disulfiram is a DNA methyltransferase inhibitor that may provide benefit for patients with prostate cancer by restoring tumor suppressor genes.
The primary hypothesis of this study is that disulfiram is a DNA methyltransferase inhibitor and may provide benefit for patients with prostate cancer by restoration of tumor suppressor genes. Disulfiram is a potent DNA methyltransferase 1 (DNMT1) inhibitor in vitro in our laboratory and it was recently found as one of the most potent inhibitors for PCa growth in vitro by screening the Johns Hopkins Drug Library. Based on this data, extensive in vitro and in vivo studies have been performed to explore its potential antitumor activities in prostate PCa. Using both androgen sensitive and insensitive PCa cell lines, we have confirmed that disulfiram can demethylate known highly methylated tumor suppressor genes such as APC and RARß in PCa cell lines. Disulfiram inhibited PCa cell growth in vitro and in vivo. In addition to these new findings, the antitumor activity of disulfiram and its other possible mechanisms of action are well documented in literature. Disulfiram has been shown to induce apoptosis in a number of cell lines including PCa. A variety of underlying mechanisms of anticancer activity have been reported. Disulfiram has been shown to reduce angiogenesis, inhibit DNA topoisomerases, inhibit nuclear factor κB, induce p21 and p53 with G1/S cell cycle arrest, induce pro-apoptotic redox-related mitochondrial membrane permeabilization, inactivate Cu/Zn superoxide dismutase by Cu2+ complexation, inhibit Zn2+-dependent matrix metalloproteinases, and prevent tumor invasion or metastasis. The disulfiram analogue pyrrolidine dithiocarbamate (PDTC) has been shown to inhibit proteasomal activity in combination with copper in human breast and PCa cell lines. Also, disulfiram or its metabolites permanently inactivate the human multidrug resistance P-glycoprotein or reverses either MDR1- or MRP1-mediated drug efflux.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
19
Cohort 1: 250mg PO daily for 28 days Cohort 2: 500mg PO daily for 28 days
Johns Hopkins Hospital
Baltimore, Maryland, United States
Duke University
Durham, North Carolina, United States
Thomas Jefferson Universith
Philadelphia, Pennsylvania, United States
Proportion of Subjects With a Demethylation Response at Each Dose Level
For both of the doses explored (i.e. disulfiram 250 mg PO daily and 500 mg PO daily) the proportion of subjects with a demethylation response was computed. A demethylation response was defined as a \>=10% decrease from baseline in global 5-methyl cytosine content as assessed from peripheral blood mononuclear cells.
Time frame: 24 months
Clinical Response
To assess the clinical response measured by prostate specific antigen (PSA) progression at 6 months after treatment with the defined dose of disulfiram in prostate cancer (PCa) patients with evidence of biochemical relapse after local therapy. Reported as number of participants with PSA progression by 6 months. Criteria used to assess: A rise in PSA noted at 6 months, greater than 50% over PSA value at baseline and \> 2 ng/ml, above the nadir. The rise was confirmed by a second PSA value obtained at least 1 week from that reference value.
Time frame: Up to 6 months
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