Effects of taxol

Another drug is taxol, which is extracted from the bark of the Pacific yew tree, Taxus brevijolia. Unlike colchicine and the vinca alkaloids, taxol binds tightly to microtubules and stabilizes them against depolymerization by Ca. It also enhances the rate and yield of microtubule assembly, thereby decreasing the amount of soluble tubulin in the cytosol pool. Again, the overall effect of taxol is to arrest dividing cells in mitosis. Taxol is used in cancer chemotherapy. 

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. 

Wehbe T, Glantz M, Choy H, Glantz L, Cortez S, Akerley W 3rd, Mills P, Cole B. Histologic evidence of aradiosensitizing effect of Taxol in patients with astrocytomas. JNeurooncol 1998 39(3) 245-251. 

Sharma, A., Mayhew, E., and Straubinger, R. M. (1993). Antitumor effect of taxol-containing liposomes in a taxol-resistant murine tumor modSancer Res., 53, 5877-5881. 

A. Sharma, E. Mayhew and R.M. Straubinger, Antitumor effect of Taxol-containing liposomes in a Taxol-resistant murine tumor model, Cancer Res. 53 (1993) 5877-5881. 

Numerous phase I clinical trials have already been conducted in the United States in which, using various protocols 156-160), the effects of taxol on solid tumors and on adult leukemia [a single study (767)] were evaluated. These studies have permitted determination of the doses (200-250 mg/m ) and the protocol (30 mg/m /day preceded by treatment with glucocorticoids and antihistamines) recommended for phase II evaluation, keeping in mind the main side effects caused by the solubilizing agent as well as leukopenic and neurotoxic effects. These phase II trials are currently underway, and only the results of one study (on a renal carcinoma) are presently available (762). It should be noted that one of the main obstacles to more rapid development of therapeutic uses of taxol is the very limited quantities of this drug available, for reasons already discussed. 

Figure 4. Electron micrograph of the effects of taxol on the R biotype of Eleusine. The walls in this figure have extensive groups of microtubules (arrows) along the wavy wall (w). Bar = 0.5 pm.

Note the role of dynamic instability in grotving microtubules. Describe the effects of taxol on the polymerization and depolymerization of microtubules. 

These include rhazinilam (15.4.6) 494), which inhibits the disassembly of microtubules but has a different mechanism of action than taxol, laulimalide (15.4.7) and isolaulimalide (15.4.8) 496), WS9885B (15.4.9) 497), and polyisoprenylated benzophenones such as guttiferone E (15.4.10) 497). The naturally occurring 3(2H)-furanone derivative geiparvin has been found to counteract the microtubule-assembly effects of taxol, suggesting that it is a competitive inhibitor at the taxol-binding site of tubulin 498). 

A third approach to the taxol pharmacophore was developed by Giannakakou et al 503), who compared the effects of taxol and various epothilone analogs on the polymerization of native tubulin and of modified tubulins carrying / -tubulin mutations near the taxol-binding... 

This polymer has also been investigated as an implantable ODD. For example, Lee et al. [60] investigated the effect of the implantation of a 5-fluorouracil loaded P(CPP-SA) DDS on the success of a glaucoma filtering surgery in a rabbit model, while Jumper et al. [61] used a primate model to evaluate the effect of taxol or etaposide loaded P(CPP-SA) implants in the outcomes of the same kind of surgical procedure. 

Kumar G, Ray S, Walle T, Huang Y, WilUngham M, Self S, Bhalla K. Comparative in vitro cytotoxic effects of Taxol and its major human metabolite 6 alpha-hydro-xytaxol. Cancer Chemother Pharmacol 1995 36(2) 129 35. 

