Disulfiram is a potent in vitro inhibitor of DNA topoisomerases

The drug disulfiram. is a thiol-reacting drug that is relatively nontoxic when used alone and has been used in the therapy of alcohol abuse for more than 40 years. Several effects of this drug have been reported for DNA synthesis and cell proliferation. In this study, the inhibitory effect of disulfiram on topoisomerase I and II activity was investigated by measuring the relaxation of superhelical plasmid pBR322 DNA. Disulfiram (1-100 muM) inhibited topoisomerase I and II in a concentration-dependent manner (IC50 congruent to 42 :+/- 8 and 30 +/- 9 muM, respectively). Consistent with the assumption that a thiol residue is involved, dithiothreitol (1 mM) markedly prevented the inhibitory effect of disulfiram on the activity of both classes of topoisomerases. These findings might explain certain aspects of disulfiran toxicity and encourage new studies to determine the usefulness of this drug and its analogues as antineoplastic agent. (C) 2001 Elsevier Science.