Breast cancer taxol

F.14 Paclitaxel, which is extracted from the Pacific yew tree Taxus brevifolia, has antitumor activity for ovarian and breast cancer. It is sold under the trade name Taxol. On analysis, its mass percentage composition is 66.11% C, 6.02% H, and 1.64% N, with the balance being oxygen. What is the empirical formula of paclitaxel ... 

The chromatid separation process has also remained mysterious. It is an autonomous process that does not direcdy depend on the mitotic spindle (Wilson 1925, Mazia 1961). This is most vividly seen in cells whose spindles have been destroyed by spindle poisons such as colchicine. In many organisms, in particular in plant cells, the cell cycle delay induced by colchicine is only transient and chromatids eventually split apart in the complete absence of a mitotic spindle (Mole-Bajer 1958, Rieder Palazzo 1992) (Fig. 2). Mitosis in the presence of colchicine or colcemid (known as c-mitosis) leads to the production of daughter cells with twice the normal complement of chromosomes. This process is routinely used for manipulating plant genomes and may contribute to the therapeutic effects of taxol in treating breast cancer. 

Since the discovery of the anticancer potential of Taxol , a complex compound isolated from the bark extract of the Pacific yew tree, more than 20 years ago, there has been an increasing demand for the clinical application of this compound. First, the promising results of the 1991 clinical trials in breast cancer patients were announced, and soon after Bristol-Myers-Squibb trade-marked the name Taxol and used it as an anticancer drug. At that point, the only source of the drug was the bark of the endangered yew tree. Fortunately, it was soon discovered that a precursor of Taxol could be obtained from an extract of the tree needles instead of the bark. 

Paclitaxel (Taxol, Bristol-Myers Squibb) is a chemotherapy drug for ovarian cancer, breast cancer, and certain lung cancers. It was discovered by the US National Cancer Institute in the 1960s. Originally, it was extracted from the bark of the North American yew tree (Taxus brevifo-lia). Clinical tests had necessitated the harvesting of the bark, and this method damaged the trees irreversibly. 

Huang Y, Ray S, Reed JC, et al. Estrogen increases intracellular p26Bcl-2 to p21Bax ratios and inhibits taxol-induced apoptosis of human breast cancer MCF-7 cells. Breast Cancer Res Treat 1997 42( 1 ) 73—81. 

There are several books on the history of the development of taxol, which is one of the most remarkable stories in product development. In fact, it inspired the 1992 motion picture Medicine Man, starring Sean Connery as a research botanist looking for a cancer cure in the Brazilian rain forest. For a time, it became a moral drama pitting the needs of patients of intractable ovarian and breast cancer against the passions of environmentalists to preserve an obscure Pacific yew tree. Suffness and Wall are two of the principals in this story, and they wrote (1995) It [Taxol] is not an obvious winner till the very end, and there were a number of times till the very end when it seemed highly likely that it would not be put into development at all, or that once it had been accepted, it would be dropped. More than 30 years passed between the discovery of taxol, with its potential as an anticancer drug, and its approval by the Food and Drug Administration (FDA) for clinical use. 

Some 60,000 U.S. women die of ovarian and breast cancer each year. Each patient would need 2g of taxol, which means 120 kg of taxol per year. This would mean 800,000 Taxus trees per year, assuming a yield of 1500 ppm. Since six century-old trees had to be killed to treat each patient, the destruction or extinction of these trees aroused the anger of many environmentalists. To ensure the future supply of trees, the Weyerhauser company was asked to grow more than 500,000 yew plants as starter material for future production. In 1990, a large-scale clinical Phase III trial began on ovarian cancer, and the supply of taxol for these crucial clinical trials became... 

In 1992, a New Drug Application for taxol was filed by BMS. The FDA approved taxol for the treatment of refractory ovarian cancer 6 months after filing. In December 1992, the FDA approved taxol for marketing. It had been 30 years since the first collection of Pacific yew for testing at the Research Triangle Institute. In 1993, taxol was marketed by BMS. In 1994, a supplemental FDA approval was issued for taxol in treatment of metastatic breast cancer. 

Taxol is the showcase for the billions spent by the NCI over many decades. But there has not yet been a dramatic decrease in the death rate from cancer in the United States. Future challenges include discovering whether some derivatives of taxol would be even more effective than taxol, more easy to administer, and could be made at lower cost. The total synthesis of taxol also gives us the tool to investigate numerous alternatives. Another challenge is whether we can go beyond ovarian and breast cancer to treat the big killers of lung and stomach cancer. 

Taxol—One of the most effective modern cancer drugs, came out of a massive government search for new cancer medicines from plants. Taxol is used to treat cancer of the ovary, breast, and certain forms of lung cancer. Taxol comes from the bark and needles of a yew tree. 