The first synthesis of Taxol was completed by Robert Holton and co-workers and is outlined in Scheme 13.53. One of the key steps occurs early in the synthesis in sequence A and effects fragmentation of 4 to 5. The intermediate epoxide 4 was prepared from a sesquiterpene alcohol called patchino. 35 The epoxide was then converted to 5 by a BF3-mediated rearrangement. 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

The 5-fluorouracil (5-FU) and NONOate conjugates (Fig. 1.7) were prepared and their cytotoxicity was tested [90]. The median effect doses of the conjugates for DU145 and HeLa cancer cell lines were 2-4-fold lower than that of 5-FU. In another study by Wink et al, the cytotoxicity of cisplatin was enhanced about 60-fold after NONOate pretreatment for 30 min [91]. The enhancement of cytotoxicity of 5-FU/NONOate conjugates and cisplatin-NONOate combination has shown that there is a synergistic effect between anticancer drugs and NO. Another study by Jia et al. demonstrated that the cytotoxicity of Taxol was enhanced by S-nitrosocaptopril (Fig. 1.7) [92]. This effect is primarily mediated via the increased influx of Taxol by NO into intracellular compartments, while NO-induced cytotoxicity cannot be excluded. 

Other than RIF and Taxol, many other commonly used clinical drugs have also been shown to activate PXR. These include peptide-mimetic HIV protease inhibitors [53], the cholesterol-lowering lovastatin and the anti-inflammatory dexamethasone [54]. A more comprehensive analysis of the effect of commonly used clinical drugs on PXR activation has recently been published by Sinz and colleagues [55]. 

Fig. 2.3 Therapeutic effect of dEpoB and padi- on days 6, 8,10,12 and 14. o, control with taxel (Taxol ) in nude mice bearing CCRF- vehicle only co, paclitaxel 20 mg/kg and X, CEM/paclitaxel xenografts (57-fold resistant to dEpoB 30 mg/kg. The average tumor volume of paclitaxel) following Q2D x 5, i.v. 6 h infusion. the control group on days 12,14,16,18, and 24...

Fig. 2.4 Therapeutic effect of dEpoB and padi-taxel (Taxol ) in nude mice bearing MCF-7/Adr xenografts following Q2D x 5, i.v. treatment. Adriamycin (DX)-resistant human mammary adenocarcinoma (MCF-7/Adr) tissue 50 mg was implanted subcutaneously into nude mice on day 0. Six-hour i.v. infusions for control, dEpoB and paditaxel and i.v. injection for VBL, DX, and VP-16 were given on days 8,10,12,14 and 16. o, control with vehicle only to, VBL,...

Vincristine resistance has been studied in Chinese hamster ovary cell lines cells resistant to vincristine also are resistant to vinblastine and vindesine. Suggestions were made that, in cells with relatively low levels of drug resistance, at least two prominent mechanisms of resistance can occur (22). In the first instance, cellular resistance may be attributable to membrane alterations that are reversible, functionally, by treatment with verapamil. In the second, resistance has been postulated to be due to an altered sensitivity of tubulin to the effects of the drugs the primary basis for postulating an altered interaction with tubulin was that a subgroup of cells resistant to vincristine showed enhanced sensitivity to taxol, a drug that can stabilize microtubules. It should be emphasized that differential sensitivities of tubulins from different tumor cells to the effects of vincristine or vinblastine has been proposed as a basis for the susceptibilities of cells to the cytotoxic effects of such drugs (23). Differences have been described in the electrophoretic patterns for tubulins obtained from vin-... 

Mason KA, Milas L, Peters LJ. Effect of paclitaxel (taxol) alone and in combination with radiation on the gastrointestinal mucosa. Int J Radiat Oncol Biol Phys 1995 32(5) 1381-1389. 

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. 

In later work, Mioskowski and co-workers (320) used cyclohexenone 160 to prepare oxime 161 as part of a twofold nitrile oxide strategy to synthesize the basic taxol ring system. Cycloaddition of 161 was effected by means of sodium hypochlorite and gave tricyclic isoxazoline 162, which feamres rings A and C of taxol (320) (Scheme 6.79). Nagaoka and co-worker tried to apply a related intramolecular cycloaddition toward the synthesis of the taxane A/B ring but this approach failed, producing only the oxime derivative (248) (see Scheme 6.44, Section 6.3.1). 

The story of the discovery of taxol illustrates one of the major problems in seeking pharmaceutical agents among the himdreds of thousrmds of NPs made by plants. An effective, valuable chemical might be formd but a practical, economic source of the chemical might not be. Indeed, a natural source of a very important drug could be very bad news for threatened habitats. How that problem might be resolved is discussed later. 

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