Camptothecin, over four decades of surprising findings

• Published in: Phytochemistry (Oxford) 2004-10, Vol.65 (20), p.2735-2749
• Main Authors: Lorence, Argelia, Nessler, Craig L.
• Format: Article
• Language: English
• Subjects: antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; biochemical pathways; Biological and medical sciences; biosynthesis; Camptotheca acuminata; Camptothecin; Camptothecin - biosynthesis; Camptothecin - pharmacology; Chemical constitution; chemical structure; DNA topoisomerase; enzyme inhibition; Fundamental and applied biological sciences. Psychology; human health; indole alkaloids; literature reviews; Magnoliopsida - genetics; Magnoliopsida - metabolism; Metabolic engineering; Molecular Structure; Monoterpene indole-alkaloids; monoterpenoids; Ophiorrhiza pumila; Phylogeny; phytochemicals; Plant Bark - chemistry; Plant Leaves - chemistry; Plant physiology and development; secondary metabolites; Seeds - chemistry; Topoisomerase I Inhibitors
• ISSN: 0031-9422; 1873-3700
• DOI: 10.1016/j.phytochem.2004.09.001

Here we describe the distribution of camptothecin (CPT) and its metabolites, the present understanding of its mechanism of action, the biosynthetic route leading to CPT formation in plants and we conclude with strategies that might aid in the development of alternative and more sustainable sources of this family of outstanding antitumor agents. Camptothecin (CPT) is a modified monoterpene indole alkaloid produced by Camptotheca acuminata (Nyssaceae), Nothapodytes foetida, Pyrenacantha klaineana, Merrilliodendron megacarpum (Icacinaceae), Ophiorrhiza pumila (Rubiaceae), Ervatamia heyneana (Apocynaceae) and Mostuea brunonis (Gelsemiaceae), species belonging to unrelated orders of angiosperms. From the distribution of CPT and other secondary metabolites, it has been postulated that the genes encoding enzymes involved in their biosynthesis evolved early during evolution. These genes were presumably not lost during evolution but might have been “switched off” during a certain period of time and “switched on” again at some later point. The CPT derivatives, irinotecan and topotecan, are used throughout the world for the treatment of various cancers, and over a dozen more CPT analogues are currently at various stages of clinical development. The worldwide market size of irinotecan/topotecan in 2002 was estimated at about $750 million and at $1 billion by 2003. In spite of the rapid growth of the market, CPT is still harvested by extraction from bark and seeds of C. acuminata and N. foetida. All parts of C. acuminata contain some CPT, although the highest level is found in young leaves (∼4–5 mg g −1 dry weight), approximately 50% higher than in seeds and 250% higher than in bark. The development of hairy root cultures of O. pumila and C. acuminata, and the cloning and characterization of genes encoding key enzymes of the pathway leading to CPT formation in plants has opened new possibilities to propose alternative and more sustainable production systems for this important alkaloid.