Taxol Terpenoid Ovarian, breast cancer Taxus brevifolia (western yew tree)... 

Investigators found that human breast cancer cell lines with BRCAl mutations showed a twofold to fourfold increase in apoptosis after treatment with ionizing radiation, cisplatin, or doxorubicin, compared with cells free of mutations. They also found that BRCAl tumor cell lines were resistant to other agents, such as paclitaxel (Taxol) and docetaxel (Taxotere), treatments used commonly in ovarian cancer and advanced-stage breast cancers. 

Vinblastine (6.73) is an antimitotic drug that prevents polymerization of tubulin (Figure 6.26). When incubated with tubulin, vinblastine complexes in a 1 1 ratio with tubulin proteins. By blocking polymerization, vinblastine prevents microtubule formation and therefore mitosis. In contrast, paclitaxel (Taxol, 6.74) and epothilone B (6.75) stabilize aggregated tubulin. As a result, in the presence of paclitaxel and epothilone B, cells form static bundles of microtubules that are nonfunctional. Vinblastine and paclitaxel are both approved for clinical use against cancer. Ixabepilone (6.76), an analogue of epothilone B (6.75), has been approved by the FDA for treatment of certain forms of breast cancer. The European Medicines Agency (EMEA) did not approve ixabepilone out of concern over severe side effects.27... 

Several other events occur simultaneously with these activities. Some events focus on extending therapeutic applications and formulations. Clinical studies are conducted to extend the diseases (indications) for which the drug is proven efficacious and safe. For example, TAXOL was initially approved for the treatment of ovarian cancer, and was later extended for the treatment of breast cancer after follow-on clinical studies demonstrated efficacy for the new indication. In addition, new product formulations are investigated to extend the routes of administration for patient convenience, increased bioavailability, and new disease therapies. For example, a drug initially developed as an injectable product may be formulated as a tablet for oral administration. 

The ADEPT approach has been recently investigated as a means of overcoming the side-effects of using taxol to treat breast cancer by utilizing a /Mactamasc enzyme antitumor antibody conjugate and a cepham sulfoxide derivative of taxol (PROTAX). The localized /Mactamase enzyme, which is not normally found in any other tissues, ensures selective release of taxol at the tumor site. The prodrag is almost as effective as... 

The efficacy and toxicity of Caelyx in combination with paclitaxel (Taxol) were investigated as a first-line therapy in 34 patients with advanced breast cancer in a multicentric phase II study [428], Paclitaxel at a dose of 175 mg/m2 and Caelyx (30 mg/m2) were administered intravenously every 3 weeks. It was shown that the response rates of the combination were over 70% while the median time to treatment failure was 45 weeks. No significant clinical cardiotoxicity was observed and the usual side effects (mucositis, stomatitis, hand-foot syndrome) were treated accordingly. 

Vorobiof, D. A., Rapoport, B. L., Chasen, M. R., Slabber, C., McMichael, G., Eek, R., and Mohammed, C. (2004), First in line therapy with paclitaxel (Taxol ) and pegylated liposomal doxorubicin (Caelyx ) in patients with metstatic breast cancer A multicentre phase II study, Breast, 13,219-226. 

In 2004, Liu et al. made an effort to incorporate estradiol into C-2, 7, and 10 positions in Taxol to target the drug to estrogen receptor (ER) positive breast cancer. For C-2 and C-7 conjugates, no satisfactory results were obtained for either activity or selectivity. But a 7-epi-lO-conjugated taxoid (119) did exhibit some selectivity between ER-positive and negative cancer cells, and ER-(3 (MDA-MB-231 cell) and ER-a expressing (MCF-7) cancer cells. " ... 

The importance of organic synthesis in preparing useful drugs such as aspirin and taxol, an anticancer dmg used to treat breast cancer (Section 7.19)... 

Liu C, Strobl JS, Bane S, Schilling JK, McCracken M, Chat-terjee SK, Rahim-Bata R, Kingston DGI. Design, synthesis, and bioactivities of steroid-Unked taxol analogues as potential targeted drugs for prostate and breast cancer. J. Nat. Prod. 2004 67 152-159. 

Wilson W, Berg S, Kang K. Phase Fll study of Taxol. 96 hour infusion in refractory lymphoma and breast cancer pharmacodynamics and analysis of multi drug resistance (mdr-1). Proc Am Soc Clin Oncol 1993 335 134. 

Holmes FA, Walters RS, Therianlt RL, Forman AD, Newton LK, Raber MN, Bnzdar AU, Frye DK, Hortobagyi GN. Phase II trial of taxol, an active drng in the treatment of metastatic breast cancer. J Natl Cancer Inst 1991 83(24) 1797-805. 

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