title: Pharmacodynamic study of disulfiram in men with non-metastatic recurrent prostate cancer.
abstract: BACKGROUND
  Preclinical drug screens identified disulfiram as a potent in vitro inhibitor of prostate cancer (PCa) cell growth. Although many mechanisms for its anticancer activity have been proposed, tumor suppressor gene re-expression through promoter demethylation emerged as one of the more plausible.
  
  
  METHODS
  We conducted an open-label, dose escalation trial of disulfiram in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating 'response' (that is, 10% decrease in peripheral blood mononuclear cell (PBMC) global 5-methyl cytosine (5(me)C) content) was observed in <3 patients in cohort 1. Cohorts 1 and 2 received disulfiram 250 mg and 500 mg daily, respectively. The primary end point was the proportion of subjects with a demethylation response. Secondary end points included the rate of PSA progression at 6 months, changes in PSA doubling time and safety/tolerability.
  
  
  RESULTS
  Changes in global 5(me)C content were observed in two of nine patients (22.2%) in cohort 1 and 3 of 10 (30.0%) in cohort 2. Only five subjects were on trial for 6 months, all were in cohort 1 and all had PSA progression by 6 months. No changes in PSA kinetics were observed in either cohort. Disulfiram was poorly tolerated with six patients experiencing grade 3 adverse events (three per cohort). Three of the responders displayed pretreatment instability in their 5(me)C content.
  
  
  CONCLUSIONS
  A minority of patients had transient global PBMC demethylation changes. Instability in 5(me)C may limit the reproducibility of these findings, limiting our ability to confirm our hypothesis. Given the toxicities and no clinical benefits, further development of disulfiram should not be pursued in this population.
authors: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors: M T
authors: MT
authors: Schweizer
authors: J
authors: J
authors: Lin
authors: A
authors: A
authors: Blackford
authors: A
authors: A
authors: Bardia
authors: S
authors: S
authors: King
authors: A J
authors: AJ
authors: Armstrong
authors: M A
authors: MA
authors: Rudek
authors: S
authors: S
authors: Yegnasubramanian
authors: M A
authors: MA
authors: Carducci
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D002570:Ceruloplasmin / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004221:Disulfiram / Q000009:adverse effects / Q000493:pharmacokinetics*; D044127:Epigenesis, Genetic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D002570:Ceruloplasmin; D017430:Prostate-Specific Antigen; D004221:Disulfiram
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