Towards the biosynthesis of an alternative to Taxol

Abstract

Kosan Biosciences (Burlingame, CA, USA) has received a Phase I Small Business Innovative Research Grant from the US National Cancer Institute to support their work on the biosynthetic pathway of the epothilones, a group of polyketides first isolated from the soil myxobacterium Sorangium cellulosum, as potential alternatives to the anticancer drug paclitaxel (Taxol).`We would anticipate that epothilones, if proven to be safe and effective, would find use as a treatment for Taxol-resistant tumors and other tumor types found to be responsive to Taxol. Taxol is particularly effective in ovarian and breast cancers, and its range of applications is expanding,' says Michael Ostrach, Chief Operating Officer of Kosan.During cell division, a dynamic process of tubulin polymerization and depolymerization transforms cytoskeletal microtubules into the mitotic spindle. The epothilones, like paclitaxel, stabilize microtubules by binding to tubulin, thus preventing spindle formation and blocking mitosis. `Two decades after the discovery of Taxol, epothilones represent the first class of compounds that mimic the microtubule-stabilizing effect of the taxane structure,' says Ostrach.' Unlike paclitaxel, the epothilones do not appear to possess endotoxin-like properties, which may be responsible for some of the drug's side effects.Between five and 50 bacterial enzymes and carrier proteins are involved in the biosynthesis of polyketide molecules, and are collectively known as polyketide synthases (PKS). Each PKS is encoded by a gene cluster, so once a component of the gene cluster has been identified, the whole cluster can be sequenced, thus providing the code for the entire biosynthetic pathway.Scientists at Kosan will develop an over-expression system, probably in Streptomyces spp. , Escherichia coli, or yeast, to produce the epothilones in large quantities for therapeutic use. Small amounts of epothilone—sufficient for in vitro and animal studies—have been produced by fermenting myxobacteria, but the organisms grow too slowly and do not produce sufficient quantities of epothilone for industrial production. `We would hope that more developed production organisms would be more economical,' says Ostrach. Future plans include the production of epothilone analogues by modifying the gene cluster.