The antitrypanosomal and antifiliarial
drug suramin is currently under investigation for treatment of advanced
malignancies including
prostatic cancer,
adrenocortical cancer, and some
lymphomas and
sarcomas. Here we show that
suramin is a potent inhibitor of the nuclear
enzyme DNA topoisomerase II.
Suramin inhibited purified yeast
topoisomerase II with an IC50 of about 5 microM, as measured by decatenation or relaxation assays.
Suramin did not stabilize the covalent
DNA-topoisomerase II reaction intermediate ("cleavable complex"), whereas other inhibitors of this
enzyme, such as
amsacrine,
etoposide, and the
ellipticines, are known to stabilize the intermediate. In contrast, the presence of
suramin strongly inhibited the cleavable-complex formation induced by
amsacrine or
etoposide. Accumulation of the endogenous cleavable complex was also inhibited.
Suramin entered the nucleus of DC-3F Chinese hamster
fibrosarcoma cells exposed to radiolabeled
suramin for 24 hr as shown by both optic and electron microscopy. The
suramin present in the nucleus seemed to interact with
topoisomerase II, since
suramin reduced the number of
amsacrine-induced
protein-associated
DNA strand breaks in DC-3F cells and protected these cells from the cytotoxic action of
amsacrine. Cells resistant to
9-hydroxyellipticine, which have been shown to have an altered
topoisomerase II activity, are about 7-fold more resistant to
suramin than the sensitive parental cells as shown by 72-hr growth inhibition assay. Our results suggest that
DNA topoisomerase II is a target of
suramin action and that this action may play a role in the cytotoxic activity of
suramin.