Taxol side effects

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... 

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. 

This type of tubulin activity has so far been exclusively found in the four above-mentioned natural products and some derivatives, although far more then 140000 synthetic compounds and extracts have been tested. Of these four compounds, epothilones appear to be the best candidates. They are equally or even more active, e.g. up to 35 000 times better then Taxol in resistant cell lines [2]. They also have better cytotoxic potential connected to the tubulin activity, as not all microtubule stabilizers lead to sufficient cell death, and they allow extensive derivatization much faster then Taxol or discodermolide [3, 4]. Also, improvements in the applicability to patients compared to the sparingly soluble Taxol arc expected, eliminating some of the severe side effects connected to the latter drug. Since the binding sites of Taxol and epothilones overlap, epitope comparisons and models of binding... 

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. 

Several other groups have reported effective dioxirane systems employing Oxone as the terminal oxidant. For example, Armstrong et al. have developed a spirocyclic iV-carbethoxy-azabicyclo[3.2.1]octanone precatalyst, which affords up to 91.5% ee in the epoxidation of stilbenes (eq 102). Shing et al. have developed an arabinose-derived ketone and employed this in the enantioselective synthesis of the Taxol side chain however, enantioselectivities for the epoxidation were only up to 68% (eq 103). Bortolini et al. have also described the epoxidation of alkenes with the stoichiometric keto bile acid-Oxone system, a range of ee values were observed over several substrate types but up to 98% was observed for the epoxidation of tran -stilbene, although the yield was only 50% (eq 104). ... 

With the aim to overcome the excessive VSMC proliferation observed after BMS implantation, devices able to locally deliver antiproliferative drugs (drug-eluting stents [DESs]) have been developed (Figure 15.21). The most used antiproliferative drugs are sirolimus (Rapamycin ) and paclitaxel (Taxol ). The delivery of these antiproliferative drugs from DES reduces artery restenosis (down to 5%-10% of treated patients [211,212]) more efficiently than BMS. However, DESs did not completely solve the problem [213] as they can trigger unwanted side effects such as stent thrombosis (ST) and delayed restenosis compared to BMS [214,215]. 

The phosphonate analog 7.7.3 of the taxol side chain has been prepared by addition of dimethyl phosphite to racemic A -Boc-phenyl-glycinal 7.7.1, followed by crystallization to give the 5yn-diastereomer 7.7.2 in 50% yield. Resolution to give 7.7.3 was effected via the (5)-0-methylmandelate esters (292, 293), Similar syntheses have been applied to the docetaxel side chain 294). 

Standard methods, and this was protected as the cyclic 1,2-carbonate and oxidized to 12.21. Removal of the cinnamoyl side chain was effected by osmylation followed by mild base to give the triol 12.22 and, in a nice touch, the diol 12.23 the latter compound was obtained in optically pure form and could be converted to the taxol side chain by known chemistry. Formation of the oxetane 12.24 from 12.22 followed the same pathway used by Scheeren and his coworkers 406), and ring-opening of the carbonate followed by reduction at C-13 gave 7-deoxybaccatin III (12.25). The synthesis was completed by attachment of the side chain to give 7-deoxytaxol (12.26). 

This chapter is going to summarize the different aspects of discovery, analysis, semisynthesis, clinical application, side effects, and also related compounds of taxol as a valuable natural product in cancer therapy. 

Paclitaxel and docetaxel, as very powerful anticancer drugs, proved to be a life saver for thousands of patients with various types of cancer. However, these drugs are expensive and difficult to synthesize and cause undesirable side effects as well as drug resistance, and their natural sources are limited. These mean that to remain taxol as an inexpensive drug in the pharmaceutical markets, separadmi of other biologically active compounds from renewable sources and new methods of synthesis or biotechnological cultivation techniques of plant cell and tissues to supply new generation of taxoids would be demanded. 

An interesting application of this methodology concerns the potassium t-butoxide induced preparation of the 33 -diethoxy-4-phenyl-azetidinone which represents an interesting intermediate for the synthesis of the taxol 3 side chain (Scheme 17). For this purpose, the 3,3 -diethoxy-azetidinone was prqtared in 90% yield by treatment of the ethyl ester of diethoxyacetic acid with the p-methoxyphenylimine of benzaldehyde. This compounds is then hydrolyzed with sulfuric acid to give the azetidin-2,3-dione in 93% yield. The effectiveness of this compound as a synthon of the taxol side chain has already been demostrated. ... 

Taxol obviously is not made for human consumption. It is not made to fit human physiology. Taxol is not soluble in water, for one thing, and hence difficult to administer, and, though unusually well tolerated by humans, it does have some side effects and some resistance to it would develop. To improve the effectiveness of a drug and reduce the side effects, one tries to modify the drug. This part is the realm of chemistry (sometimes called medicinal chemistry ). Two entirely different ways can be used to do this. One is trial and error, and the other is a more rational way. In the first. 

N-octyl-O-sulfate chitosan Micelles Drug carrier/reduce toxicity and improve bioavailability New formulation of Paclitaxel (Taxol)-PTX with better efficacy and fewer side effects for cancer treatment... 

The current clinical formulation of anti-cancer drug taxol is in a 50 50 mixture of Cremophore EL and ethanol, which is physically incompatible with intravenous infusion system and causes serious side effects such as hypersensitivity and neurotoxicity. (31) Here, degradable OCL worm micelles prove to be compatible with cultured cells and blood, offering great advantage over the conventionally surfactants as a potential alternative carrier for taxol. 

---