Inconveniently, the only current method to synthesize the chemotherapy agent etoposide is by using extracts from a plant. Now researchers have successfully manipulated Nicotiana benthamiana (tobacco) to create a more immediate and potent precursor. The research was published in the journal Science (1) (2).
Etoposide is a topoisomerase inhibitor used to treat a variety of malignancies, including lung cancer and leukemia. There is currently no way to produce the drug without one of its precursors, podophyllotoxin, which is found in the slow-growing Himalayan Mayapple plant. Four partial pathways behind podophyllotoxin are known, but the full recipe for this mysterious compound has eluded researchers, in part because of the Mayapple's immense genome.
To tap into the Mayapple's chemotherapeutic potential, researchers focused on the four genes that are known in the production of podophyllotoxin, and then analyzed RNA-sequencing data of the Mayapple to identify similar genes. They then manipulated tobacco to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry. In total, the authors identified six new pathway enzymes that, combined with the original four, produce the immediate etoposide precursor (-)-4-desmethyl-epipodophyllotoxin, which outperforms podophyllotoxin as a chemotherapy ingredient.
The eventual goal is to put the genes in yeast, which can be grown in large vats in the lab to better provide a stable source of drugs. Producing a drug in yeast also provides some flexibility that isn't present when isolating a drug from plants.
Based on material originally posted by American Association for the Advancement of Science.