Etoposide is an important chemotherapeutic agent that is used to treat a wide spectrum of human
cancers. It has been in clinical use for more than two decades and remains one of the most highly prescribed anticancer drugs in the world. The primary cytotoxic target for
etoposide is
topoisomerase II. This ubiquitous
enzyme regulates
DNA under- and overwinding, and removes knots and tangles from the genome by generating transient double-stranded breaks in the double helix.
Etoposide kills cells by stabilizing a covalent
enzyme-cleaved
DNA complex (known as the cleavage complex) that is a transient intermediate in the catalytic cycle of
topoisomerase II. The accumulation of cleavage complexes in treated cells leads to the generation of permanent
DNA strand breaks, which trigger recombination/repair pathways, mutagenesis, and
chromosomal translocations. If these breaks overwhelm the cell, they can initiate death pathways. Thus,
etoposide converts
topoisomerase II from an essential
enzyme to a potent cellular toxin that fragments the genome. Although the
topoisomerase II-DNA cleavage complex is an important target for
cancer chemotherapy, there also is evidence that
topoisomerase II-mediated
DNA strand breaks induced by
etoposide and other agents can trigger
chromosomal translocations that lead to specific types of
leukemia. Given the central role of
topoisomerase II in both the cure and initiation of human
cancers, it is imperative to further understand the mechanism by which the
enzyme cleaves and rejoins the double helix and the process by which
etoposide and other anticancer drugs alter
topoisomerase II function.