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C. Paclitaxel (Taxol)

Paclitaxel (taxol) is a diterpene compound initially isolated from Tax us brev-ifolia (Pacific yew) in 1971 as a cytotoxic substance against leukemia cells (118). It is also found in all species belonging to the genus Taxus. Paclitaxel was discovered through an extensive program in the United States to screen plant extracts for discovery of new anticancer drugs among 110,000 compounds from 35,000 species (119). It is now clinically used for the treatment of ovarian and breast cancer. The mechanism of action is to promote the assembly of microtubules and inhibit the disassembly process.

For the clinical trials, the limited supply of paclitaxel only from the bark of T. brevifolia was problematic. Total synthesis of paclitaxel was achieved; however, the synthetic process involved long steps and a low yield and was not commercially feasible. The semisynthesis of paclitaxel from its precursors isolated from leaves and stems of Taxus cultivars is also established. However, plant cell culture has a strong long-term potential for production of paclitaxel or its precursors, in particular, by adopting advances in biosynthetic understanding and genetic engineering.

The production of paclitaxel and related compounds in plant cell culture has been investigated with several species of the genus Taxus, e.g., T. brevifolia, T. baccata, T. chinensis, T. canadensis, T. cuspidata, and T. x media. A number of trials of production in callus and cell suspension cultures of these Taxus plants have been reported as summarized by Wickremesinhe and Arteca (119). The highest producibility of paclitaxel was achieved upon inducion by methyl jasmonate with T. media cell culture (120). They found that the addition of 100 /itM methyl jasmonate increased paclitaxel production up to 0.6% content in cells and 110 mg/L medium for 14 days. This producibility was fivefold higher than that of the control without addition of methyl jasmonate. The content of baccatin III was also induced 20-fold (0.2% of cell weight) with T. baccata culture. Jasmonate is known to play a role in a signal transduction system involved in the defense process in plant cells. This is a good example of how one can manipulate the production of secondary compounds in cell culture by a particular signal molecule.

D. Podophyllotoxin

Podophyllotoxin is a lignan compound derived from two phenyl propanoid units. The clinically used antitumor compounds etoposide and teniposide are semisynthetic derivatives of podophyllotoxin (Fig. 3). They act as inhibitors of the microtubule assembly for antitumor activity.

The rhizomes of Podophyllum species are the source for extraction of podophyllotoxin. However, the occurrence of these plants is limited and the growth of the plants is slow. Therefore, production by cell culture has been

Table 5 Podophyllotoxin Production in Cell Culture

Species

Tissue

Ptox content (% dry wt)

Growth rate

Comments

Reference

Linum album

Cell

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