Paclitaxel plant cell fermentation

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. 

Figure 15.1 Plant cell fermentation process for paclitaxel. Source Bristol-Myers Squibb.

Since the 1990s, paclitaxel has also been produced by plant cell fermentation. 

Plants have also provided a key source of potential cancer treatments. A well-known example is paclitaxel (Taxol ), isolated from the bark of the Pacific yew tree, which has become a blockbuster drug and analogues have also been approved for use that demonstrate improved efficacy (Fig. 1.4) [6]. Taxol also provides an excellent example to illustrate the challenges that remain in total synthesis. Numerous examples of the total synthesis of Taxol have been reported [7-13]. However, the overall yield and the number of steps required means it is not economically viable to synthesise the quantities required for its medicinal application. It is therefore obtained industrially via a semi-synthetic route starting from 10-deacetylbaccatin HI, a biosynthetic precursor, which can be isolated, in much larger quantities than Taxol itself, from the leaves of a different species of yew tree. More recently however, a plant cell fermentation approach has been developed for the industrial production of Taxol. 

Finally, fermentation of endophytic fungi from higher plants has also been considered for the production of plant natural products. Fungal fermentation is much simpler than plant tissue culture but, at least for paclitaxel, production by fermentation of various Taxus endophytic fungi was lower compared with that of plant cells.35... 

A more efficient process to paclitaxel involves fermentation [69-71]. The biosynthesis starts from isoprenyl diphosphate and farnesyl diphosphate (Scheme 8.17). To achieve a high titer of paclitaxel production, cell cultures from various species of Taxus were investigated. For example, methyl jasmonate was able to enhance paclitaxel production to 55 mg I 1 per week in a cell suspension culture. The plant... 

In the cell fermentation stage of the process, calluses of a specific Taxus cell line are propagated in a wholly aqueous medium in large fermentation tanks under controlled conditions at ambient temperature and pressure. The feedstock for the cell growth consists of renewable nutrients sugars, amino acids, vitamins, and trace elements. BMS now extracts paclitaxel directly from plant cell cultures, then purifies it by chromatography and isolates it by crystallization. 

Preparation from fermentation using endophytic fungi from Taxus species has been studied as an alternative source of material, but the yields are low. For example, fermentation broth from Taxomyced andeanane contains only 24—50 ng/L of paclitaxel (374). Plant cell cultures are also the subject of much research but, again, yields tend to be low, e.g., 153 mg/L/6 weeks [375, 376]. Work continues in this area and it is likely that commercial processes will be developed in time. 

For many plants, methyl jasmonate is a key elicitor, which initiates a series of response mechanisms to herbivores, like the synthesis of protease inhibitors and the increased formation of secondary metabolites (cf section 3.3- Jasmonoids). The effects were already well-known for tomato and tobacco plants, but also for Catharanthus and Cinchona seedlings and for soya beans. In the case of yew cells, this additive enabled to increase the paclitaxel production from 3 to 117 mg, and later to 295 mg per litre of fermentation broth. 

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