Etoposide is a widely used anticancer
drug successfully used for the treatment of many types of
cancer in children and adults. Its use, however, is associated with an increased risk of development of secondary
acute myelogenous leukemia involving the mixed-lineage
leukemia (MLL) gene (11q23) translocations. Previous studies demonstrated that the
phenoxyl radical of
etoposide can be produced by action of
myeloperoxidase (MPO), an
enzyme found in developing myeloid progenitor cells, the likely origin for
myeloid leukemias. We hypothesized, therefore, that one-electron oxidation of
etoposide by MPO to its
phenoxyl radical is important for converting this anticancer
drug to genotoxic and carcinogenic species in human CD34(+) myeloid progenitor cells. In the present study, using electron paramagnetic resonance spectroscopy, we provide conclusive evidence for MPO-dependent formation of
etoposide phenoxyl radicals in
growth factor-mobilized CD34(+) cells isolated from human umbilical cord blood and demonstrate that MPO-induced oxidation of
etoposide is amplified in the presence of
phenol. Formation of
etoposide radicals resulted in the oxidation of endogenous
thiols, thus providing evidence for
etoposide-mediated MPO-catalyzed redox cycling that may play a role in enhanced
etoposide genotoxicity. In separate studies,
etoposide-induced DNA damage and MLL gene rearrangements were demonstrated to be dependent in part on MPO activity in CD34(+) cells. Together, our results are consistent with the idea that MPO-dependent oxidation of
etoposide in human hematopoietic CD34(+) cells makes these cells especially prone to the induction of
etoposide-related
acute myeloid leukemia.