Paclitaxel, marketed under the name of Taxol, is derived from the bark of mature Pacific yew trees. Oncologists use it to combat ovarian and breast cancer, and also to treat lung carcinomas. It gradually kills off cancerous cells by inhibiting cell division.
To date there is only one other effective drug on the market, which is similar to Taxol and belongs to the same taxane class. One of the reasons for this is that the precursors of these drugs are derived from natural sources, and the chemical routes required to arrive at a final active pharmaceutical ingredient (API) tend to be complex and cumbersome.
An additional problem is confounded by the slow growth of the tree and the minute quantities of paclitaxel produced.
Researchers from the Institute for Bioprocessing and Analytical Measurement Techniques (IBA) pinpointed the foliage of the cultivated European common yew which offered a viable starting point. It produces the compound 10-deacetylbaccatin III (DAB), from which Taxol can be synthesized in a few steps.
"We use an enzyme isolated from the yew-needle extract to process the DAB," explains Professor Gerald Lauckner of the IBA. "This produces baccatin III, a precursor to paclitaxel, which pharmaceutical companies can then use to synthesize the final product."
The new method involves producing the enzyme using a genetically modified strain of the bacterium E. coli. The bacteria are then immobilized in the microscopic pores of a membrane. When a solution of DAB flows over the membrane in the reactor, it is converted to baccatin III. The product is separated using a halogen-free solvent, and any unconverted DAB is allowed to flow back into the reactor. An online analysis system continuously monitors and controls the inflow of DAB. The concentration is held at a constant level, thus raising the efficiency of the enzymatic reaction.
"The production cost is five times lower than for processes that extract the product from natural sources," Lauckner said. He added when a suitable partner could be found, they would look to scale up the process. The present output of the iba laboratory prototype is about four grams per litre of reagent solution.
The scarcity of this active ingredient and the potential market worldwide has created a handful of companies vying to be the first to come up with a viable and costwise method of extraction.
Italian company Indena has developed a new semisynthetic pathway for a new taxane, called ortataxel (14 beta-hydroxydeacetylbaccatin), which could become the third drug in this class to reach the market after Taxol and Sanofi-Aventis' Taxotere (docetaxel).
Taxotere sales were €1.4 billion last year, while sales of Bristol-Myers Sqibb' Taxol continued to show the effects of generic competition but still reached $934 million (€770m).