Drugs paclitaxel

The significance of P-gp, however, in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in knockout mice that do not have intestinal P-gp. The gene responsible for producing that protein has been knocked out of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) of the anticancer drug paclitaxel (Taxol) compared to the control animals [54]. Another line of evidence is the recent report... 

A fine example of such a semi-synthesis is the preparation of the anti-cancer drug paclitaxel (Taxol ), a relatively scarce compound from Taxus brevifolia. Here, the natural and better accessible 10-deacetylbaccatin III, isolated from the leaves of Taxus baccata, provides the complicated ring system of paclitaxel, including all substituents with the right stereostructure (Scheme 5.1). In just four reaction steps [5] paclitaxel is obtained from 10-deacetylbaccatin III. 

Anticancer drugs Paclitaxel Docetaxel Vinblastine Vincristine Tipifarnib Diflomotecan Iiinotecan Doxorubicin Daunorubicin Etoposide Tenoposide Tamoxifen (i)... 

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). ... 

A brilliant example for the industrial-scale application of plant cell fermentation is the new process for the production of the anticancer drug paclitaxel developed by Bristol-Myers Squibb (see Figure 15.1). It starts with clusters of paclitaxel producing cells from the needles of the Chinese yew, T. chinensis, and was introduced in 2002. The API is isolated from the fermentation broth and is purified by chromatography and crystallization. The new process substitutes the previously used semisynthetic route. It started with lO-deacetylbaccatin(III), a compound that contains most of the structural complexity of paclitaxel and can be extracted from leaves and twigs of the European yew, T. baccata. The chemical process to convert 10-deacetylbaccatin(III) to paclitaxel is complex. It includes 11 synthetic steps and has a modest yield. 

The taxanes are a group of polycyclic diterpenes produced by various species of trees (such as yew) and are most commonly known as the potent anticancer drug paclitaxel (Taxol). The extraction process is costly. 

Other chemicals, which affect tubulin polymerization or spindle microtubule stability, are podophyllotoxin and the drugs, paclitaxel, benomyl, griseofulvin, nocodazole, and colecimid. 

Tange S, Scherer MN, Graeb C, et al. The antineoplastic drug paclitaxel has immunosuppressive properties that can effectively promote allograft survival in a rat heart transplant model. Transplantation 2002 73(2) 216-223. 

We applied the similar strategy for ultrasensitive quantification of a clinically important anticancer drug, paclitaxel. Although conventional high-dose therapeutic regiments of paclitaxel has been widely used for solid tumors treatment, severe side effects and acquired drug resistance are becoming major issue in clinical. Numerous... 

Eight different human tumor cell lines have been used to find the most effective dose of the drug paclitaxel, and for what period it should be given. 

Bahadur N, Leathart JBS, Mutch E et al. (2002) CYP2C8 polymorphisms in Caucasians and their relationship with pacli-taxel 6a-hydroxylase activity in human livermicrosomes. Biochem Pharmacol 64 1579-1589 Dai D, Zeldin DC, Blaisdell JA et al. (2001) Polymorphisms in CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 11 597-607... 

Larotaxel (XRP-9881, RPR 109881A) 59 (Sanofi-Aventis) is undergoing Phase III trials in patients with advanced pancreatic cancer who had been previously treated with gemcitabine, as well as in combination with cisplatin to treat locally advanced/metastatic urothelial tract or bladder cancer.124 A Phase III trial for the treatment of advanced breast cancer has been completed. Larotaxel 59129>130 js a semi-synthetic derivative of 10-deacetyl baccatin III with a docetaxel-like side chain that has a low affinity for the P-glycoprotein drug efflux pump, an efflux mechanism that diminishes the effectiveness of the marketed drugs paclitaxel 60 and docetaxel. Importantly, this low affinity should enable larotaxel 59 to be effective in tumours resistant to paclitaxel 60... 

EPIRUBICIN ANTICANCER AND IMMUNOMODULATING DRUGS-PACLITAXEL t plasma concentrations of epirubicin (t AUC by 37% and 1 clearance by 25%), particularly following sequential administration of paditaxel followed by epirubicin Attributed to altered distribution of epirubicin in the plasma and inhibition of P-gp by Cremophor, the vehicle of paditaxel formulation, resulting in 1 clearance Epirubicin should always be given prior to paditaxel... 

GEMCITABINE ANTICANCER AND IMMUNOMODULATING DRUGS-PACLITAXEL Possibly 1 anti-tumour effect in breast cancer Based on experiments on breast cell lines Avoid co-administration except in clinical trials... 

Additional polyesters were synthesized by the polycondensation of lactic acid and castor oil (Figure 5) and examined as injectable controlled delivery carriers for cytotoxic drugs (paclitaxel, methotrexate, 5FU and cis-platin). 

Taxus (yew) trees contain alkaloids called taxanes that have anticancer activity and are the basis of the semisynthetic anticancer drugs paclitaxel and docetaxel (see separate monographs), which are based on taxol, from Taxus brevifolia. 

Fig. 4. Anticancer drugs paclitaxel and docetaxel. Both compounds can be obtained by chemical structure modification of baccatin III or 10-deacetyl baccatin III...

Mase, H. Hiraoka, M. Suzuki, A. Nakanomyo, H. [Determination of new anticancer drug, paclitaxel, in biological fluids by high performance liquid chromatography]. Yakugaku.Zasshi., 1994,114, 351-355... 

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