Disulfiram is a potent in vitro inhibitor of DNA topoisomerases

The drug disulfiram. is a thiol-reacting drug that is relatively nontoxic w hen used alone and has been used in the therapy of alcohol abuse for more t han 40 years. Several effects of this drug have been reported for DNA synth esis and cell proliferation. In this study, the inhibitory effect of disulf iram on topoisomerase I and II activity was investigated by measuring the r elaxation of superhelical plasmid pBR322 DNA. Disulfiram (1-100 muM) inhibi ted topoisomerase I and II in a concentration-dependent manner (IC50 congru ent to 42 :+/- 8 and 30 +/- 9 muM, respectively). Consistent with the assum ption that a thiol residue is involved, dithiothreitol (1 mM) markedly prev ented the inhibitory effect of disulfiram on the activity of both classes o f topoisomerases. These findings might explain certain aspects of disulfira n toxicity and encourage new studies to determine the usefulness of this dr ug and its analogues as antineoplastic agent. (C) 2001 Elsevier Science.