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¹ Cannon Research Center, Carolinas Medical Center, Charlotte, North Carolina; ² U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; ³ Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina; and ⁴ AAI Research, Wilmington, North Carolina

Requests for reprints: Thomas P. Kennedy, Department of Medicine, University of Utah Medical Center, Wintrobe 743A, 50 North Medical Drive, Salt Lake City, UT 84132. Phone: 801-581-7806; Fax: 801-585-3355. E-mail: Thomas.Kennedy{at}hsc.utah.edu

The thiocarbamate alcoholism drug disulfiram blocks the P-glycoprotein extrusion pump, inhibits the transcription factor nuclear factor-B, sensitizes tumors to chemotherapy, reduces angiogenesis, and inhibits tumor growth in mice. Thiocarbamates react with critical thiols and also complex metal ions. Using melanoma as the paradigm, we tested whether disulfiram might inhibit growth by forming mixed disulfides with critical thiols in a mechanism facilitated by metal ions. Disulfiram given to melanoma cells in combination with Cu²⁺ or Zn²⁺ decreased expression of cyclin A and reduced proliferation in vitro at lower concentrations than disulfiram alone. In electrophoretic mobility shift assays, disulfiram decreased transcription factor binding to the cyclic AMP-responsive element in a manner potentiated by Cu²⁺ ions and by the presence of glutathione, suggesting that thiocarbamates might disrupt transcription factor binding by inducing S-glutathionylation of the transcription factor DNA binding region. Disulfiram inhibited growth and angiogenesis in melanomas transplanted in severe combined immunodeficient mice, and these effects were potentiated by Zn²⁺ supplementation. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism also induced >50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects. These findings present a novel strategy for treating metastatic melanoma by employing an old drug toward a new therapeutic use.

Note: This work is the subject of U.S. patents 6,548,540; 6,589,987; and 6,706,759, which are owned by the Charlotte-Mecklenberg Hospital Authority.

Received 3/29/04; revised 5/14/04; accepted 6/18/04.