Enhanced production of taxol and taxanes by cell cultures of taxus species

Abstract

This invention provides methods whereby taxol, baccatin III, and other taxol-like compounds, or taxanes, can be produced in very high yield from all known Taxus species, e.g., brevifolia, canadensis, cuspidata, baccata, globosa, floridana, wallichiana, media and chinensis. Particular modifications of culture conditions (i.e., media composition and operating modes) have been discovered to enhance the yield of various taxanes from cell culture of all species of Taxus. Particularly preferred enhancement agents include silver ion or complex, jasmonic acid (especially the methyl ester), auxin-related growth regulators, and inhibitors of the phenylpropanoid pathway, such as 3,4-methylenedioxy-6-nitrocinnamic acid. These enhancement agents may be used alone or in combination with one another or other yield-enhancing conditions. While the yield of taxanes from plant cell culture of T. chinensis is particularly enhanced by use of one or more of these conditions, yield of taxanes for all Taxus species has been found to benefit from use of these conditions.

Description

[0001] This application is a continuation-in-part of International application PCT / US97 / 08907, designating the U.S. filed May 27, 1997, and a continuation-in-part of U.S. Ser. No. 08 / 653,036, filed May 24, 1996, which is a continuation-in-part of U.S. Ser. No. 08 / 370,494, filed Jan. 9, 1995, which is a divisional of U.S. Ser. No. 07 / 874,344, now U.S. Pat. No. 5,407,816, filed Apr. 24, 1992, which is a continuation-in-part of U.S. Ser. No. 07 / 839,144, filed Feb. 20, 1992. The text of each priority application is expressly incorporated herein by reference to the extent that the text of the respective priority application differs from this application.BACKGROUND OF THE INVENTION [0002] A. Field of the Invention [0003] This invention is directed to methods for the enhanced production and recovery of taxol, baccatin III and other taxanes by cell cultures of Taxus species. [0004] B. Related Art The Taxane Supply Challenge [0005] Taxol is a diterpenoid alkaloid originally isolated from th...

AI Technical Summary

Benefits of technology

This approach enables the production of taxanes at significantly higher rates and shorter times than previous methods, with Taxus chinensis achieving high volumetric productivities of taxol and baccatin III, facilitating a cost-effective and sustainable commercial production process.

Problems solved by technology

Total synthesis, while accomplished by academic laboratories, shows little promise as a viable commercial route to taxol.

Since aseptic, large-scale, plant cell cultivation is inherently expensive, a cell culture process becomes commercially relevant only when these costs are offset by high productivity.

A survey of secondary metabolite productivity among gymnosperm cultures also points to the difficulty of inducing rapid biosynthesis compared to herbaceous species.

However, these results were obtained with a slow-growing (30% biomass increase in 18 days) and low cell density (5 to 7 grams dry weight per liter) culture.

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