Etoposide Pathway

Etoposide and teniposide, the epipodophyllotoxins, stabilize the double stranded DNA cleavage normally catalyzed by topoisomerase II and inhibit faithful religation of DNA breaks. Topoisomerase II is also the target of anthracyclines, such as doxorubicin, daunorubicin, epirubicin, and idarubicin. These double-strand DNA breaks trigger the desired antitumor effects of the drugs, and they are highly effective anticancer agents, but can cause a delayed toxicity: treatment-related acute myeloid leukemia or myelodysplastic syndrome (t-ML). The formation of MLL fusion genes has been associated with the development of t-ML. The O-demethylated metabolites (catechol and quinone) of etoposide have similar potency at inhibiting topoisomerase II and are more oxidatively reactive than the parent drug. Even though etoposide inhibits both topo II alpha and beta, the anti-tumor activity of etoposide is shown to be delivered primarily through inhibition of topo II alpha (PMID: 11531262) whilst the carcinogenic effect is largely attributable to the beta isoform (PMID: 17578914). Glutathione and glucuronide conjugation appear to inactivate parent drug and metabolite, with glutathione conjugates being substrates for efflux transporters. Recently, 64 genetic variants that contribute to etoposide-induced cytotoxicity were identified through a whole-genome association study. (PMID: 17537913).