The production of podophyllotoxin and related cytotoxic lignans by plant cell cultures

Podophyllotoxin is a lignan that occurs in several plant species. Its cytotoxic activity is well-known, but it can not be applied clinically because of severe toxic side effects. Attempts have been undertaken to develop less toxic and more specifically acting antitumour drugs derived from podophyllotoxin. Presently, etoposide and teniposide are clinically applied chemotherapeutics that are especially effective against testicular and small cell lung cancer. Podophyllotoxin is the starting compound for the chemical synthesis of these two cytostatics. Although several methods for a total chemical synthesis of podophyllotoxin have been reported, the foreseeable future will probably not yield a commercially attractive synthesis. Therefore, the availability of podophyllotoxin depends on its presence in the plant. However, the availability of Podophyllum plants, the best natural source of podophyllotoxin, has its limitations: the occurrence of the plants is scarce, they have a long juvenile phase and poor reproduction capacities. Potloyhyllrtm hexandrum has even become a threatened species due to the intense collection and the lack of organized cultivation. The biotechnological production of podophyllotoxin and related compounds is considered to be an alternative. Investigations in that direction are described in this Ph.D. thesis.