SURAMIN IS AN INHIBITOR OF DNA TOPOISOMERASE-II INVITRO AND IN CHINESE-HAMSTER FIBROSARCOMA CELLS

The antitrypanosomal and antifiliarial drug suramin is currently under investigation for treatment of advanced malignancies including prosta tic cancer, adrenocortical cancer, and some lymphomas and sarcomas. He re we show that suramin is a potent inhibitor of the nuclear enzyme DN A topoisomerase II. Suramin inhibited purified yeast topoisomerase II with an IC50 of about 5-mu-M, as measured by decatenation or relaxatio n 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, ar e known to stabilize the intermediate. In contrast, the presence of su ramin strongly inhibited the cleavable-complex formation induced by am sacrine or etoposide. Accumulation of the endogenous cleavable complex was also inhibited. Suramin entered the nucleus of DC-3F Chinese hams ter fibrosarcoma cells exposed to radiolabeled suramin for 24 hr as sh own by both optic and electron microscopy. The suramin present in the nucleus seemed to interact with topoisomerase II, since suramin reduce d 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 s hown to have an altered topoisomerase II activity, are about 7-fold mo re resistant to suramin than the sensitive parental cells as shown by 72-hr growth inhibition assay. Our results suggest that DNA topoisomer ase II is a target of suramin action and that this action may play a r ole in the cytotoxic activity of suramin.