Advancements in the understanding of Paclitaxel metabolism in tissue culture.

Paclitaxel is a potent chemotherapeutic agent approved in the treatment of a variety of cancers, and under evaluation for the treatment of Alzheimer's and heart disease. Originally isolated from Taxus brevifolia, this highly substituted ring diterpenoid belongs to a family of plant secondary metabolites known as taxoids. Paclitaxel is currently supplied through both a semi-synthetic process and plant cell culture. Taxus spp. cell culture offers the potential to produce large amounts of paclitaxel and related taxoids, although variability in accumulation and low yields represent key limitations. Thus, intense efforts have been put forth towards understanding Taxus spp. metabolism to increase paclitaxel accumulation in cell culture. While elicitation and environmental optimization have provided some success in increasing paclitaxel accumulation in vitro, understanding metabolism of paclitaxel on the molecular level is essential for process optimization. Utilizing direct and indirect molecular techniques, a further understanding of paclitaxel biosynthesis has been gained, though knowledge into other aspects of paclitaxel global metabolism, such as regulation, transport, and degradation is lacking. Taxus spp. cell cultures are highly heterogeneous, displaying significant cell-cell variability in growth and paclitaxel accumulation. Information gathered on culture subpopulations as well as putative transcriptional bottlenecks in paclitaxel biosynthesis, coupled with successful transformation of Taxus spp. will allow for the targeted metabolic engineering of Taxus spp. or other model organisms for paclitaxel accumulation to ensure future supply of this important pharmaceutical.