant use with anthracyclines such as... 

Sampath D, Discafani CM, Loganzo F, Beyer C, Liu H, Tan X, Musto S, Annable T, Gallagher P, Rios C, Greenberger LM. (2003) MAC-321, a novel taxane with greater efficacy than pachtaxel and docetaxel in vitro and in vivo. Mol Cancer Ther 2 873-884. 

As will be mentioned further in this chapter, the discovery of the anticancer drug, paclitaxel (21), was soon followed by sourcing issues due to the low yield of this compound in the source plant, Taxus brevifolia Nutt. This led to the semisynthesis of paclitaxel (21), from a precursor molecule, 10-deacetylbaccatin III, readily available from the leaves of Taxus baccata L., a renewable source with high yields of this compound.Docetaxel (37) is a second taxane class anticancer drug and is a semisynthetic derivative of paclitaxel (21). ... 

Fig. 1. Chemical structure of the taxanes. The chemical structures of docetaxel and paclitaxel. From ref. 5.

These preclinical works with the taxanes have now lead to the clinic where experience has shown that concurrent radiation and paclitaxel or docetaxel leads to impressive... 

The success of taxane-based therapy in cancer treatment has stimulated interest in further improving its efficacy profile and in identifying new tubulin-active agents. Two taxane analogs, BMS-184476 and BMS-188797, demonstrate greater activity than paclitaxel or docetaxel in a number of human tumor cell lines as well as in rodent solid tumors and human xenografts (4,145). BMS-184476 was discovered to be more potent... 

The initial experience with the taxanes and especially with paclitaxel in the realm of combined modality therapy has had a substantial impact on the treatment of cancers both in the United States and worldwide. Paclitaxel delivered in concert with radiation provides a classical model of the development of clinically applicable treatment strategies from laboratory-based studies. The initial in vitro works of Tishler (39) and Choy (40) have translated in a very tangible way into approaches that are clinically applicable and in the next generation of randomized clinical trials their efficacy will be compared to more traditional chemotherapies in the combined modality setting. While the experience to date with both paclitaxel and docetaxel has been largely positive, the mortality rates in many of the solid tumor types remind us that much more needs to be done. 

The taxanes, paclitaxel and docetaxel, act by promoting the assembly of microtubules. The taxanes induce cell cycle arrest in the most radiosensitive phase, G2/M thereby promoting radiosensitivity. In vitro studies have also demonstrated apoptosis in cell culture lines with paclitaxel (32). Paclitaxel dose-dependent synergy is also seen in squamous carcinoma cell lines (33). Much literature has been published reg arding the use of taxanes when combined with radiotherapy. 

The taxanes are practically insoluble in water and solubility is limited to mixtures of ethanol with poly-ethoxylated castor oil. They are generally administered in 3-24 hour infusions. The taxanes are for 90-95% plasma protein bound and primarily metabolized by P450 enzymes in the liver. Less than 10% is excreted in the urine as parent compounds. The elimination half-life of docetaxel is approximately 10 hours while that of paclitaxel has been vary-ingly reported between 5 and 50 hours. Inhibitors of the cytochrome P450 isoenzyme Cyp3A4, like keto-conazole and erythromycine, are contraindicated. 

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