Redox interaction between evofosfamide radical anion and doxorubicin

The redox interaction between the evofosfamide radical anion and doxorubicin is a biochemical process observed in combination cancer therapies. Evofosfamide (TH-302) is a 2-nitroimidazole hypoxia-activated prodrug that undergoes one-electron reduction by enzymes such as NADPH-cytochrome P450 reductase (POR) to form a radical anion intermediate (Hunter et al., 2015, Mol Cancer Ther). In the absence of oxygen, this intermediate fragments to release the cytotoxic bromo-isophosphoramide mustard (Br-IPM), while in the presence of oxygen, it is back-oxidized to the parent compound (Sun et al., 2012, Clin Cancer Res). Doxorubicin, an anthracycline, also undergoes one-electron reduction to a semiquinone radical, which can lead to the production of superoxide and other reactive oxygen species (Minotti et al., 2004, Chem Res Toxicol). The interaction between these two drugs involves competition for the same reductive enzymes or direct electron transfer between their radical intermediates, which can significantly alter the pharmacodynamics of both agents (Meng et al., 2012, Cancer Res). This interaction is primarily studied in the context of solid tumors, such as soft tissue sarcoma, where hypoxia is a common feature (Tap et al., 2017, Lancet Oncol). Understanding this mechanism is essential for evaluating the efficacy and safety of combining hypoxia-activated prodrugs with standard chemotherapy (Weiss et al., 2011, J Clin Oncol).

Other names

TH-302 and doxorubicin redox interactionEvofosfamide-doxorubicin radical couplingTH-302/Doxorubicin interaction

The interaction involves the one-electron reduction of evofosfamide to a radical anion, which can potentially transfer electrons to doxorubicin or compete for reductive enzymes like NADPH-cytochrome P450 reductase.